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Vaccination Status of Children Who Were Hospitalized

Accuracy of vaccine histories, inpatient interventions, conclusions, pediatric inpatient immunizations: a literature review.

POTENTIAL CONFLICT OF INTEREST: Dr Pannaraj receives research funding from Pfizer and MedImmune; and Dr Mihalek and Ms Kysh have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Pannaraj receives research funding from Pfizer and MedImmune; and Dr Mihalek and Ms Kysh have indicated they have no financial relationships relevant to this article to disclose.

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Alexandra J. Mihalek , Lynn Kysh , Pia S. Pannaraj; Pediatric Inpatient Immunizations: A Literature Review. Hosp Pediatr July 2019; 9 (7): 550–559. https://doi.org/10.1542/hpeds.2019-0026

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Timely vaccine uptake in children remains suboptimal. Eliminating missed opportunities is key to increasing childhood immunization rates, and hospitalization offers another potential setting to vaccinate.

To better understand pediatric inpatient immunization programs, including vaccination rates of inpatients, parental and provider attitudes, barriers to vaccine delivery, and interventions to increase provision of inpatient vaccines.

A search was conducted of PubMed, Embase, and Web of Science to identify articles and conference abstracts related to pediatric inpatient immunization.

Inclusion criteria were studies published in English between January 1990 and January 2019 in which pediatric vaccination in the hospital setting was discussed. Findings from 30 articles and conference abstracts were summarized and organized by topic area.

Abstracts were screened for relevance, articles were read, and themes were identified.

Children who are hospitalized have been shown to have lower immunization rates compared with the general population, with 27% to 84% of pediatric inpatients due or overdue for vaccines nationally when verified with official records. Unfortunately, little is done to catch up these children once they have been identified. Access to accurate vaccine histories remains a major barrier in inpatient immunization programs because providers frequently under document and parents over recall a child’s vaccine status. Strategies identified to increase inpatient vaccination included creation of a multidisciplinary immunization team, educational interventions, visual reminders, catch-up vaccine plans, order sets, and nursing-driven screening. When offered inpatient vaccination, a majority of parents accepted immunizations for their children.

Hospitalization may provide an opportunity to augment vaccine uptake. Further research is needed to develop evidence-based strategies to overcome barriers to inpatient vaccination.

Vaccines are 1 of the greatest public health achievements to date. 1 – 3   However, vaccination coverage remains suboptimal. In 2017, only 70% of children had completed the combined childhood vaccination series * , less than half of adolescents were up to date on human papillomavirus vaccination, and >40% of children had not received the seasonal influenza vaccine. 4 – 6   The American Academy of Pediatrics recommends using every health care visit as an opportunity to review and update vaccine status, and in their best practice guidelines, the Advisory Committee on Immunization Practices specifically includes a recommendation to immunize patients who are hospitalized. 7 – 9  

Hospitalization represents a potential setting to augment vaccine uptake: pediatric inpatients have lower rates of vaccination coverage than the general public, and hospitalization has been shown to be a risk factor for underimmunization in children. 10 – 16   Although the exact reason for this discrepancy is unknown, several causes have been hypothesized. Patient populations at some inpatient centers may have a lower socioeconomic status than those in the surrounding area, and children with chronic illness, who are more frequently hospitalized, may be perceived as too ill or may miss the usual time frame for outpatient vaccines. 13 , 17 – 20   Inpatient vaccination may also help to reduce health care disparities because discrepancies in inpatient immunization status have been demonstrated between income and racial and/or ethnic groups. 15 , 17 , 21   Patients who experience barriers to outpatient immunization, such as limited access to a primary care physician (PCP), transiency, and transportation difficulties, may have these barriers eliminated while hospitalized. 20 , 22 , 23  

Reducing missed opportunities by immunizing children who are hospitalized has been proposed for decades, yet little is known about this subject. 20   In an effort to further understand pediatric inpatient immunization delivery, from inpatient vaccination coverage to strategies to improve inpatient vaccine uptake, we reviewed the published literature for relevant articles.

A search of PubMed, Embase, and Web of Science was conducted in November 2018 by using search terms developed in conjunction with our institution’s clinical and research librarian. A combination of keywords and controlled vocabulary (when available) were used for the following concepts: vaccination, hospitalization, pediatric, and opportunistic or quality improvement (see the Supplemental Information for complete search strategies). Two hundred seventy-eight abstracts were identified and screened. Articles and conference abstracts available in English, published in 1990 or later, and pertaining to pediatric inpatient immunization were reviewed. Articles pertaining solely to the NICU and adult patients were excluded. Reference lists from each of the included articles were screened, and further applicable studies were identified. This process generated 30 articles and conference abstracts. Themes were identified, and results were organized into 4 topic areas: vaccination status of children who were hospitalized, accuracy of inpatient vaccine histories, barriers to optimal inpatient immunization programs, and interventions to increase documentation and delivery of vaccines to children who were hospitalized. This search was last repeated on January 9, 2019, to determine if new literature had been published during the production of this review.

Multiple steps are required to successfully deliver immunizations in the inpatient setting, the first of which relies on determining a patient’s vaccination status ( Fig 1 ). Vaccination coverage rates among children who are hospitalized have been studied both nationally and abroad ( Table 1 , Fig 2 ). These studies occurred exclusively at single centers and with varied criteria for ages, for vaccines included, for what qualify as “overdue,” and for whether verification with an official registry occurs. Thus, although exact comparisons between results may be difficult, studies consistently revealed that opportunities to immunize in the inpatient setting abound.

Key steps involved in delivering immunizations in the inpatient setting.

Studies Used to Evaluate Vaccination Coverage in Children Who Were Hospitalized

Study publication year as well as year of data collection, as included in each article’s methods section, is included to aid in comparison with local vaccination rates and immunization schedule recommendations during that time period. Method of verifying vaccination status refers to the source of official records (i.e., “parent” indicates parent-held records, such as an immunization card, not parental recall and report).

Vaccination rates from this study’s preimplementation phase.

The methods section does not define the exact dates of the study nor the specific age range for preschool-aged patients; however, in the results section, the authors discuss patients aged 3–66 mo.

Greater than or equal to 3 mo overdue for vaccines.

Data collection years and exact age criteria were not included in the conference abstract.

Percentage of inpatients requiring vaccinations.

In the United States, vaccination status of pediatric inpatients of all ages was evaluated in 2 studies; in 1 study, the influenza vaccine was excluded from analysis, and in 1 study, it was included for analysis. 23 , 24   The former revealed that 27% of patients who were hospitalized required at least 1 vaccine, compared with 84% in the latter; in both studies, the majority of patients who were undervaccinated were adolescents. 23 , 24   In 3 additional studies, the preschool age group was evaluated exclusively, and it was shown that 38% to 56% of inpatients were due or overdue for at least 1 vaccine. 10 , 25 , 26  

Inpatient vaccination coverage has also been evaluated internationally, particularly in Australia and New Zealand, where national vaccine registries exist and assessment of immunization status and opportunistic immunization are hospital benchmarks of performance. 11 , 15 , 27 – 30   Fourteen percent to 34% of inpatients were due or overdue for vaccines in 5 studies from Australia. 11 , 12 , 14 , 17 , 31   In New Zealand, 40% of preschool-aged inpatients were due or overdue for immunizations in 1 study, and 52% were at least 4 weeks overdue in the second. 15 , 27   Six additional single-center studies in Europe and Africa revealed that 14% to 49% of inpatients were underimmunized. 13 , 21 , 22 , 32 – 34  

Factors associated with lower levels of vaccination coverage included ethnic minority groups, 15 , 17   lower socioeconomic status, 21   self-pay patients, 25   male sex, lack of day care attendance, history of previous missed opportunities to immunize, lack of transportation, 10   and increasing age. 24   Uptake of the influenza vaccine was also significantly associated with being fully up to date on other vaccines. 24   Authors of 2 studies collected data on outpatient vaccination rates, finding generally lower immunization rates in inpatients. 14 , 15  

Research has also been focused on single vaccines, most notably the influenza vaccine, which has been shown to be cost-effective when delivered in the inpatient setting. 35   One study revealed that 42% of patients who were undervaccinated and hospitalized with influenza had experienced a missed vaccine opportunity, with 15% of these occurring during inpatient stays. 18   In addition, a study in which the Pediatric Health Information System database was used revealed that 16% of patients hospitalized with influenza had been hospitalized previously that season, suggesting a potential impact of an inpatient influenza vaccination program. 36   In these studies, patients with a previous visit and those with missed vaccination opportunities both increased in children with comorbidities. 18 , 36  

Although children who are hospitalized may often be due for vaccines, the ability to immunize requires an accurate vaccine history. This can prove to be challenging in the inpatient setting. Providers have varying rates of documentation of inpatient immunization status, ranging between 63% and 99% of admissions. 10 , 11 , 17 , 24 , 27 , 31 , 32   However, provision of a full immunization history, including documentation of all vaccines instead of merely writing “up to date,” reveals more dismal results: 1 study revealed that this was completed in only 1.5% of patients. 32   In addition, discrepancies between parental or guardian (hereafter referred to as “parent”) report and true vaccination coverage rates exist, with parental recall often overestimating vaccination status ( Table 1 ). 10 , 17 , 22 , 24 , 27   This is compounded by the fact that parents often do not have formal immunization records with them at the time of hospital admission. 14   In 1 study, 92% of patients with inpatient vaccine histories were documented as up to date; however, only 23% were fully immunized when compared with PCP records. 24  

The inpatient setting provides additional time to obtain and verify a complete immunization history. 22   Interventions to improve vaccine history documentation were included in 2 studies: in 1, the implementing of staff education and a visual admission form; in the second, routine printing of vaccine records from an official database. 31 , 34   Both revealed significantly improved proportions of patients with adequate and accurate immunization histories after their interventions. 31 , 34   This suggests there are feasible strategies to optimize the ability of providers to deliver vaccines to children who are hospitalized.

Unfortunately, 1 common theme in the published literature is that when children who are hospitalized are recognized as underimmunized, little is done to catch them up. 17 , 27 , 32   Authors of various studies have tested interventions to improve vaccine delivery; these interventions were largely performed at single centers and had varying degrees of complexity, ranging from simply offering vaccines to the construction of full immunization delivery teams ( Table 2 ).

Studies Used to Evaluate Inpatient Interventions to Increase Vaccine Uptake in Reverse Chronological Order

Studies exclusively used to evaluate the influenza vaccine are described in Table 3 . DM, diabetes mellitus; PPSV23, 23-valent pneumococcal polysaccharide vaccine; UTD, up to date.

P values are not provided for these statistics.

Sample size refers to patients eligible for immunization or the intervention.

Includes opportunistic immunizations in the inpatient setting, the emergency department, and outpatient hospital (not PCP) clinics; authors did not stratify analysis by site of immunization.

Exact methods for offering inpatient vaccines and the time line of postdischarge follow-up was not specified in the methods section.

In the study, the authors evaluated both inpatient and emergency department settings (sample size and results for inpatient data only).

Four studies were focused on verifying vaccine status with official records and offering inpatient catch-up vaccines; ultimately, 23% to 75% of eligible patients were vaccinated. 13 , 21 , 22 , 25   In 1 of these studies, the authors trialed multiple means of communicating the need for vaccines with inpatient providers and found that visual reminders were most effective. 25   Staff education and visual prompts led to a 14% increase in opportunistic inpatient vaccination in an additional study, whereas routine printing of official immunization records in another improved identification, but not catch-up vaccination, of patients who were underimmunized. 31 , 34  

The authors of 2 studies developed individualized catch-up vaccine plans for patients who were underimmunized. 11 , 23   In 1 study, 25% of eligible patients were brought up to date within 1 month of discharge; the second study revealed that patients who were given a plan were significantly more likely to have received needed vaccines 30 and 90 days later. 11 , 23   In a third study, inpatient vaccine counseling to parents and PCPs led to a significant increase in patients receiving catch-up vaccines within 1 month of discharge. 33  

In 2 studies, authors relied on an immunization champion as the focus of their intervention. 12 , 15   In 1, 42% of patients overdue or due for immunizations received catch-up vaccines within 1 month of discharge, 51% of whom were vaccinated while hospitalized. 12   The other intervention occurred in the inpatient setting, the emergency department, and outpatient hospital-based clinics simultaneously, and 68% of eligible patients were vaccinated across these settings. 15   Missed opportunities were identified in 17% of eligible patients, with a majority of these occurring in inpatients. 15  

Strategies to increase influenza vaccination rates were also evaluated ( Table 3 ). In 1 study, the authors compared provider reminders, family education, and electronic medical record (EMR) prompts, and showed that provider reminders were the most effective method. 37   In another, the authors evaluated a nurse-driven screening and vaccine-ordering tool and found that patients in the intervention period had significantly increased rates of influenza screening and vaccination. 38   A third study was focused solely on patients with cancer, and an influenza vaccine was included in the hospital admission order set as part of a multifaceted inpatient and outpatient intervention. 39   Although the overall percentage of patients receiving and completing the influenza vaccination series increased, the proportion vaccinated in the inpatient setting was unchanged. 39  

Studies Used to Evaluate Inpatient Influenza Immunization Exclusively

All descriptions of vaccines or vaccination refer to the influenza vaccine. Studies pertaining to interventions to increase inpatient influenza vaccine screening and delivery are presented first. Studies occurred at single centers unless otherwise noted. PHIS, Pediatric Health Information System.

In addition to the influenza vaccine, 2 studies were focused on pneumococcal polysaccharide vaccination in special populations. 40 , 41   In 1 study, nursing-driven assessments and standing orders were used to increase vaccination in children who were hospitalized with risk factors as well as in adults who were hospitalized at their institution; in the second study, staff education and EMR order sets were used for patients with diabetes mellitus, and both led to increased inpatient immunization rates by 15% and 43%, respectively. 40 , 41  

Through these studies, lessons were learned that may better inform further interventions. Increased involvement and empowerment of the nursing staff was frequently cited in successful programs, and multiple studies relied on a nurse coordinator or on nursing-driven protocols to improve vaccine uptake. 12 , 13 , 15 , 38 , 40   Further strategies for improvement included the development of clinical guidelines, standardized screening forms, online staff resources, EMR prompts, education, and adding underimmunization to a hospitalized patient’s acute problem list. 12 , 18 , 22 , 42 , 43   These mirror approaches already identified in the adult literature, including nursing-driven vaccination screening, standing orders, immunization histories taken by pharmacists, clinical pathways, chart reminders, and patient education. 40 , 44  

Challenges surrounding construction and implementation of optimal inpatient immunization programs were identified. One frequently cited barrier, as noted previously, is lack of an accurate vaccine history or lack of easily accessible immunization records. 17 , 25   The steps needed to verify immunization status can be time consuming if they are not streamlined into the admission process. 13 , 22 , 23 , 25   Additional obstacles to opportunistic immunization programs included absence of formal policies and systems regarding inpatient immunization, insufficient staff knowledge and training, lack of physician confidence in discussing vaccinations with parents, out-of-date parental information, limited vaccine supply, staff perception that there is not adequate time to address immunizations, and reluctance to vaccinate children who were hospitalized. 17 , 19 , 21 , 27 , 32   In a study of the influenza vaccine, providers identified forgetting to assess immunization status or order the vaccine as barriers to inpatient immunization. 42  

Provider attitudes regarding inpatient vaccination, and the perception that immunization is exclusively the realm of the PCP, can also represent a challenge to opportunistic immunization programs. 19   In 1 study, staff members involved in direct patient care were interviewed, and it was found that 55% expressed concerns about the appropriateness of immunizing children in the inpatient setting or at a tertiary center; the authors of 2 further studies cited the need for provider buy-in for successful inpatient vaccination programs. 21 , 22 , 31   In contrast, inpatient providers had a favorable opinion of inpatient vaccination in a study in which the influenza vaccine was evaluated, and a majority of outpatient pediatricians and family physicians agree with vaccination in the inpatient setting, especially those practicing in high-risk urban areas. 32 , 42 , 45   Finally, although inpatient providers may assume patients will have unobstructed access to PCPs and outpatient immunization, this does not always hold true (all of the patients who were underimmunized in 1 study identified a PCP). 23  

Inpatient providers may also express concerns that parents will not accept immunization while their child is hospitalized; however, this was not the main finding in these studies. In 1 pilot program designed to increase inpatient vaccine uptake, only 6% of parents of eligible children refused vaccination. 25   Additional studies echoed this, revealing that most parents were willing to have their children immunized while hospitalized and were sometimes unaware that their child needed catch-up vaccine doses. 13 , 21 – 23 , 26   This was also seen with the influenza vaccine; a majority of parents in 1 study reported that they would agree to inpatient influenza immunization, including 37% who did not regularly vaccinate against influenza. 42   When reasons for parental refusal of inpatient influenza vaccines were evaluated in a separate study, vaccine refusal was found to be more likely in patients who were white, girls, privately insured, and otherwise not up to date on immunizations. 43  

Although children who are hospitalized may have lower vaccination rates than those in the general population, currently, little is done to identify or catch up pediatric inpatients who are underimmunized. In the United States, between 27% and 56% of pediatric inpatients were due or overdue for vaccines during hospital admission, and this number increased to 84% when the influenza vaccine was also included. 10 , 23 , 24   Although outpatient practices will remain the primary setting for delivering immunizations, this large proportion of underimmunized hospitalized children reveals that the inpatient setting may provide a greater opportunity to increase vaccine uptake than is often acknowledged. Hospitalization gives time to verify vaccine records, provide vaccinations, and educate families on the importance of vaccines before discharge. 20   The inpatient setting also represents a largely untapped niche for vulnerable groups of patients, such as adolescents who may visit their PCP less frequently or children with chronic medical conditions who may be at higher risk of complications from vaccine-preventable infections. 18 , 38 , 46 – 48  

Although providers may be interested in delivering catch-up vaccines to children who are hospitalized, the inability to obtain an accurate and accessible vaccine history remains a major barrier. Strategies for streamlining access to electronic state-based or national immunization registries, as well as standardized screening methods, deserve investigation. In addition, the hospital-level cost and societal benefits of stocking and delivering vaccines to inpatients, especially in the era of diagnosis-related reimbursement plans, has yet to be fully explored. Hospital partnerships with the Vaccines for Children program, which provides vaccines free of charge to eligible patients, may be 1 strategy to mitigate hospital costs; however, meeting the program requirements of ordering and maintaining separate Vaccines for Children and private stocks in a large institution may lead to further obstacles.

Parental and provider attitudes regarding inpatient immunization have begun to be investigated, but further research in this realm is warranted. To date, there are no published studies on attitudes regarding inpatient administration of a majority of vaccines, including adolescent immunizations. Collaboration with PCPs must also be a cornerstone to any successful opportunistic immunization program, and interviews with outpatient providers could identify best practices for information sharing after vaccines have been delivered. Successful communication with PCPs and state-based vaccine registries are needed to prevent duplicate vaccine doses and to maintain the correct intervals between vaccine administrations.

There are currently no published studies in which pediatric inpatient immunization practices across the country are described because the literature to date largely consists of single-center studies with a variety of methodologies. Research into the rates at which inpatient vaccines are given at various hospitals and research into contributing factors could inform best practices and strategies to increase inpatient vaccine delivery and develop effective workflows. In addition, single-center pilot studies could be expanded into multicenter prospective efforts to ensure that the most robust and replicable methodology is used. Finally, interventions that have been successfully used for 1 immunization type, such as nurse-driven influenza screening and vaccine ordering, could be implemented in additional vaccine groups.

The large number of pediatric inpatients who are underimmunized reveals a potentially significant public health impact if assessment of vaccine histories and vaccine delivery in the hospital setting can be optimized. Parents are largely accepting of opportunistic inpatient immunization, and strategies have begun to be explored to increase inpatient vaccine uptake. Further research is needed to investigate inpatient immunization practices more broadly, thereby identifying key strategies for increasing childhood vaccine uptake overall.

The combined vaccine series, as defined by the National Immunization Survey-Child, is ≥4 doses of diphtheria, tetanus, and acellular pertussis; ≥3 doses of poliovirus; ≥1 dose of measles; ≥3 or 4 doses of Haemophilus influenzae type b; ≥3 doses of hepatitis B; ≥1 dose of varicella; and ≥4 doses of pneumococcal conjugate vaccines. 5  

Dr Mihalek conceptualized and designed the study and drafted the initial manuscript; Ms Kysh designed the search terms and critically reviewed the manuscript; Dr Pannaraj conceptualized the study and critically reviewed the manuscript; and all authors approved the final manuscript as submitted.

FUNDING: No external funding.

Competing Interests

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• Review Article
• Published: 22 December 2020

A guide to vaccinology: from basic principles to new developments

• Andrew J. Pollard   ORCID: orcid.org/0000-0001-7361-719X 1 , 2 &
• Else M. Bijker 1 , 2  

Nature Reviews Immunology volume  21 ,  pages 83–100 ( 2021 ) Cite this article

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• Infectious diseases

A Publisher Correction to this article was published on 05 January 2021

This article has been updated

Immunization is a cornerstone of public health policy and is demonstrably highly cost-effective when used to protect child health. Although it could be argued that immunology has not thus far contributed much to vaccine development, in that most of the vaccines we use today were developed and tested empirically, it is clear that there are major challenges ahead to develop new vaccines for difficult-to-target pathogens, for which we urgently need a better understanding of protective immunity. Moreover, recognition of the huge potential and challenges for vaccines to control disease outbreaks and protect the older population, together with the availability of an array of new technologies, make it the perfect time for immunologists to be involved in designing the next generation of powerful immunogens. This Review provides an introductory overview of vaccines, immunization and related issues and thereby aims to inform a broad scientific audience about the underlying immunological concepts.

Introduction

Vaccines have transformed public health, particularly since national programmes for immunization first became properly established and coordinated in the 1960s. In countries with high vaccine programme coverage, many of the diseases that were previously responsible for the majority of childhood deaths have essentially disappeared 1 (Fig.  1 ). The World Health Organization (WHO) estimates that 2–3 million lives are saved each year by current immunization programmes, contributing to the marked reduction in mortality of children less than 5 years of age globally from 93 deaths per 1,000 live births in 1990 to 39 deaths per 1,000 live births in 2018 (ref. 2 ).

The introduction of vaccination against infectious diseases such as diphtheria (part a ), capsular group C meningococcus (part b ), polio (part c ), Haemophilus influenzae type B (part d ), measles (part e ) and pertussis (part f ) led to a marked decrease in their incidence. Of note, the increase in reports of H. influenzae type B in 2001 led to a catch-up vaccination campaign, after which the incidence reduced. For pertussis, a decline in vaccine coverage led to an increase in cases in the late 1970s and 1980s, but disease incidence reduced again after vaccine coverage increased. Adapted with permission from the Green Book, information for public health professionals on immunisation, Public Health England , contains public sector information licensed under the Open Government Licence v3.0.

Vaccines exploit the extraordinary ability of the highly evolved human immune system to respond to, and remember, encounters with pathogen antigens . However, for much of history, vaccines have been developed through empirical research without the involvement of immunologists. There is a great need today for improved understanding of the immunological basis for vaccination to develop vaccines for hard-to-target pathogens (such as Mycobacterium tuberculosis , the bacterium that causes tuberculosis (TB)) 3 and antigenically variable pathogens (such as HIV) 4 , to control outbreaks that threaten global health security (such as COVID-19 or Ebola) 5 , 6 and to work out how to revive immune responses in the ageing immune system 7 to protect the growing population of older adults from infectious diseases.

In this Review, which is primarily aimed at a broad scientific audience, we provide a guide to the history (Box  1 ), development, immunological basis and remarkable impact of vaccines and immunization programmes on infectious diseases to provide insight into the key issues facing immunologists today. We also provide some perspectives on current and future challenges in continuing to protect the world’s population from common pathogens and emerging infectious threats. Communicating effectively about the science of vaccination to a sceptical public is a challenge for all those engaged in vaccine immunobiology but is urgently needed to realign the dialogue and ensure public health 8 . This can only be achieved by being transparent about what we know and do not know, and by considering the strategies to overcome our existing knowledge gaps.

Box 1 A brief history of vaccination

Epidemics of smallpox swept across Europe in the seventeenth and eighteenth centuries, accounting for as much as 29% of the death rate of children in London 137 . Initial efforts to control the disease led to the practice of variolation, which was introduced to England by Lady Mary Wortley Montagu in 1722, having been used in the Far East since the mid-1500s (see Nature Milestones in Vaccines ). In variolation, material from the scabs of smallpox lesions was scratched into the skin in an attempt to provide protection against the disease. Variolation did seem to induce protection, reducing the attack rate during epidemics, but sadly some of those who were variolated developed the disease and sometimes even died. It was in this context that Edward Jenner wrote ‘An Inquiry into the Causes and Effects of the Variole Vaccinae…’ in 1798. His demonstration, undertaken by scratching material from cowpox lesions taken from the hands of a milkmaid, Sarah Nelms, into the skin of an 8-year-old boy, James Phipps, who he subsequently challenged with smallpox, provided early evidence that vaccination could work. Jenner’s contribution to medicine was thus not the technique of inoculation but his startling observation that milkmaids who had had mild cowpox infections did not contract smallpox, and the serendipitous assumption that material from cowpox lesions might immunize against smallpox. Furthermore, Jenner brilliantly predicted that vaccination could lead to the eradication of smallpox; in 1980, the World Health Assembly declared the world free of naturally occurring smallpox.

Almost 100 years after Jenner, the work of Louis Pasteur on rabies vaccine in the 1880s heralded the beginning of a frenetic period of development of new vaccines, so that by the middle of the twentieth century, vaccines for many different diseases (such as diphtheria, pertussis and typhoid) had been developed as inactivated pathogen products or toxoid vaccines. However, it was the coordination of immunization as a major public health tool from the 1950s onwards that led to the introduction of comprehensive vaccine programmes and their remarkable impact on child health that we enjoy today. In 1974, the World Health Organization launched the Expanded Programme on Immunization and a goal was set in 1977 to reach every child in the world with vaccines for diphtheria, pertussis, tetanus, poliomyelitis, measles and tuberculosis by 1990. Unfortunately, that goal has still not been reached; although global coverage of 3 doses of the diphtheria–tetanus–pertussis vaccine has risen to more than 85%, there are still more than 19 million children who did not receive basic vaccinations in 2019 (ref. 105 ).

What is in a vaccine?

A vaccine is a biological product that can be used to safely induce an immune response that confers protection against infection and/or disease on subsequent exposure to a pathogen. To achieve this, the vaccine must contain antigens that are either derived from the pathogen or produced synthetically to represent components of the pathogen. The essential component of most vaccines is one or more protein antigens that induce immune responses that provide protection. However, polysaccharide antigens can also induce protective immune responses and are the basis of vaccines that have been developed to prevent several bacterial infections, such as pneumonia and meningitis caused by Streptococcus pneumoniae , since the late 1980s 9 . Protection conferred by a vaccine is measured in clinical trials that relate immune responses to the vaccine antigen to clinical end points (such as prevention of infection, a reduction in disease severity or a decreased rate of hospitalization). Finding an immune response that correlates with protection can accelerate the development of and access to new vaccines 10 (Box  2 ).

Vaccines are generally classified as live or non-live (sometimes loosely referred to as ‘inactivated’) to distinguish those vaccines that contain attenuated replicating strains of the relevant pathogenic organism from those that contain only components of a pathogen or killed whole organisms (Fig.  2 ). In addition to the ‘traditional’ live and non-live vaccines, several other platforms have been developed over the past few decades, including viral vectors, nucleic acid-based RNA and DNA vaccines, and virus-like particles (discussed in more detail later).

Schematic representation of different types of vaccine against pathogens; the text indicates against which pathogens certain vaccines are licensed and when each type of vaccine was first introduced. BCG, Mycobacterium bovis bacillus Calmette–Guérin.

The distinction between live and non-live vaccines is important. The former may have the potential to replicate in an uncontrolled manner in immunocompromised individuals (for example, children with some primary immunodeficiencies, or individuals with HIV infection or those receiving immunosuppressive drugs), leading to some restrictions to their use 11 . By contrast, non-live vaccines pose no risk to immunocompromised individuals (although they may not confer protection in those with B cell or combined immunodeficiency, as explained in more detail later).

Live vaccines are developed so that, in an immunocompetent host, they replicate sufficiently to produce a strong immune response, but not so much as to cause significant disease manifestations (for example, the vaccines for measles, mumps, rubella and rotavirus, oral polio vaccine, the Mycobacterium bovis bacillus Calmette–Guérin (BCG) vaccine for TB and live attenuated influenza vaccine). There is a trade-off between enough replication of the vaccine pathogen to induce a strong immune response and sufficient attenuation of the pathogen to avoid symptomatic disease. For this reason, some safe, live attenuated vaccines require multiple doses and induce relatively short-lived immunity (for example, the live attenuated typhoid vaccine, Ty21a) 12 , and other live attenuated vaccines may induce some mild disease (for example, about 5% of children will develop a rash and up to 15% fever after measles vaccination) 13 .

The antigenic component of non-live vaccines can be killed whole organisms (for example, whole-cell pertussis vaccine and inactivated polio vaccine), purified proteins from the organism (for example, acellular pertussis vaccine), recombinant proteins (for example, hepatitis B virus (HBV) vaccine) or polysaccharides (for example, the pneumococcal vaccine against S. pneumoniae ) (Fig.  2 ). Toxoid vaccines (for example, for tetanus and diphtheria) are formaldehyde-inactivated protein toxins that have been purified from the pathogen.

Non-live vaccines are often combined with an adjuvant to improve their ability to induce an immune response (immunogenicity). There are only a few adjuvants that are used routinely in licensed vaccines. However, the portfolio of adjuvants is steadily expanding, with liposome-based adjuvants and oil-in-water emulsions being licensed in the past few decades 14 . The mechanism of action of aluminium salts (alum), although extensively used as an adjuvant for more than 80 years, remains incompletely understood 15 , but there is increasing evidence that immune responses and protection can be enhanced by the addition of newer adjuvants that provide danger signals to the innate immune system . Examples of these novel adjuvants are the oil-in-water emulsion MF59, which is used in some influenza vaccines 16 ; AS01 , which is used in one of the shingles vaccines and the licensed malaria vaccine 17 ; and AS04 , which is used in a vaccine against human papillomavirus (HPV) 18 .

Vaccines contain other components that function as preservatives, emulsifiers (such as polysorbate 80) or stabilizers (for example, gelatine or sorbitol). Various products used in the manufacture of vaccines could theoretically also be carried over to the final product and are included as potential trace components of a vaccine, including antibiotics, egg or yeast proteins, latex, formaldehyde and/or gluteraldehyde and acidity regulators (such as potassium or sodium salts). Except in the case of allergy to any of these components, there is no evidence of risk to human health from these trace components of some vaccines 19 , 20 .

Box 2 Correlates of protection

The identification of correlates of protection is helpful in vaccine development as they can be used to compare products and to predict whether the use of an efficacious vaccine in a new population (for example, a different age group, medical background or geographical location) is likely to provide the same protection as that observed in the original setting. There is considerable confusion in the literature about the definition of a correlate of protection. For the purposes of this discussion, it is useful to separate out two distinct meanings. A mechanistic correlate of protection is the specific functional immune mechanism that is believed to confer protection. For example, antitoxin antibodies, which are induced by the tetanus toxoid vaccine, confer protection directly by neutralizing the activity of the toxin. A non-mechanistic correlate of protection does not in itself provide the protective function but has a statistical relationship with the mechanism of protection. An example of a non-mechanistic correlate of protection is total IgG antibody levels against pneumococci. These IgG antibodies contain the mechanistic correlate (thought to be a subset of opsonophagocytic antibodies ) but the mechanism of protection is not being directly measured. Correlates of protection can be measured in clinical trials if there are post-vaccination sera available from individuals who do or do not develop disease, although large-scale serum collection from participants is rarely undertaken in phase III clinical efficacy trials. An alternative approach is to estimate the correlates of protection by extrapolating from sero-epidemiological studies in a vaccinated population and relating the data to disease incidence in the population. Human challenge studies have also been used to determine correlates of protection, although the dose of challenge bacterium or virus and the experimental conditions may not relate closely to natural infection, which can limit the utility of these observations.

Vaccines induce antibodies

The adaptive immune response is mediated by B cells that produce antibodies (humoral immunity) and by T cells (cellular immunity). All vaccines in routine use, except BCG (which is believed to induce T cell responses that prevent severe disease and innate immune responses that may inhibit infection; see later), are thought to mainly confer protection through the induction of antibodies (Fig.  3 ). There is considerable supportive evidence that various types of functional antibody are important in vaccine-induced protection, and this evidence comes from three main sources: immunodeficiency states, studies of passive protection and immunological data.

The immune response following immunization with a conventional protein antigen. The vaccine is injected into muscle and the protein antigen is taken up by dendritic cells, which are activated through pattern recognition receptors (PRRs) by danger signals in the adjuvant, and then trafficked to the draining lymph node. Here, the presentation of peptides of the vaccine protein antigen by MHC molecules on the dendritic cell activates T cells through their T cell receptor (TCR). In combination with signalling (by soluble antigen) through the B cell receptor (BCR), the T cells drive B cell development in the lymph node. Here, the T cell-dependent B cell development results in maturation of the antibody response to increase antibody affinity and induce different antibody isotypes. The production of short-lived plasma cells, which actively secrete antibodies specific for the vaccine protein, produces a rapid rise in serum antibody levels over the next 2 weeks. Memory B cells are also produced, which mediate immune memory. Long-lived plasma cells that can continue to produce antibodies for decades travel to reside in bone marrow niches. CD8 + memory T cells can proliferate rapidly when they encounter a pathogen, and CD8 + effector T cells are important for the elimination of infected cells.

Immunodeficiency states

Individuals with some known immunological defects in antibodies or associated immune components are particularly susceptible to infection with certain pathogens, which can provide insight into the characteristics of the antibodies that are required for protection from that particular pathogen. For example, individuals with deficiencies in the complement system are particularly susceptible to meningococcal disease caused by infection with Neisseria meningitidis 21 because control of this infection depends on complement-mediated killing of bacteria, whereby complement is directed to the bacterial surface by IgG antibodies. Pneumococcal disease is particularly common in individuals with reduced splenic function 22 (which may be congenital, resulting from trauma or associated with conditions such as sickle cell disease); S. pneumoniae bacteria that have been opsonized with antibody and complement are normally removed from the blood by phagocytes in the spleen, which are no longer present in individuals with hyposplenism. Antibody-deficient individuals are susceptible to varicella zoster virus (which causes chickenpox) and other viral infections, but, once infected, they can control the disease in the same way as an immunocompetent individual, so long as they have a normal T cell response 23 .

Passive protection

It has been clearly established that intramuscular or intravenous infusion of exogenous antibodies can provide protection against some infections. The most obvious example is that of passive transfer of maternal antibodies across the placenta, which provides newborn infants with protection against a wide variety of pathogens, at least for a few months after birth. Maternal vaccination with pertussis 24 , tetanus 25 and influenza 26 vaccines harnesses this important protective adaptation to reduce the risk of disease soon after birth and clearly demonstrates the role of antibodies in protection against these diseases. Vaccination of pregnant women against group B streptococci 27 and respiratory syncytial virus (RSV) 28 has not yet been shown to be effective at preventing neonatal or infant infection, but it has the potential to reduce the burden of disease in the youngest infants. Other examples include the use of specific neutralizing antibodies purified from immune donors to prevent the transmission of various viruses, including varicella zoster virus, HBV and measles virus 29 . Individuals with inherited antibody deficiency are without defence against serious viral and bacterial infections, but regular administration of serum antibodies from an immunocompetent donor can provide almost entirely normal immune protection for the antibody-deficient individual.

Immunological data

Increasing knowledge of immunology provides insights into the mechanisms of protection mediated by vaccines. For example, polysaccharide vaccines, which are made from the surface polysaccharides of invasive bacteria such as meningococci ( N. meningitidis ) 30 and pneumococci ( S. pneumoniae ) 31 , provide considerable protection against these diseases. It is now known that these vaccines do not induce T cell responses, as polysaccharides are T cell-independent antigens , and thus they must mediate their protection through antibody-dependent mechanisms. Protein–polysaccharide conjugate vaccines contain the same polysaccharides from the bacterial surface, but in this case they are chemically conjugated to a protein carrier (mostly tetanus toxoid, or diphtheria toxoid or a mutant protein derived from it, known as CRM 197 ) 32 , 33 , 34 . The T cells induced by the vaccine recognize the protein carrier (a T cell-dependent antigen ) and these T cells provide help to the B cells that recognize the polysaccharide, but no T cells are induced that recognize the polysaccharide and, thus, only antibody is involved in the excellent protection induced by these vaccines 35 . Furthermore, human challenge studies offer the opportunity to efficiently assess correlates of protection (Box  2 ) under controlled circumstances 36 , and they have been used to demonstrate the role of antibodies in protection against malaria 37 and typhoid 38 .

Vaccines need T cell help

Although most of the evidence points to antibodies being the key mediators of sterilizing immunity induced by vaccination, most vaccines also induce T cell responses. The role of T cells in protection is poorly characterized, except for their role in providing help for B cell development and antibody production in lymph nodes. From studies of individuals with inherited or acquired immunodeficiency, it is clear that whereas antibody deficiency increases susceptibility to acquisition of infection, T cell deficiency results in failure to control a pathogen after infection. For example, T cell deficiency results in uncontrolled and fatal varicella zoster virus infection, whereas individuals with antibody deficiency readily develop infection but recover in the same way as immunocompetent individuals. The relative suppression of T cell responses that occurs at the end of pregnancy increases the severity of infection with influenza and varicella zoster viruses 39 .

Although evidence for the involvement of T cells in vaccine-induced protection is limited, this is likely owing, in part, to difficulties in accessing T cells to study as only the blood is easily accessible, whereas many T cells are resident in tissues such as lymph nodes. Furthermore, we do not yet fully understand which types of T cell should be measured. Traditionally, T cells have been categorized as either cytotoxic (killer) T cells or helper T cells. Subtypes of T helper cells (T H cells) can be distinguished by their profiles of cytokine production. T helper 1 (T H 1) cells and T H 2 cells are mainly important for establishing cellular immunity and humoral immunity, respectively, although T H 1 cells are also associated with generation of the IgG antibody subclasses IgG1 and IgG3. Other T H cell subtypes include T H 17 cells (which are important for immunity at mucosal surfaces such as the gut and lung) and T follicular helper cells (located in secondary lymphoid organs, which are important for the generation of high-affinity antibodies (Fig.  3 )). Studies show that sterilizing immunity against carriage of S. pneumoniae in mice can be achieved by the transfer of T cells from donor mice exposed to S. pneumoniae 40 , which indicates that further investigation of T cell-mediated immunity is warranted to better understand the nature of T cell responses that could be harnessed to improve protective immunity.

Although somewhat simplistic, the evidence therefore indicates that antibodies have the major role in prevention of infection (supported by T H cells), whereas cytotoxic T cells are required to control and clear established infection.

Features of vaccine-induced protection

Vaccines have been developed over the past two centuries to provide direct protection of the immunized individual through the B cell-dependent and T cell-dependent mechanisms described above. As our immunological understanding of vaccines has developed, it has become apparent that this protection is largely manifested through the production of antibody. Another important feature of vaccine-induced protection is the induction of immune memory . Vaccines are usually developed to prevent clinical manifestations of infection. However, some vaccines, in addition to preventing the disease, may also protect against asymptomatic infection or colonization, thereby reducing the acquisition of a pathogen and thus its onward transmission, establishing herd immunity. Indeed, the induction of herd immunity is perhaps the most important characteristic of immunization programmes, with each dose of vaccine protecting many more individuals than the vaccine recipient. Some vaccines may also drive changes in responsiveness to future infections with different pathogens, so called non-specific effects, perhaps by stimulating prolonged changes in the activation state of the innate immune system.

Immune memory

In encountering a pathogen, the immune system of an individual who has been vaccinated against that specific pathogen is able to more rapidly and more robustly mount a protective immune response. Immune memory has been shown to be sufficient for protection against pathogens when the incubation period is long enough for a new immune response to develop (Fig.  4a ). For example, in the case of HBV, which has an incubation period of 6 weeks to 6 months, a vaccinated individual is usually protected following vaccination even if exposure to the virus occurs some time after vaccination and the levels of vaccine-induced antibody have already waned 41 . Conversely, it is thought that immune memory may not be sufficient for protection against rapidly invasive bacterial infections that can cause severe disease within hours or days following acquisition of the pathogen 42 (Fig.  4b ). For example, there is evidence in the case of both Haemophilus influenzae type B (Hib) and capsular group C meningococcal infection that individuals with vaccine-induced immune memory can still develop disease once their antibody levels have waned, despite mounting robust, although not rapid enough, memory responses 43 , 44 . The waning of antibody levels varies depending on the age of the vaccine recipient (being very rapid in infants as a result of the lack of bone marrow niches for B cell survival), the nature of the antigen and the number of booster doses administered. For example, the virus-like particles used in the HPV vaccine induce antibody responses that can persist for decades, whereas relatively short-term antibody responses are induced by pertussis vaccines; and the inactivated measles vaccine induces shorter-lived antibody responses than the live attenuated measles vaccine.

Antibody levels in the circulation wane after primary vaccination, often to a level below that required for protection. Whether immune memory can protect against a future pathogen encounter depends on the incubation time of the infection, the quality of the memory response and the level of antibodies induced by memory B cells. a | The memory response may be sufficient to protect against disease if there is a long incubation period between pathogen exposure and the onset of symptoms to allow for the 3–4 days required for memory B cells to generate antibody titres above the protective threshold. b | The memory response may not be sufficient to protect against disease if the pathogen has a short incubation period and there is rapid onset of symptoms before antibody levels have reached the protective threshold. c | In some cases, antibody levels after primary vaccination remain above the protective threshold and can provide lifelong immunity.

So, for infections that are manifest soon after acquisition of the pathogen, the memory response may be insufficient to control these infections and sustained immunity for individual protection through vaccination can be difficult to achieve. One solution to this is the provision of booster doses of vaccine through childhood (as is the case, for example, for diphtheria, tetanus, pertussis and polio vaccines), in an attempt to sustain antibody levels above the protective threshold. It is known that provision of five or six doses of tetanus 45 or diphtheria 46 vaccine in childhood provides lifelong protection, and so booster doses of these vaccines throughout adult life are not routine in most countries that can achieve high coverage with multiple childhood doses. Given that, for some infections, the main burden is in young children, continued boosting after the second year of life is not undertaken (for example, the invasive bacterial infections including Hib and capsular group B meningococci).

The exception is the pertussis vaccine, where the focus of vaccine programmes is the prevention of disease in infancy; this is achieved both by direct vaccination of infants as well as by the vaccination of other age groups, including adolescents and pregnant women in some programmes, to reduce transmission to infants and provide protection by antibody transfer across the placenta. Notably, in high-income settings, many countries (starting in the 1990s) have switched to using the acellular pertussis vaccine, which is less reactogenic than (and therefore was thought to be preferable to) the older whole-cell pertussis vaccine that is still used in most low-income countries. It is now apparent that acellular pertussis vaccine induces a shorter duration of protection against clinical pertussis and may be less effective against bacterial transmission than is the whole-cell pertussis vaccine 47 . Many high-income countries have observed a rise in pertussis cases since the introduction of the acellular vaccine, a phenomenon that is not observed in low-income nations using the whole-cell vaccine 48 .

By contrast, lifelong protection seems to be the rule following a single dose with some of the live attenuated viral vaccines, such as yellow fever vaccine 49 (Fig.  4c ), although it is apparent that protection is incomplete with others. In the case of varicella zoster and measles–mumps vaccines, some breakthrough cases are described during disease outbreaks among those individuals who have previously been vaccinated, although it is unclear whether this represents a group in whom immunity has waned (and who therefore needed booster vaccination) or a group for whom the initial vaccine did not induce a successful immune response. Breakthrough cases are less likely in those individuals who have had two doses of measles–mumps–rubella vaccine 50 or varicella zoster vaccine 51 , and cases that do occur are usually mild, which indicates that there is some lasting immunity to the pathogen.

An illustration of the complexity of immune memory and the importance of understanding its underlying immunological mechanisms in order to improve vaccination strategies is provided by the concept of ‘original antigenic sin’. This phenomenon describes how the immune system fails to generate an immune response against a strain of a pathogen if the host was previously exposed to a closely related strain, and this has been demonstrated in several infections, including dengue 52 and influenza 53 . This might have important implications for vaccine development if only a single pathogen strain or pathogen antigen is included in a vaccine, as vaccine recipients might then have impaired immune responses if later exposed to different strains of the same pathogen, potentially putting them at increased risk of infection or more severe disease. Strategies to overcome this include the use of adjuvants that stimulate innate immune responses, which can induce sufficiently cross-reactive B cells and T cells that recognize different strains of the same pathogen, or the inclusion of as many strains in a vaccine as possible, the latter approach obviously being limited by the potential of new strains to emerge in the future 54 .

Herd immunity

Although direct protection of individuals through vaccination has been the focus of most vaccine development and is crucial to demonstrate for the licensure of new vaccines, it has become apparent that a key additional component of vaccine-induced protection is herd immunity, or more correctly ‘herd protection’ (Fig.  5 ). Vaccines cannot protect every individual in a population directly, as some individuals are not vaccinated for various reasons and others do not mount an immune response despite vaccination. Fortunately, however, if enough individuals in a population are vaccinated, and if vaccination prevents not only the development of disease but also infection itself (discussed in more detail below), transmission of the pathogen can be interrupted and the incidence of disease can fall further than would be expected, as a result of the indirect protection of individuals who would otherwise be susceptible.

The concept of herd immunity for a highly contagious disease such as measles. Susceptible individuals include those who have not yet been immunized (for example, being too young), those who cannot be immunized (for example, as a result of immunodeficiency), those for whom the vaccine did not induce immunity, those for whom initial vaccine-induced immunity has waned and those who refused immunization.

For highly transmissible pathogens, such as those causing measles or pertussis, around 95% of the population must be vaccinated to prevent disease outbreaks, but for less transmissible organisms a lower percentage of vaccine coverage may be sufficient to have a substantial impact on disease (for example, for polio, rubella, mumps or diphtheria, vaccine coverage can be ≤86%). For influenza, the threshold for herd immunity is highly variable from season to season and is also confounded by the variability in vaccine effectiveness each year 55 . Modest vaccine coverage, of 30–40%, is likely to have an impact on seasonal influenza epidemics, but ≥80% coverage is likely to be optimal 56 . Interestingly, there might be a downside to very high rates of vaccination, as the absence of pathogen transmission in that case will prevent natural boosting of vaccinated individuals and could lead to waning immunity if booster doses of vaccine are not used.

Apart from tetanus vaccine, all other vaccines in the routine immunization schedule induce some degree of herd immunity (Fig.  5 ), which substantially enhances population protection beyond that which could be achieved by vaccination of the individual only. Tetanus is a toxin-mediated disease acquired through infection of breaks in the skin contaminated with the toxin-producing bacteria Clostridium tetani from the environment — so, vaccination of the community with the tetanus toxoid will not prevent an unvaccinated individual acquiring the infection if they are exposed. As an example of the success of herd immunity, vaccination of children and young adults (up to 19 years of age) with capsular group C meningococcal vaccine in a mass campaign in 1999 resulted in almost complete elimination of disease from the UK in adults as well as children 57 . Currently, the strategy for control of capsular groups A, C, W and Y meningococci in the UK is vaccination of adolescents, as they are mainly responsible for transmission and vaccine-mediated protection of this age group leads to community protection through herd immunity 58 . The HPV vaccine was originally introduced to control HPV-induced cervical cancer, with vaccination programmes directed exclusively at girls, but it was subsequently found to also provide protection against HPV infection in heterosexual boys through herd immunity, which led to a marked reduction in the total HPV burden in the population 59 , 60 .

Prevention of infection versus disease

Whether vaccines prevent infection or, rather, the development of disease after infection with a pathogen is often difficult to establish, but improved understanding of this distinction could have important implications for vaccine design. BCG vaccination can be used as an example to illustrate this point, as there is some evidence for the prevention of both disease and infection. BCG vaccination prevents severe disease manifestations such as tuberculous meningitis and miliary TB in children 61 and animal studies have shown that BCG vaccination reduces the spread of M. tuberculosis bacteria in the blood, mediated by T cell immunity 62 , thereby clearly showing that vaccination has protective effects against the development of disease after infection. However, there is also good evidence that BCG vaccination reduces the risk of infection. In a TB outbreak at a school in the UK, 29% of previously BCG-vaccinated children had a memory T cell response to infection, as indicated by a positive interferon-γ release assay , as compared with 47% of the unvaccinated children 63 . A similar effect was seen when studying Indonesian household members of patients with TB, who had a 45% reduced chance of developing a positive interferon-γ release assay response to M. tuberculosis if they had previously been BCG vaccinated 64 . The lack of a T cell response in previously vaccinated individuals indicates that the BCG vaccine induces an innate immune response that results in ‘early clearance’ of the bacteria and prevents infection that induces an adaptive immune response. It will be hugely valuable for future vaccine development to better understand the induction of such protective innate immune responses so that they might be reproduced for other pathogens.

In the case of the current pandemic of the virus SARS-CoV-2, a vaccine that prevents severe disease and disease-driven hospitalization could have a substantial public health impact. However, a vaccine that could also block acquisition of the virus, and thus prevent both asymptomatic and mild infection, would have much larger impact by reducing transmission in the community and potentially establishing herd immunity.

Non-specific effects

Several lines of evidence indicate that immunization with some vaccines perturbs the immune system in such a way that there are general changes in immune responsiveness that can increase protection against unrelated pathogens 65 . This phenomenon has been best described in humans in relation to BCG and measles vaccines, with several studies showing marked reductions in all-cause mortality when these vaccines are administered to young children that are far beyond the expected impact from the reduction in deaths attributed to TB or measles, respectively 66 . These non-specific effects may be particularly important in high-mortality settings, but not all studies have identified the phenomenon. Although several immunological mechanisms have been proposed, the most plausible of which is that epigenetic changes can occur in innate immune cells as a result of vaccination, there are no definitive studies in humans that link immunological changes after immunization with important clinical end points, and it remains unclear how current immunization schedules might be adapted to improve population protection through non-specific effects. Of great interest in the debate, recent studies have indicated that measles disease casts a prolonged ‘shadow’ over the immune system, with depletion of existing immune memory, such that children who have had the disease have an increased risk of death from other causes over the next few years 67 , 68 . In this situation, measles vaccination reduces mortality from measles as well as the unconnected diseases that would have occurred during the ‘shadow’, resulting in a benefit that seems to be non-specific but actually relates directly to the prevention of measles disease and its consequences. This illustrates a limitation of vaccine study protocols: as these are usually designed to find pathogen-specific effects, the possibility of important non-specific effects cannot be assessed.

Factors affecting vaccine protection

The level of protection afforded by vaccination is affected by many genetic and environmental factors, including age, maternal antibody levels, prior antigen exposure, vaccine schedule and vaccine dose. Although most of these factors cannot be readily modified, age of vaccination and schedule of vaccination are important and key factors in planning immunization programmes. The vaccine dose is established during early clinical development, based on optimal safety and immunogenicity. However, for some populations, such as older adults, a higher dose might be beneficial, as has been shown for the influenza vaccine 69 , 70 . Moreover, intradermal vaccination has been shown to be immunogenic at much lower (fractional) doses than intramuscular vaccination for influenza, rabies and HBV vaccines 71 .

Age of vaccination

The highest burden of and mortality from infectious disease occur in the first 5 years of life, with the youngest infants being most affected. For this reason, immunization programmes have largely focused on this age group where there is the greatest benefit from vaccine-induced protection. Although this makes sense from an epidemiological perspective, it is somewhat inconvenient from an immunological perspective as the induction of strong immune responses in the first year of life is challenging. Indeed, vaccination of older children and adults would induce stronger immune responses, but would be of little value if those who would have benefited from vaccination have already succumbed to the disease.

It is not fully understood why immune responses to vaccines are not as robust in early infancy as they are in older children. One factor, which is increasingly well documented, is interference from maternal antibody 72 — acquired in utero through the placenta — which might reduce antigen availability, reduce viral replication (in the case of live viral vaccines such as measles 73 ) or perhaps regulate B cell responses. However, there is also evidence that there is a physiological age-dependent increase in antibody responses in infancy 72 . Furthermore, bone marrow niches to support B cells are limited in infancy, which might explain the very short-lived immune responses that are documented in the first year of life 74 . For example, after immunization with 2 doses of the capsular group C meningococcal vaccine in infancy, only 41% of infants still had protective levels of antibody by the time of the booster dose, administered 7 months later 75 .

In the case of T cell-independent antigens — in other words, plain polysaccharides from Hib, typhoid-causing bacteria, meningococci and pneumococci — animal data indicate that antibody responses depend on development of the marginal zone of the spleen, which is required for the maturation of marginal zone B cells, and this does not occur until around 18 months of age in human infants 76 . These plain polysaccharide vaccines do not induce memory B cells (Fig.  6 ) and, even in adults, provide protection for just 2–3 years, with protection resulting from antibody produced by plasma cells derived from marginal zone B cells 77 . However, converting plain polysaccharide vaccines into T cell-dependent protein–polysaccharide conjugate vaccines, which are immunogenic from 2 months of age and induce immune memory, has transformed prevention of disease caused by the encapsulated bacteria (pneumococci, Hib and meningococci) over the past three decades 78 . These are the most important invasive bacterial pathogens of childhood, causing most cases of childhood meningitis and bacterial pneumonia, and the development of the conjugate vaccine technology in the 1980s has transformed global child health 9 .

a | Polysaccharide vaccines induce antibody-producing plasma cells by cross-linking the B cell receptor (BCR). However, affinity maturation of the antibody response and the induction of memory B cells do not occur. b | Protein–polysaccharide conjugate vaccines can engage T cells that recognize the carrier protein, as well as B cells that recognize the polysaccharide. T cells provide help to B cells, leading to affinity maturation and the production of both plasma cells and memory B cells. TCR, T cell receptor. Adapted from ref. 35 , Springer Nature Limited.

Immune responses are also poor in the older population and most of the vaccines used in older adults offer limited protection or a limited duration of protection, particularly among those older than 75 years of age. The decline in immune function with age (known as immunosenescence) has been well documented 79 but, despite the burden of infection in this age group and the increasing size of the population, has not received sufficient attention so far amongst immunologists and vaccinologists. Interestingly, some have raised the hypothesis that chronic infection with cytomegalovirus (CMV) might have a role in immunosenescence through unfavourable effects on the immune system, including clonal expansion of CMV-specific T cell populations, known as ‘memory inflation’, and reduced diversity of naive T cells 80 , 81 .

In high-income countries, many older adults receive influenza, pneumococcal and varicella zoster vaccines, although data showing substantial benefits of these vaccines in past few decades in the oldest adults (more than 75 years of age) are lacking. However, emerging data following the recent development and deployment of new-generation, high-dose or adjuvanted influenza vaccines 82 and an adjuvanted glycoprotein varicella zoster vaccine 83 suggest that the provision of additional signals to the immune system by certain adjuvants (such as AS01 and MF59) can overcome immunosenescence. It is now necessary to understand how and why, and to use this knowledge to expand options for vaccine-induced protection at the extremes of life.

Schedule of vaccination

For most vaccines that are used in the first year of life, 3–4 doses are administered by 12 months of age. Conventionally, in human vaccinology, ‘priming’ doses are all those administered at less than 6 months of age and the ‘booster’ dose is given at 9–12 months of age. So, for example, the standard WHO schedule for diphtheria–tetanus–pertussis-containing vaccines (which was introduced in 1974 as part of the Expanded Programme on Immunization 84 ) consists of 3 priming doses at 6, 10 and 14 weeks of age with no booster. This schedule was selected to provide early protection before levels of maternal antibody had waned (maternal antibody has a half-life of around 30–40 days 85 , so very little protection is afforded to infants from the mother beyond 8–12 weeks of age) and because it was known that vaccine compliance is better when doses are given close together. However, infant immunization schedules around the world are highly variable — few high-income or middle-income countries use the Expanded Programme on Immunization schedule — and were largely introduced with little consideration of how best to optimize immune responses. Indeed, schedules that start later at 8–12 weeks of age (when there is less interference from maternal antibody) and have longer gaps between doses (8 weeks rather than 4 weeks) are more immunogenic. A large number of new vaccines have been introduced since 1974 as a result of remarkable developments in technology, but these have generally been fitted into existing schedules without taking into account the optimal scheduling for these new products. The main schedules used globally for diphtheria–tetanus–pertussis vaccine are presented in Supplementary Table 1 , and the changes to the UK immunization schedule since 1963 are presented in Supplementary Table 2 . It should also be noted that surveys show vaccines are rarely delivered on schedule in many countries and, thus, the published schedule may not be how vaccines are actually delivered on the ground. This is particularly the case in remote areas (for example, where health professionals only visit occasionally) and regions with limited or chaotic health systems, leaving children vulnerable to infection.

Safety and side effects of vaccines

Despite the public impression that vaccines are associated with specific safety concerns, the existing data indicate that vaccines are remarkably safe as interventions to defend human health. Common side effects, particularly those associated with the early innate immune response to vaccines, are carefully documented in clinical trials. Although rare side effects might not be identified in clinical trials, vaccine development is tightly controlled and robust post-marketing surveillance systems are in place in many countries, which aim to pick these up if they do occur. This can make the process of vaccine development rather laborious but is appropriate because, unlike most drugs, vaccines are used for prophylaxis in a healthy population and not to treat disease. Perhaps because vaccines work so well and the diseases that they prevent are no longer common, there have been several spurious associations made between vaccines and various unrelated health conditions that occur naturally in the population. Disentangling incorrect claims of vaccine harm from true vaccine-related adverse events requires very careful epidemiological studies.

Common side effects

Licensure of a new vaccine normally requires safety studies involving from 3,000 to tens of thousands of individuals. Thus, common side effects are very well known and are published by the regulator at the time of licensure. Common side effects of many vaccines include injection site pain, redness and swelling and some systemic symptoms such as fever, malaise and headache. All of these side effects, which occur in the first 1–2 days following vaccination, reflect the inflammatory and immune responses that lead to the successful development of vaccine-induced protection. About 6 days after measles–mumps–rubella vaccination, about 10% of 12-month-old infants develop a mild viraemia, which can result in fever and rash, and occasionally febrile convulsions (1 in 3,000) 86 . Although these side effects are self-limiting and relatively mild — and are trivial in comparison with the high morbidity and mortality of the diseases from which the vaccines protect — they can be very worrying for parents and their importance is often underestimated by clinicians who are counselling families about immunization.

Immunodeficiency and vaccination

Most vaccines in current use are inactivated, purified or killed organisms or protein and/or polysaccharide components of a pathogen; as they cannot replicate in the vaccine recipient, they are thus not capable of causing any significant side effects, resulting in very few contraindications for their use. Even in immunocompromised individuals, there is no risk from use of these vaccines, although the induction of immunity may not be possible, depending on the nature of the immune system defect. More caution is required for the use of live attenuated, replicating vaccines (such as yellow fever, varicella zoster, BCG and measles vaccines) in the context of individuals with T cell immunodeficiency as there is a theoretical risk of uncontrolled replication, and live vaccines are generally avoided in this situation 87 . A particular risk of note is from the yellow fever vaccine, which is contraindicated in individuals with T cell immunodeficiency and occasionally causes a severe viscerotropic or neurotropic disease in individuals with thymus disease or after thymectomy, in young infants and adults more than 60 years of age 88 . In individuals with antibody deficiency, there may be some merit in the use of routine live vaccines, as T cell memory may be induced that, although unlikely to prevent future infection, could improve control of the disease if infection occurs.

The myth of antigenic overload

An important parental concern is that vaccines might overwhelm their children’s immune systems. In a telephone survey in the USA, 23% of parents agreed with the statement ‘Children get more immunizations than are good for them’, and 25% indicated that they were concerned that their child’s immune system could be weakened by too many immunizations 89 . However, there is ample evidence to disprove these beliefs. Although the number of vaccines in immunization programmes has increased, the total number of antigens has actually decreased from more than 3,200 to approximately 320 as a result of discontinuing the smallpox vaccine and replacing the whole-cell pertussis vaccine with the acellular vaccine 90 , 91 . Vaccines comprise only a small fraction of the antigens that children are exposed to throughout normal life, with rapid bacterial colonization of the gastrointestinal tract after birth, multiple viral infections and environmental antigens. Moreover, multiple studies have shown that children who received vaccinations had a similar, or even reduced, risk of unconnected infections in the following period 92 , 93 , 94 , 95 . Looking at children who presented to the emergency department with infections not included in the vaccine programme, there was no difference in terms of their previous antigen exposure by vaccination 96 .

Significant rare side effects

Serious side effects from vaccines are very rare, with anaphylaxis being the most common of these rare side effects for parenteral vaccines , occurring after fewer than one in a million doses 97 . Individuals with known allergies (such as egg or latex) should avoid vaccines that may have traces of these products left over from the production process with the specific allergen, although most cases of anaphylaxis are not predictable in advance but are readily managed if vaccines are administered by trained health-care staff.

Very rare side effects of vaccines are not usually observed during clinical development, with very few documented, and they are only recognized through careful surveillance in vaccinated populations. For example, there is a very low risk of idiopathic thrombocytopenic purpura (1 in 24,000 vaccine recipients) after measles vaccination 86 . From 1 in 55,000 to 1 in 16,000 recipients of an AS03-adjuvanted 2009 pandemic H1N1 influenza vaccine 98 , 99 , who had a particular genetic susceptibility (HLA DQB1*0602) 100 , developed narcolepsy , although the debate continues about whether the trigger was the vaccine, the adjuvant or some combination, perhaps with the circulating virus also having a role.

Despite widespread misleading reporting about links between the measles–mumps–rubella vaccine and autism from the end of the 1990s, there is no evidence that any vaccines or their components cause autism 101 , 102 . Indeed, the evidence now overwhelmingly shows that there is no increased risk of autism in vaccinated populations. Thiomersal (also known as thimerosal) is an ethyl mercury-containing preservative that has been used widely in vaccines since the 1930s without any evidence of adverse events associated with it, and there is also no scientific evidence of any link between thiomersal and autism despite spurious claims about this 102 . Thiomersal has been voluntarily withdrawn from most vaccines by manufacturers as a precautionary measure rather than because of any scientific evidence of lack of safety and is currently used mainly in the production of whole-cell pertussis vaccines.

The risk of hospitalization, death or long-term morbidity from the diseases for which vaccines have been developed is so high that the risks of common local and systemic side effects (such as sore arm and fever) and the rare more serious side effects are far outweighed by the massive reductions in disease achieved through vaccination. Continuing assessment of vaccine safety post licensure is important for the detection of rare and longer-term side effects, and efficient reporting systems need to be in place to facilitate this 103 . This is particularly important in a pandemic situation, such as the COVID-19 pandemic, as rapid clinical development of several vaccines is likely to take place and large numbers of people are likely to be vaccinated within a short time.

Challenges to vaccination success

Vaccines only work if they are used. Perhaps the biggest challenge to immunization programmes is ensuring that the strong headwinds against deployment, ranging from poor infrastructure and lack of funding to vaccine hesitancy and commercial priorities, do not prevent successful protection of the most vulnerable in society. It is noteworthy that these are not classical scientific challenges, although limited knowledge about which antigens are protective, which immune responses are needed for protection and how to enhance the right immune responses, particularly in the older population, are also important considerations.

Access to vaccines

The greatest challenge for protection of the human population against serious infectious disease through vaccination remains access to vaccines and the huge associated inequity in access. Access to vaccines is currently limited, to varying degrees in different regions, by the absence of a health infrastructure to deliver vaccines, the lack of convenient vaccine provision for families, the lack of financial resources to purchase available vaccines (at a national, local or individual level) and the marginalization of communities in need. This is perhaps the most pressing issue for public health, with global vaccine coverage having stalled; for example, coverage for diphtheria–tetanus–pertussis-containing vaccines has only risen from 84% to 86% since 2010 (ref. 104 ). However, this figure hides huge regional variation, with near 100% coverage in some areas and almost no vaccinated children in others. For the poorest countries in the world, Gavi, the Vaccine Alliance provides funding to assist with new vaccine introductions and has greatly accelerated the broadening of access to new vaccines that were previously only accessible to high-income countries. However, this still leaves major financial challenges for countries that do not meet the criteria to be eligible for Gavi funding but still cannot afford new vaccines. Inequity remains, with approximately 14 million children not receiving any vaccinations and another 5.7 million children being only partially vaccinated in 2019 (ref. 105 ).

Other important issues can compromise vaccine availability and access. For example, most vaccines must be refrigerated at 2–8 °C, requiring the infrastructure and capacity for cold storage and a cold chain to the clinic where the vaccine is delivered, which is limited in many low-income countries. The route of administration can also limit access; oral vaccines (such as rotavirus, polio or cholera vaccines) and nasal vaccines (such as live attenuated influenza vaccine) can be delivered rapidly on a huge scale by less-skilled workers, whereas most vaccines are injected, which requires more training to administer and takes longer. Nevertheless, these hurdles can be overcome: in Sindh Province, Pakistan, 10 million doses of injected typhoid conjugate vaccine were administered to children to control an outbreak of extensively drug-resistant typhoid in just a few weeks at the end of 2019 (ref. 106 ).

The anti-vaccination movement

Despite access being the main issue affecting global vaccine coverage, a considerable focus is currently on the challenges posed by the anti-vaccination movement, largely as a result of worrying trends of decreasing vaccine coverage in high-income settings, leading to outbreaks of life-threatening infectious diseases, such as measles. In 2018, there were 140,000 deaths from measles worldwide, and the number of cases in 2019 was the highest in any year since 2006 (ref. 107 ). Much has been written about the dangerous role of social media and online search engines in the spread of misinformation about vaccines and the rise of the anti-vaccination movement, but scientists are also at fault for failing to effectively communicate the benefits of vaccination to a lay public. If this is to change, scientists do not need to counter or engage with the anti-vaccination movement but to use their expertise and understanding to ensure effective communication about the science that underpins our remarkable ability to harness the power of the immune system through vaccination to defend the health of our children.

Commercial viability

A third important issue is the lack of vaccines for some diseases for which there is no commercial incentive for development. Typically, these are diseases that have a restricted geographical spread (such as Rift Valley fever, Ebola, Marburg disease or plague) or occur in sporadic outbreaks and only affect poor or displaced communities (such as Ebola and cholera). Lists of outbreak pathogens have been published by various agencies including the WHO 108 , and recent funding initiatives, including those from US and European governments, have increased investment in the development of orphan vaccines . The Coalition for Epidemic Preparedness Innovations (CEPI) is set to have a major role in funding and driving the development of vaccines against these pathogens.

Immunological challenges

For other pathogens, there is likely to be a commercial market but there are immunological challenges for the development of new vaccines. For example, highly variable pathogens, including some with a large global distribution such as HIV and hepatitis C virus, pose a particular challenge. The genetic diversity of these pathogens, which occurs both between and within hosts, makes it difficult to identify an antigen that can be used to immunize against infection. In the case of HIV, antibodies can be generated that neutralize the virus, but the rapid mutation of the viral genome means that the virus can evade these responses within the same host. Some individuals do produce broadly neutralizing antibodies naturally, which target more conserved regions of the virus, leading to viral control, but it is not clear how to robustly induce these antibodies with a vaccine. Indeed, several HIV vaccines have been tested in clinical trials that were able to induce antibody responses (for example, RV144 vaccine showed 31% protection 109 ) and/or T cell responses, but these vaccines have not shown consistent evidence of protection in follow-up studies, and several studies found an increased risk of infection among vaccine recipients 110 .

For other pathogens, such as Neisseria gonorrhoeae (which causes gonorrhoea) and Treponema pallidum (which causes syphilis), antigenic targets for protective immune responses have not yet been determined, partly owing to limited investment and a poor understanding of the mechanisms of immunity at mucosal surfaces, or have thus far only resulted in limited protection. For example, the licensed malaria vaccine, RTSS, provides only 30–40% protection and further work is needed to develop suitable products 111 . New malaria vaccines in development target more conserved antigens on the parasite surface or target different stages of the parasite life cycle. Combinations of these approaches in a vaccine (perhaps targeting multiple stages of the life cycle), together with anti-vector strategies such as the use of genetically modified mosquitoes or Wolbachia bacteria to infect mosquitoes and reduce their ability to carry mosquito parasites 112 , as well as mosquito-bite avoidance, have the potential to markedly reduce malaria parasite transmission.

Seasonal influenza vaccines have, in recent decades, been used to protect vulnerable individuals in high-income countries, including older adults, children and individuals with co-morbidities that increase risk of severe influenza. These vaccines are made from virus that is grown in eggs; purified antigen, split virions or whole virions can be included in the final vaccine product. The vaccines take around 6 months to manufacture and have highly variable efficacy from one season to another, partly owing to the difficulty in predicting which virus strain will be circulating in the next influenza season, so that the vaccine strain may not match the strain causing disease 113 . Another issue that is increasingly recognized is egg adaptation, whereby the vaccine strain of virus becomes adapted to the egg used for production, leading to key mutations that mean it is not well matched to, and does not protect against, the circulating viral strain 114 . Vaccine-induced protection might be improved by the development of mammalian or insect cell-culture systems for growing influenza virus to avoid egg adaptation, and the use of MF59-adjuvanted vaccines and high-dose influenza vaccines to improve immune responses. Because of the cost of purchasing seasonal influenza vaccines annually, and the problem of antigenic variability, the search for a universal influenza vaccine receives considerable attention, with a particular focus on vaccines that induce T H cells or antibodies to conserved epitopes 115 , but there are currently no products in late-stage development.

Although BCG is the most widely used vaccine globally, with 89% of the world population receiving it in 2018 (ref. 105 ), there is still a huge global burden of TB and it is clear that more effective TB vaccines are needed. However, the optimal characteristics of a prophylactic TB vaccine, which antigens should be included and the nature of protective immunity remain unknown, despite more than 100 years of TB vaccine research. A viral vector expressing a TB protein, 85A, has been tested in a large TB-prevention trial in South Africa but this vaccine did not show protection, which was attributed by the authors to poor immunogenicity in the vaccinated children 116 . However, the publication of a study in 2019 showing that a novel TB vaccine, M72/AS01E (an AS01-adjuvanted vaccine containing the M. tuberculosis antigens MTB32A and MTB39A), could limit progression to active TB disease in latently infected individuals with efficacy of 50% over 3 years gives a glimmer of hope that TB control may be realized in the future by novel vaccine approaches 117 . Questions remain about the duration of the effect, but the demonstrated efficacy can now be interrogated thoroughly to determine the nature of protective immunity against TB.

Future vaccine development

There are several important diseases for which new vaccines are needed to reduce morbidity and mortality globally, which are likely to have a market in both high-income and low-income countries, including vaccines for group B Streptococcus (a major cause of neonatal meningitis), RSV and CMV. Group B Streptococcus vaccines are currently in trials of maternal vaccination, with the aim of inducing maternal antibodies that cross the placenta and protect the newborn passively 118 . RSV causes a lower respiratory tract infection, bronchiolitis, in infancy and is the commonest cause of infant hospitalization in developed countries and globally one of the leading causes of death in those less than 12 months of age. As many as 60 new RSV vaccine candidates are in development as either maternal vaccines or infant vaccines, or involving immunization with RSV-specific monoclonal antibodies that have an extended half-life. A licensed RSV vaccine would have a huge impact on infant health and paediatric hospital admissions. CMV is a ubiquitous herpesvirus that is responsible for a significant burden of disease in infants; 15–20% of congenitally infected children develop long-term sequelae, most importantly sensorineural hearing loss, and CMV thus causes more congenital disease than any other single infectious agent. A vaccine that effectively prevents congenital infection would provide significant individual and public health benefits. A lack of understanding of the nature of protective immunity against CMV has hampered vaccine development in the past, but the pipeline is now more promising 119 , 120 .

Another major line of development of new vaccines is to combat hospital-acquired infections, particularly with antibiotic-resistant Gram-positive bacteria (such as Staphylococcus aureus ) that are associated with wound infections and intravenous catheters and various Gram-negative organisms (such as Klebsiella spp. and Pseudomonas aeruginosa ). Progress has been slow in this field and an important consideration will be targeting products to the at-risk patient groups before hospital admission or surgery.

Perhaps the largest area of growth for vaccine development is for older adults, with few products aimed specifically at this population currently. With the population of older adults set to increase substantially (the proportion of the population who are more than 60 years of age is expected to increase from 12% to 22% by 2050 (ref. 121 )), prevention of infection in this population should be a public health priority. Efforts to better understand immunosenescence and how to improve vaccine responses in the oldest adults are a major challenge for immunologists today.

Novel technologies

Important challenges to overcome in the following years are genetic diversity (for example, of viruses such as HIV, hepatitis C virus and influenza), the requirement for a broader immune response including T cells for protection against diseases such as TB and malaria, and the need to swiftly respond to emerging pathogens and outbreak situations. Traditionally, vaccine development takes more than 10 years 122 , but the COVID-19 pandemic has demonstrated the urgency for vaccine technologies that are flexible and facilitate rapid development, production and upscaling 123 .

Novel technologies to combat these hurdles will include platforms that allow for improved antigen delivery and ease and speed of production, application of structural biology and immunological knowledge to aid enhanced antigen design and discovery of better adjuvants to improve immunogenicity. Fortunately, recent advances in immunology, systems biology, genomics and bio-informatics offer great opportunities to improve our understanding of the induction of immune responses by vaccines and to transform vaccine development through increasingly rational design 124 .

New platforms include viral vectored vaccines and nucleic acid-based vaccines. Antigen-presenting cells such as dendritic cells, T cell-based vaccines and bacterial vectors are being explored as well, but are still at early stages of development for use against infectious pathogens. Whereas classic whole-organism vaccine platforms require the cultivation of the pathogen, next-generation viral vectored or nucleic acid-based vaccines can be constructed using the pathogen genetic sequence only, thereby significantly increasing the speed of development and manufacturing processes 125 .

Viral vectored vaccines are based on a recombinant virus (either replicating or not), in which the genome is altered to express the target pathogen antigen. The presentation of pathogen antigens in combination with stimuli from the viral vector that mimic natural infection leads to the induction of strong humoral and cellular immune responses without the need for an adjuvant. A potential disadvantage of viral vectored vaccines is the presence of pre-existing immunity when a vector such as human adenovirus is used that commonly causes infection in humans. This can be overcome by using vectors such as a simian adenovirus, against which almost no pre-existing immunity exists in humans 126 . Whether immune responses against the vector will limit its use for repeated vaccinations with different antigens will need to be investigated.

Nucleic acid-based vaccines consist of either DNA or RNA encoding the target antigen, which potentially allows for the induction of both humoral and cellular immune responses once the encoded antigens are expressed by the vaccine recipient after uptake of the nucleic acid by their cells. A huge advantage of these vaccines is that they are highly versatile and quick and easy to adapt and produce in the case of an emerging pathogen. Indeed, the SARS-CoV-2 mRNA-based vaccine mRNA-1273 entered clinical testing just 2 months after the genetic sequence of SARS-CoV-2 was identified 127 and the BNT162b2 lipid nanoparticle-formulated, nucleoside-modified RNA vaccine was the first SARS-CoV-2 vaccine to be licensed 128 . One of the disadvantages of these vaccines is that they need to be delivered directly into cells, which requires specific injection devices, electroporation or a carrier molecule and brings with it a risk of low transfection rate and limited immunogenicity 129 . Furthermore, the application of RNA vaccines has been limited by their lack of stability and requirement for a cold chain, but constant efforts to improve formulations hold promise to overcome these limitations 130 , 131 .

A beautiful example of how immunological insight can revolutionize vaccine development is the novel RSV vaccine DS-Cav1. The RSV surface fusion (F) protein can exist in either a pre-fusion (pre-F) conformation, which facilitates viral entry, or a post-fusion (post-F) form. Whereas previous vaccines mainly contained the post-F form, insight into the atomic-level structure of the protein has allowed for stable expression of the pre-F protein, leading to strongly enhanced immune responses and providing a proof of concept for structure-based vaccine design 132 , 133 .

In addition to the novel vaccine platforms mentioned above, there are ongoing efforts to develop improved methods of antigen delivery, such as liposomes (spherical lipid bilayers), polymeric particles, inorganic particles, outer membrane vesicles and immunostimulating complexes. These, and other methods such as self-assembling protein nanoparticles, have the potential to optimally enhance and skew the immune response to pathogens against which traditional vaccine approaches have proven to be unsuccessful 129 , 134 . Furthermore, innovative delivery methods, such as microneedle patches, are being developed, with the potential advantages of improved thermostability, ease of delivery with minimal pain and safer administration and disposal 135 . An inactivated influenza vaccine delivered by microneedle patch was shown to be well tolerated and immunogenic in a phase I trial 136 . This might allow for self-administration, although it would be important for professional medical care to be available if there is a risk of severe side effects such as anaphylaxis.

Conclusions and future directions

Immunization protects populations from diseases that previously claimed the lives of millions of individuals each year, mostly children. Under the United Nations Convention on the Rights of the Child, every child has the right to the best possible health, and by extrapolation a right to be vaccinated.

Despite the outstanding success of vaccination in protecting the health of our children, there are important knowledge gaps and challenges to be addressed. An incomplete understanding of immune mechanisms of protection and the lack of solutions to overcome antigenic variability have hampered the design of effective vaccines against major diseases such as HIV/AIDS and TB. Huge efforts have resulted in the licensure of a partially effective vaccine against malaria, but more effective vaccines will be needed to defeat this disease. Moreover, it is becoming clear that variation in host response is an important factor to take into account. New technologies and analytical methods will aid the delineation of the complex immune mechanisms involved, and this knowledge will be important to design effective vaccines for the future.

Apart from the scientific challenges, sociopolitical barriers stand in the way of safe and effective vaccination for all. Access to vaccines is one of the greatest obstacles, and improving infrastructure, continuing education and enhancing community engagement will be essential to improve this, and novel delivery platforms that eliminate the need for a cold chain could have great implications. There is a growing subset of the population who are sceptical about vaccination and this requires a response from the scientific community to provide transparency about the existing knowledge gaps and strategies to overcome these. Constructive collaboration between scientists and between scientific institutions, governments and industry will be imperative to move forwards. The COVID-19 pandemic has indeed shown that, in the case of an emergency, many parties with different incentives can come together to ensure that vaccines are being developed at unprecedented speed but has also highlighted some of the challenges of national and commercial interests. As immunologists, we have a responsibility to create an environment where immunization is normal, the science is accessible and robust, and access to vaccination is a right and expectation.

Change history

05 january 2021.

A Correction to this paper has been published: https://doi.org/10.1038/s41577-020-00497-5.

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Acknowledgements

The authors thank all those whose work in the development, policy and delivery of vaccines underpins immunization programmes to defend our health and the health of our children.

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Andrew J. Pollard & Else M. Bijker

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A.J.P. is Chair of the UK Department of Health and Social Care’s (DHSC) Joint Committee on Vaccination and Immunisation (JCVI), a member of the World Health Organization (WHO) Strategic Advisory Group of Experts on Immunization (SAGE) and a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article do not necessarily represent the views of the DHSC, JCVI, NIHR or WHO. E.M.B. declares no competing interests. Oxford University has entered into a partnership with AstraZeneca for the development of a viral vectored coronavirus vaccine.

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Supplementary information

Supplementary information.

Parts of the pathogen (such as proteins or polysaccharides) that are recognized by the immune system and can be used to induce an immune response by vaccination.

The state in which an individual does not develop disease after being exposed to a pathogen.

A reduction in the virulence of a pathogen (through either deliberate or natural changes in virulence genes).

Particles constructed of viral proteins that structurally mimic the native virus but lack the viral genome.

An agent used in a vaccine to enhance the immune response against the antigen.

Molecules that stimulate a more robust immune response together with an antigen. Endogenous mediators that are released in response to infection or injury and that interact with pattern recognition receptors such as Toll-like receptors to activate innate immune cells such as dendritic cells.

The evolutionarily primitive part of the immune system that detects foreign antigens in a non-specific manner.

A liposome-based adjuvant containing 3- O -desacyl-4′-monophosphoryl lipid A and the saponin QS-21. AS01 triggers the innate immune system immediately after vaccination, resulting in an enhanced adaptive immune response.

An adjuvant consisting of aluminium salt and the Toll-like receptor agonist monophosphoryl lipid A.

A network of proteins that form an important part of the immune response by enhancing the opsonization of pathogens, cell lysis and inflammation.

A state of a pathogen in which antibodies or complement factors are bound to its surface.

Antibodies that bind to a pathogen, which subsequently can be eliminated by phagocytosis.

Antigens against which B cells can mount an antibody response without T cell help.

An antigen for which T cell help is required in order for B cells to mount an antibody response.

Studies in which volunteers are deliberately infected with a pathogen, in a carefully conducted study, to evaluate the biology of infection and the efficacy of drugs and vaccines.

The capacity of the immune system to respond quicker and more effectively when a pathogen is encountered again after an initial exposure that induced antigen-specific B cells and T cells.

The period from acquisition of a pathogen to the development of symptomatic disease.

Repeat administration of a vaccine after an initial priming dose, given in order to enhance the immune response.

An assay in which blood is stimulated with Mycobacterium tuberculosis antigens, after which levels of interferon-γ (produced by specific memory T cells if these are present) are measured.

Changes in the expression of genes that do not result from changes in DNA sequence.

A severe and potentially life-threatening reaction to an allergen.

Vaccines that are administered by means avoiding the gastrointestinal tract (for example, by intramuscular, subcutaneous or intradermal routes).

An acquired autoimmune condition characterized by low levels of platelets in the blood caused by antibodies to platelet antigens.

A rare chronic sleep disorder characterized by extreme sleepiness during the day and sudden sleep attacks.

Vaccines that are intended for a limited scope or targeting infections that are rare, as a result of which development costs exceed their market potential.

Blebs made from the outer membrane of Gram-negative bacteria, containing the surface proteins and lipids of the organism in the membrane.

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Pollard, A.J., Bijker, E.M. A guide to vaccinology: from basic principles to new developments. Nat Rev Immunol 21 , 83–100 (2021). https://doi.org/10.1038/s41577-020-00479-7

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CDC’s vaccine safety systems help ensure vaccines are as safe as possible. These monitoring systems help scientists conduct high-quality vaccine safety research. This research is then peer-reviewed and published in reputable scientific outlets.

CDC also closely partners with other federal, state, and local agencies, as well as private entities, to monitor and communicate about the safety of vaccines.

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In 2014, AHRQ developed a report based on a systematic review of vaccine safety that builds upon the 2011 Institute of Medicine (IOM) report: Adverse Effects of Vaccines: Evidence and Causality.   Since the first report came out, the vaccination schedule evolved to include newly approved vaccines and changes to several existing vaccines.

Safety of Vaccines Used for Routine Immunization in the United States: An Update – 2021

Agency for Healthcare Research and Quality. Safety of Vaccines Used for Routine Immunization in the United States: An Update. external icon AHRQ Publication No. 21-EHC024 May 2021.

In May 2021, AHRQ released an updated report of the Safety of Vaccines Used for Routine Immunization in the United States. Researchers conducted a systematic review of the published scientific research (literature) on the following vaccines, which are recommended for routine immunization in adults, pregnant people and children and adolescents:

• Diphtheria, Tetanus and Acellular Pertussis (DTaP)
• Haemophilus influenzae type b (Hib)
• Hepatitis A
• Hepatitis B
• Human Papillomavirus (Gardasil)
• Influenza (inactivated, recombinant and live)
• Inactivated Polio
• Measles, Mumps, and Rubella (MMR)
• Meningococcal ACWY
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• Pneumococcal (13- and 23-valent)
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• Tetanus, diphtheria and acellular pertussis (Tdap)
• Shingles (Shingrix)
• Varicella (chickenpox)

For this update, researchers reviewed nearly 57,000 citations and found 189 studies that addressed key questions evaluating the vaccines above and in the specific populations, adding to data in the prior 2014 report, for a total of 338 included studies reported in 518 publications.

Safety signals from the prior report remain unchanged for adverse events, including:

• Anaphylaxis in adults and children
• Febrile seizures in children
• Idiopathic Thrombocytopenia Purpura in children

This report did not find any new evidence of increased risk for key adverse events following administration of vaccines that are routinely recommended for adults, children, and pregnant people. There remains insufficient evidence to make conclusions about some rare potential adverse events.

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Founded in 1970 as IOM, NAM is one of three academies that make up the National Academies of Sciences, Engineering, and Medicine external icon  (the National Academies) in the United States. As part of a restructuring of the National Academies in 2015, IOM became NAM. The National Academies are private, nonprofit institutions that work outside of government to provide objective advice on matters of science, technology, and health.

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The IOM convened the Committee on Assessment of Studies of Health Outcomes Related to the Recommended Childhood Immunization Schedule to conduct an independent evaluation of the safety of the childhood immunization schedule.

The IOM issued their report on January 16, 2013. In it, the Committee expressed support for the recommended childhood immunization schedule as a tool to protect against vaccine-preventable diseases . The Committee recommended using healthcare records data to continue studying the safety of vaccines. The Committee also reconfirmed a finding of the National Vaccine Advisory Committee (NVAC) pdf icon external icon  white paper  that said conducting a study requiring some children to receive fewer vaccines than recommended, as would be needed for a randomized controlled trial, would be unethical. However, the committee concluded that the Vaccine Safety Datalink (VSD) is the best available system for studying the safety of the immunization schedule in the United States.

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HHS charged the IOM with providing a thorough review of the current medical and scientific evidence on vaccines and vaccine adverse events.

The IOM Committee on Vaccines and Adverse Events released its report on August 25, 2011. This analysis was used to update the Vaccine Injury Table pdf icon [PDF – 12 Pages] external icon for the National Vaccine Injury Compensation Program (VICP) external icon . The report provides a scientific basis for future review and decisions on VICP claims. The IOM Committee used peer-reviewed literature to review eight vaccines given to children or adults:

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• Diphtheria-toxoid-, tetanus toxoid-, and acellular pertussis-containing vaccines

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A systematic review of studies that measure parental vaccine attitudes and beliefs in childhood vaccination

• Amalie Dyda   ORCID: orcid.org/0000-0003-2806-4834 1 , 2 ,
• Catherine King 3 , 4 ,
• Aditi Dey 3 , 5 ,
• Julie Leask 6 , 3 &
• Adam G. Dunn 7 , 1  

BMC Public Health volume  20 , Article number:  1253 ( 2020 ) Cite this article

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Acceptance of vaccines is an important predictor of vaccine uptake. This has public health implications as those who are not vaccinated are at a higher risk of infection from vaccine preventable diseases. We aimed to examine how parental attitudes and beliefs towards childhood vaccination were measured in questionnaires through a systematic review of the literature .

We systematically reviewed the literature to identify primary research studies using tools to measure vaccine attitudes and beliefs, published between January 2012 and May 2018. Studies were included if they involved a quantitative survey of the attitudes and beliefs of parents about vaccinations recommended for children. We undertook a synthesis of the results with a focus on evaluating the tools used to measure hesitancy.

A total of 116 studies met the inclusion criteria, 99 used a cross sectional study design, 5 used a case control study design, 4 used a pre-post study design and 8 used mixed methods study designs. Sample sizes of included studies ranged from 49 to 12,259. The most commonly used tool was the Parent Attitudes about Childhood Vaccines (PACV) Survey ( n  = 7). The most common theoretical framework used was the Health Belief Model ( n  = 25). Questions eliciting vaccination attitudes and beliefs varied widely.

Conclusions

There was heterogeneity in the types of questionnaires used in studies investigating attitudes and beliefs about vaccination in parents. Methods to measure parental attitudes and beliefs about vaccination could be improved with validated and standardised yet flexible instruments. The use of a standard set of questions should be encouraged in this area of study.

Peer Review reports

Childhood vaccination rates vary widely by country and region, and the reasons for these variations are likely to be context-specific [ 1 , 2 , 3 ]. While access to vaccination is a perennial challenge, acceptance also remains an issue of importance to uptake which is affected by an individual’s feelings, attitudes and beliefs about vaccination [ 4 ]. There is a spectrum of attitudes towards vaccination, including those who are pro-vaccination and accept all vaccines, those who have many concerns but may fully or partially vaccinate, and those who refuse all vaccines [ 5 ]. Those who have questions and concerns have been shown to have lower levels of vaccination uptake [ 6 ] which may have a substantial impact on vaccination coverage and increases the risk of outbreaks [ 7 ]. Not only are unvaccinated individuals at higher risk of infection and adverse health outcomes, but under-vaccinated populations are at higher risk of more severe outbreaks [ 8 , 9 , 10 ].

A range of questionnaires have been developed and tested for measuring vaccination attitudes and beliefs [ 11 ]. The largest recent questionnaires in the area include The Vaccine Confidence Project [ 12 ] which collected 65,819 responses across 67 countries [ 13 ], and the Wellcome Global Monitor 2018 [ 14 ], which collected more than 140,000 responses from 140 countries. Both were based on the same set of questions, which included items about vaccine importance, effectiveness, safety, and religious compatibility.

Studies using questionnaires to understand vaccine attitudes and beliefs often modify existing items to incorporate the local context of a specific country or region. There is high variability with respect to use of behavioural theories to inform constructs and items and the comprehensiveness of validation, such as whether the items predict vaccination uptake. Moreover, high variability in how constructs such as vaccine confidence are measured between different questionnaires makes it difficult to assess how attitudes and beliefs vary globally.

Our aim was to examine how parental attitudes and beliefs towards childhood vaccination were measured in questionnaires through a systematic review of the literature.

Inclusion criteria

Studies were included if they were quantitative primary studies investigating parental vaccine attitudes and/or beliefs, regardless of whether they considered one or a combination of vaccines or vaccine-preventable diseases. For the purpose of this review studies on vaccine hesitancy were included, with vaccine hesitancy defined as “a motivational state of being conflicted about, or opposed to, getting vaccinated” [ 15 ]. Vaccine hesitancy can result in “a delay in acceptance or refusal of vaccines despite availability of vaccination services” [ 16 ]. Studies published after January 2012 were included. Studies were excluded if they investigated vaccination barriers not associated with attitudes or beliefs (e.g. measuring access other than as a factor affecting convenience), adult and adolescent vaccination, or if they were not reported in English. We applied no geographical constraints.

Search strategy

This review was developed in line with the PRISMA guidelines [ 17 ]. Key bibliographic databases were searched to identify relevant articles. The 19 databases searched included: OVID Medline, PsycINFO and Database of Systematic Reviews (see Additional File  1 for the full list of databases searched) Search terms included thesaurus terms (where available) such as ‘Immunization’, ‘Immunization programs’, ‘Vaccines’, ‘Decision Making’, ‘Decision Theory’, ‘Attitude to Health’, ‘Health Behavior’, ‘Risk Assessment’, ‘Trust’, ‘Uncertainty’, ‘Vaccination Refusal’, ‘Anti-Vaccination movement’, ‘Child, Preschool’ and ‘Infant’ These were used with relevant associated text terms. Truncation was utilised to ensure all variant spelling endings of text words were retrieved. The searches were limited to items published from 2012 and ‘Humans’. (see Additional File 1 for the full search strategy). The last search was conducted on 19 May 2018. Articles reviewed for inclusion were limited from January 2012 to May 2018 to avoid duplicating the findings of a 2014 systematic review that reviewed the global literature on vaccine hesitancy [ 5 ].

All titles and abstracts or executive summaries found through the search strategy were screened independently by two authors (Adam Dunn and Amalie Dyda) to determine if they were relevant to the review. The full text of those articles that appeared to meet the inclusion criteria were retrieved and reviewed for relevance independently by the same two authors. The reference lists of all included items were searched to identify any additional items for inclusion.

Data extraction and synthesis

Data were extracted by one author (Amalie Dyda) and confirmed by a second author (Adam Dunn). A standard data extraction form developed by the authors was used. For each study, study design information extracted from the articles included the method of recruitment and the location and type of participants, the number of participants recruited (and completing the study, where appropriate), the vaccine or set of vaccines of relevance to the study, and details of the questions used to measure attitudes and belief about vaccination including any description of behavioural theories used to inform the questionnaire design, and whether the questions were taken directly or adapted from existing instruments. We defined validated questionnaires as those that followed “the process of establishing that a survey item or measure serves the intended purpose. This process can include establishing whether it measures the intended construct using qualitative means (advice from experts, cognitive testing with lay people) and quantitative means (convergent, discriminant, predictive validity)” [ 18 ]. Data extracted from each study were tabulated and grouped by study type and study characteristics including sample size, recruitment method, and location.

The initial search strategy returned 41,570 titles and abstracts, of which 23,201 were removed as duplicates. Title and abstract screening identified 673 full text items for review. Of these, 116 met the inclusion criteria (Fig.  1 ). A review of the reference lists of included articles did not identify any additional items for inclusion.

Summary of the search strategy results and set of included studies

Summary of included studies

Of the included studies, 99 (85.3%) used a cross sectional study design (Additional File  2 ). Sample sizes across all 116 included studies ranged from 49 to 12,259 participants, with a median of 455 participants. Parental attitudes and beliefs about childhood vaccines in general were studied in 57 (49.1%) studies, and attitudes and beliefs about influenza vaccination (including pandemic H1N1 influenza) in 35 (30.2%). The other 24 (20.7%) studies asked participants about attitudes and beliefs for other specific vaccines, such as polio and rotavirus vaccines.

Thirty-four countries were represented in the included studies (Fig.  2 ). The most common country in which studies were conducted was the United States ( n  = 36), followed by Canada ( n  = 9) and the United Kingdom ( n  = 8). When aggregated by the number of participants, the United States included the largest number (40,155 participants), followed by Canada (7200 participants), and the United Kingdom (3273 participants).

Among the set of 116 included studies, 34 countries were represented

Questionnaires and survey instruments

One hundred and fourteen studies used a survey design, with the two remaining studies using interviews. The questions asked of participants varied substantially across the set of included studies. There was heterogeneity both in terms of the specific questions asked of participants as well as the provenance of those questions in theory or from standardised questionnaire sets. Sixty three studies reported at least one aspect of validation.

The most commonly used standard questionnaire was the Parent Attitudes about Childhood Vaccines (PACV) Survey Tool ( n  = 7), used in 4 studies with its full format with 15 questions [ 19 , 20 , 21 , 22 ]. In some studies, the PACV questions were adapted to match the local context or study population, such as in Malaysia [ 21 ] and for expectant parents in the United States [ 19 ]. In 3 studies, a subset of the PACV questions were used [ 23 , 24 , 25 ]. Other questionnaires used included 6 studies based on national immunisation surveys or health department questionnaires [ 26 , 27 , 28 , 29 , 30 , 31 ], 1 study based on the Parental Attitudes toward MMR Vaccine and Trust in Medical Authority questionnaire [ 32 ], and 1 that used the Vaccine Safety, Attitudes, Training and Communication measures [ 33 ].

A total of 62 (53.4%) included studies developed questionnaires using previous literature or previously developed questionnaires, 7 developed questionnaires with experts in the field, 1 used a self-developed scale, and 6 conducted a qualitative data to elicit appropriate questions. The remaining 40 studies did not report having used previous examples as the basis for the designs of their questionnaires.

A variety of theoretical frameworks were used to inform the design of the questionnaires used in the studies. The most common was the Health Belief Model (HBM), which was explicitly stated as having been used to inform the questions in 25 (19.0%) studies [ 30 , 32 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], followed by the Theory of Planned Behaviour, which was used in 5 (4.3%) studies [ 58 , 59 , 60 , 61 , 62 , 63 ]. Other studies that were adapted from existing questionnaires may have implicitly been based on these or other theoretical frameworks as a consequence of having adapted from other questionnaires but did not explicitly claim the theoretical framework as a basis for their questions.

Questions about intention to vaccinate

Of the 116 included studies, 38 (32.8%) included questions in which parents were directly asked about their vaccination intentions for one or more antigens. The specific questions that were asked varied across the set of studies. Examples included, “If you had another infant today, would you want him or her to get all the recommended shots?, “I would get a flu vaccine for my child under 5, every year, if it was free?”, and “If your child were offered it at some point in the future, would you vaccinate them against swine flu?”. This variation precluded a synthesis of the results, and the proportion of participants responding in the affirmative varied substantially across the set of studies.

Of the 38 studies which asked about vaccination intentions for one or more antigens, 16 (13.8%) of these specifically asked about whether they would have children vaccinated for all childhood vaccines. The percentages in these studies ranged from 75% in a study involving 200 parents in the United States [ 64 ] to 98% in a study involving 54 parents in Canada [ 35 ]. For the 9 (7.8%) studies that asked about intentions in relation to influenza vaccination, the percentages ranged from 29% in a study involving 236 parents in Canada [ 65 ] to 92% in a before and after study at a clinic involving 5284 and 5755 different groups of parents in rural Kenya [ 66 ].

A substantial number of studies quantitatively examine the childhood vaccination attitudes and beliefs of parents across a broad range of countries. A large number of studies did not report using a validated questionnaire. The countries in which the highest number of studies were conducted were the United States, Canada and the United Kingdom, with most other countries having either none or only a small number of studies. There were significant differences in the way in which questionnaires were developed and the questions asked in each of the studies, making synthesis or comparison of findings a challenge. The use of standardised questionnaires globally would allow findings across countries to be compared and help track longitudinal trends.

The geographical distribution of primary studies included in the review was generally consistent with a previous review on attitudes and beliefs regarding vaccination [ 5 ], in which most included studies were conducted in North America and Europe. Among the subset of studies that used standardised questionnaires, there was no clear difference in rates of vaccine hesitancy between countries, nor any clear pattern in the attitudes and beliefs that exhibited the strongest associations with intention. Given that only a relatively small subset used standardised questionnaires, this result is a reflection of the small number of studies rather than evidence of consistency in what matters most to parents exhibiting vaccine hesitancy.

There was little consistency in the provenance of the questions used to measure attitudes and beliefs across studies. A number of studies did not report how the questionnaire or survey instrument was developed, making comparison of these studies difficult. The majority of studies reported construct and item development methods such as basing the questionnaire on previous literature, expert opinion or the use of previously developed surveys.

The use of qualitative evidence is best practice for forming constructs [ 67 ] and the use of a previously validated questionnaire is the most appropriate methodology as this ensures that items have content, construct and predictive validity. Previously developed questionnaires which are not validated may not accurately capture information, which is then repeated if these questionnaires are reused [ 18 ]. However, as there is no agreed upon gold standard survey instrument, a wide range of sources were used for development, resulting in heterogeneity of questionnaires. The most commonly used standard questionnaire was the PACV Survey Tool, which has been validated in two different settings and been shown to identify vaccine hesitant parents. The questionnaire focuses on the domains of ‘Safety and efficacy’, ‘General attitudes’ and ‘Behaviour’ [ 68 , 69 ]. The use of this questionnaire for studies investigating vaccine hesitancy should be encouraged to better allow for comparison across studies.

For theoretical frameworks, we found that the HBM was most commonly used to support the development of questionnaires, which was consistent with previous reviews [ 5 ]. The HBM posits that perceptions of susceptibility, severity, benefit and barriers, cues to action and self-efficacy predict behaviour. This and other models place emphasis on risk appraisals as important predictors of vaccination. Use of the HBM is complicated by the fact that all related perceptions could apply to vaccination uptake as much as disease outcomes. Since these models look at individual psychological factors by design, they are weaker at measuring other factors like false contraindications, social influence, or access to services or vaccines, which are more likely to be effective in increasing uptake, if they are addressed [ 15 ]. Further, many models fail to measure trust, yet trust in vaccination arises as a relevant phenomenon in both qualitative accounts of under-vaccination and the influence of vaccine safety scares [ 15 ]. Trust is often “ill-defined and a loosely measured concept” [ 70 ]. Recent work on the moral foundations of behaviour suggests that measuring constructs such as contamination and liberty are also relevant [ 71 , 72 ]. Further work is needed to incorporate moral foundations, other feelings and attitudes and beliefs and trust into a single model of vaccination behaviour and test its robustness.

Future studies in this area may benefit from considering standardised questions on vaccine attitudes and beliefs and other barriers or facilitators [ 11 ]. Large international surveys based on a standardised set of questions may be useful for providing international comparisons with context-specific additional questions. To consider the local context, qualitative investigations could supplement the broad based quantitative knowledge from surveys. Both forms of data collection are useful but are also resource intensive and relatively slow to report.

Current outbreaks of measles in the US highlight the importance of monitoring and measuring attitudes and beliefs about vaccinations. From 1st January to 18th July 2019 there were a total of 1148 cases of measles identified in the US which is the largest number of infections reported since 1992. Outbreaks are occurring across a number of states, with an outbreak in Rockland County, reporting the majority (78.4%) of cases have not been vaccinated [ 73 ].

The development of the internet has increased the speed with which information and misinformation can spread in the community. This may outpace our ability to measure and report on attitudes and beliefs using current survey methods which are time and resource intensive. Due to the time lag involved, using these methods may limit the ability to support the rapid design of evidence-informed and localised interventions for debunking or mitigating the impact of misinformation.

There were several limitations to the review approach and conduct. The first limitation was that the geographical distribution of the studies included in the review may be biased by the exclusion of studies not written in English. In addition, parental beliefs and attitudes towards influenza vaccination often differ from routine childhood vaccinations [ 74 ]. This childhood vaccine was included as some countries recommend annual influenza vaccination, but this is unlikely to affect the findings regarding tools used to monitor attitudes and beliefs about vaccination.

Despite the number of studies investigating parental attitudes and beliefs about childhood vaccination which were conducted in at least 36 countries, there was heterogeneity in survey designs. Methods to measure parental attitudes and beliefs about vaccination could be improved with validated and standardised yet flexible instruments, supplemented with qualitative investigations. The use of a standard set of validated questions should be encouraged in this area of study to identify, track, and monitor longitudinal trends using quality data.

Availability of data and materials

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Abbreviations

Health belief model

Parent attitudes about childhood vaccines

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Acknowledgements

This project was funded by the Australian National Health and Medical Research Council (NHMRC) Project Grant APP1128968. The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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A.Dyda led the design and coordination of the review. CK designed and conducted the literature searches and was a contributor in writing the manuscript. A. Dey assisted in the design of the review and provided critical intellectual content throughout. JL was a major contributor to the design of the review and provided critical intellectual content throughout. A. Dunn was also was a major contributor to the design of the review, and assisted with removing duplicates and screening of titles, abstracts and full review of papers for inclusion. All authors contributed to the revision of the manuscript and provided intellectual content. All authors read and approved the final manuscript.

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Supplementary information

Additional file 1..

Search strategy. Detailed description of search strategy used for review.

Additional file 2: Table 1.

Summary of included studies. Summary table of each included study with details about study characteristics.

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Dyda, A., King, C., Dey, A. et al. A systematic review of studies that measure parental vaccine attitudes and beliefs in childhood vaccination. BMC Public Health 20 , 1253 (2020). https://doi.org/10.1186/s12889-020-09327-8

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• Immunization/immunisation
• Vaccination
• Vaccines, questionnaire

BMC Public Health

ISSN: 1471-2458

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• Research article
• Open access
• Published: 25 January 2014

Are parents' knowledge and practice regarding immunization related to pediatrics’ immunization compliance? a mixed method study

• Omer Qutaiba B Al-lela 1 ,
• Mohd Baidi Bahari 2 ,
• Harith Khalid Al-Qazaz 3 ,
• Muhannad RM Salih 4 ,
• Shazia Q Jamshed 5 &
• Ramadan M Elkalmi 5  

BMC Pediatrics volume  14 , Article number:  20 ( 2014 ) Cite this article

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Immunization rate is one of the best public health outcome and service indicators of the last 100 years. Parental decisions regarding immunization are very important to improve immunization rate. The aim of this study was to evaluate the correlation between parental knowledge-practices (KP) and children's immunization completeness.

A mixed method has been utilized in this study: a retrospective cohort study was used to evaluate immunization completeness; a prospective cross-sectional study was used to evaluate immunization KP of parents. 528 children born between 1 January 2003 and 31 June 2008 were randomly selected from five public health clinics in Mosul, Iraq. Immunization history of each child was collected retrospectively from their immunization record/card.

About half of studied children (n = 286, 56.3%) were immunized with all vaccination doses; these children were considered as having had complete immunization. 66.1% of the parents was found to have adequate KP scores. A significant association of immunization completeness with total KP groups (p < 0.05) was found.

Conclusions

Future efforts are required to improve immunization rate and parents' knowledge and practice. The study results reinforce recommendations for the periodic assessment of immunization rate and the use of educational programmes to improve the immunization rate, knowledge and practice.

Peer Review reports

Parental decisions regarding immunization are very important for increasing the immunization rate and compliance and for decreasing any possible immunization errors. Parents’ knowledge and practices regarding immunization are the major factors that contribute to their vaccination decisions [ 1 ].

There are many barriers against immunization, including misinformation about vaccines, adverse effects of vaccines, vaccine-preventable diseases, and disease development after the administration of vaccines [ 1 – 3 ]. Deficiencies in parents’ knowledge about the adverse effects and contraindications of vaccines often lead to many immunization errors. Many parents believe that mild illness is associated with vaccine contraindication, therefore mild illness is considered as a reason for not giving their children up-to-date vaccinations [ 4 – 6 ].

To improve parents’ awareness, good knowledge regarding vaccination is required. Therefore, physicians, pharmacists, nurses, and others health care providers should provide parents with correct information about the risks and benefits of vaccines [ 7 ]. Many studies showed that parents’ knowledge regarding child immunization varies according to the family physician and other medical staff [ 8 – 10 ]. Although parents would like to know about the adverse effects, the benefits and other information about vaccines, many physicians include vaccine risk in their discussions with parents without comparing it to the risks involved in infectious disease [ 11 ].

Good parental practice regarding immunization will be able to reduce the incidence of infectious diseases. Parental practice regarding vaccination is related to appropriate sources of information, the number of sources, and the way that vaccine information is received by parents. The sources of information provided by maternity clinics, the media, literature, and the internet cover vaccination benefits and the risks of vaccine-preventable diseases [ 12 , 13 ].

The most important factor affecting parental practice is communication between parents and the sources of information or immunization providers. Improving communication will improve parents’ perceptions of the benefits and risks of vaccines [ 14 – 18 ]. Parents will be more likely to continue with their child’s immunization, although at the same time they may still be doubtful about vaccination. In addition, parents may agree to proceed with their child’s vaccination, but they are also vulnerable to competing sources of information from anti-immunization proponents. This does not always mean that parents possess the knowledge and practice that constitute informed consent prior to assenting to immunization.

Most of the previous studies found a strong relationship between paediatric immunization coverage and parental knowledge and vaccination practices. This relationship showed a positive correlation between these factors. In other words, any increase in parental knowledge and practice will lead to increases in vaccination rates of children [ 19 – 24 ]. This study will provide a clear information regarding immunization in Iraq and parent knowledge- practice on paediatrics’ immunization.

An observational non-experimental cohort study design was utilized to evaluate immunization rate among children younger than 2 years of age (born between 1 January 2003 and 31 June 2008). Each child had an immunization card for recording details of the immunizations received. A prospective cross-sectional study design was used to determine parental immunization knowledge and practices in Iraq, where the data were collected through a developed and validated questionnaire via interviews [ 18 ].

This study only covered the types of vaccines administered before 2 years of age: Bacille Calmette-Guérin (BCG) vaccine, oral polio vaccine (OPV), diphtheria-tetanus-pertussis (DTP) vaccine, hepatitis B virus (Hep B or HBV) vaccine, measles-mumps-rubella (MMR) vaccine, and the measles vaccine. A child was considered up to date if the following immunizations had been received by 2 years of age: one BCG dose, five polio vaccine doses (OPV), four DTP vaccine doses, three HBV vaccine doses, and one MMR vaccine dose.

The immunization status of the children was classified into two groups depending on immunization completeness: complete immunization and partial immunization . When a child received all immunization doses, this child was considered to have had complete immunization. If a child missed at least one immunization dose, then this child was considered to have had partial immunization .

The assessment of immunization knowledge and practices by developed and translated questionnaire was adapted from previous study [ 18 ]. The immunization knowledge and practices questionnaire consisted of 20 (10 questions on knowledge and 10 questions about practices) single-choice questions from a multiple answers provided in each equation, as shown in Table  1 .

Scoring of the questions was determined by giving one point (1) for each correct answer and zero (0) for wrong answers or no response (don’t know). The total knowledge scores and practice scores of the parents were calculated by adding up the scores for each question in the test. The total knowledge and practice scores ranged from 0 to 20, with higher scores indicating a higher level of immunization knowledge and practices. According to the median split method [ 25 – 27 ], parents with a total score of less than 12 (median) were considered as having inadequate knowledge and practices regarding child immunization and parents with scores from 12 to 20 were considered as having adequate knowledge and practices. This scoring method and categorization were used to identify the degree of parental immunization knowledge and practices in the current study.

According to the Iraqi Ministry of Health Survey in 2008, a total of 116,000 children were to be immunized in Mosul [ 28 ]; the present study used this number as the total population from which the sample size was drawn. An automated software program (Raosoft sample size calculator for study: http://www.raosoft.com/samplesize.html ) was used to calculate the sample size required for this study. With an accepted margin of error of 5% and a 95% confidence interval, the sample size required was 383. With the addition of 30% (as expected drop outs) to the estimated sample size in order to overcome erroneous results and increase the reliability of the results and the conclusion, the target sample size was 500 children.

Most of the Iraqi children received their immunization doses from general and public health clinics. Cluster sampling method was used in this study. Mosul divided to five parts or clusters depending on the Mosul map. One health clinics selected from each cluster in Mosul (five health clinics from five different area or clusters). These public health clinics operate three immunization days per week (Sunday, Tuesday, and Thursday), from 9.00 am. to 2.00 pm. Approximately 25 children attend these health clinics per day. Private clinics and hospitals were not included in the setting for this study due to accessibility problems and differences in socioeconomic status.

The research proposal was submitted to the Iraqi Ministry of Health (MOH) in Baghdad, Iraq. Approval from the MOH (Reference no. 70667 in 15/12/2009) was obtained to facilitate the data collection by researchers from health clinics under Iraqi Ministry of Health before data collection was started. The parents and clinic staff were informed about the study aims and other details. The parents who were agreed to participate in the research had to sign the provided consent form before filling in the questionnaire. Most of the Iraqi children received their immunization doses from general and public health clinics. Five health clinics in different areas were selected in Mosul city, Iraq.

The data were analysed using SPSS for windows (Statistical Package for Social Science) version 20 and the level of significance was set at less than 0.05 for all analyses. Study samples were non-normal distributed, Mann–Whitney U test and Chi-square test were used in this study to evaluate the difference and association of KP among and with difference groups, respectively.

A total of 528 children and parents were recruited randomly in this study. Two hundred and eighty-sex children were immunized with all vaccination doses (56.3%); these children were considered as having had complete immunization, but less than half of the children had one or more than one missed doses and were considered as having had partial immunization.

The total knowledge-practice scores ranged from zero to 20 and the result showed an average of 12.28 (SD = 2.95), with a median score of 12. Using the categorization of the knowledge-practice scores explained in the median split method, we formed two groups of adequate and inadequate knowledge-practice of parents respectively. Out of the 528 parents who answered the questionnaire, 66.1% of the study population was found to have adequate knowledge-practice scores, whereas 33.9% were found to have inadequate knowledge-practice scores.

Table  1 shows the 20 statements of knowledge and practice. This scale consisted of two parts. The first part contained 10 statements of knowledge (1–10) and the second contained 10 statements of practice (11–20). The lowest correct answer (10.6%) was apparent in the question (8) related to the knowledge of vaccine storage, as in statements 2, 7, 18, and 20, for which the percentage of correct answers was 35.4%, 39%, 23.7%, and 40.2% respectively. The highest correct answer (96%) was apparent in the statement related to the practice of vaccine recommendation (12), as in statements 1, 6, 11, and 13, for which the percentage of correct answers was 84.7%, 81.6%, 93.9%, and 85.4%, respectively.

The study found a significant association of immunization completeness with total knowledge and practice groups ( p  < 0.05). A higher percentage of parents with adequate knowledge and practice were found for children with complete immunization (71.7%) and partial immunization (59.5) than other groups, as shown in Table  2 .

The Mann–Whitney test was used to find differences in knowledge and practice scores between immunization completeness groups. Table  3 shows the differences in knowledge and practice scores among variable groups. Significant differences in the knowledge- practice scores were shown among immunization completeness groups.

According to the findings, the children were vaccinated as a result of various reasons: the parents had a good perception of vaccination benefits and risks; the parents thought that the immunization was mandatory; and/or the parents knew that immunization was required for school registration or day care attendance [ 29 , 30 ].

Many reasons were found for not vaccinating children or not completing the vaccination schedule; firstly, this may have been due to a lack of vaccination information among parents or health care providers. Inadequate information on vaccination status may lead to inappropriately timed or missed immunizations, resulting in decreased protection against diseases, increased side effects, and increased costs [ 31 , 32 ]. Secondly, this may have been due to the immunization card or clinical records not providing a clear and complete immunization record. The immunization card is very important for the immunization provider to be able to determine which vaccination is due on a child’s visit. In addition, the immunization card is important for parents to be able to determine or check their child’s immunization status [ 30 , 32 ].

Few studies have determined parental knowledge and practice related to childhood immunization and examined the association with children’s immunization status [ 33 , 34 ]. This study is the first to evaluate Arab and Iraqi parents' knowledge and practice and to determine the relationship of knowledge and practice of parents with immunization status of children younger than two.

The result of this study was similar to other findings in an Italian study [ 35 ] in which 57.8% of parents had adequate knowledge-attitude-practice (KAP), and is supported by a study in India [ 24 ] that found parental knowledge regarding vaccination adequate.

Although the situation in Iraq after 2003 was critical, causing some families to flee from one area to another area, and many changes in their immunization and health providers occurred, this study found that most Iraqi parents had adequate knowledge and good practice regarding child vaccination. This could be because of an increase in sources of vaccination and health information represented by television, the internet and other sources. Before 2003, many restrictions were imposed on the media, especially television and the internet, whereas an increase in the number of international medical and scientific TV channels, and an increase in internet users especially after 2003 are the important causes of the increase in parents' immunization practice and in immunization knowledge [ 36 ]. In addition, it should be highlighted that a difference in knowledge and practice scores does not imply a lack of intelligence in any of the parental groups. Historical insufficiency regarding vaccination knowledge practice and also variations in past education, health services and health education underlie the findings.

Most parents were in favour of immunization for children and thought that vaccination would prevent infectious diseases in the future, as shown in question 1 when more than 83% of parents gave the correct answer. The finding is similar to results in other studies [ 22 , 37 ] in which more than 90% of parents favoured child vaccination. Although most parents knew that vaccines prevent diseases, more than 60% did not know that vaccination was for all ages but only applied to children below school age (six years). This erroneous parental behaviour regarding vaccination age may have two causes; the general idea of Iraqi families that important and necessary vaccinations should be given before school age, and the low availability in health clinics and private pharmacies of vaccines appropriate for people older than six. This negative finding is inconsistent with the positive finding in another study [ 22 ] in which more than 70% of parents knew that vaccination was for all ages without exception.

Questions 3, 4, and 5 are related to vaccine types. Most parents (70.8%) knew that there were two different vaccine types. More than 35% of parents did not know what active vaccines were made of and 54% of parents did not know what the base of passive immunization is. Vaccines are mainly used for active immunization, especially those given to children under two, which is why the parents who knew about active immunization (64.6%) outnumbered the parents who knew about passive immunization (46%).

Severe allergic reaction, prolonged seizures, prolonged systemic steroid therapy or immunodeficiency disease are the most important contraindications of immunization [ 38 ]. The present study asked the parents about vaccine contraindications (question 6): although most parents (81.6%) thought that fever was the most important vaccination barrier but did not specify the degree (mild, moderate, high), fever ≥40.5°C is a factor to be taken into account but is not a contraindication according to immunization recommendations [ 38 ]. This finding was similar to other studies [ 39 , 40 ] in which the majority of parents had low knowledge regarding immunization contraindication and the parents stated that fever, allergy to egg protein, pregnant women and breastfeeding women are immunization contraindications.

The majority of parents gave incorrect answers (61% and 89.4%) to questions or statements related to vaccine storage and handling (Q.7 and Q.8), possibly because of the level of parents' education or type of employment. Most of the parents who gave correct answers might have medical or scientific bachelor's degrees or higher.

Approximately 65% of parents were able to answer correctly the question related to vaccination schedules (Question 9) and identify the timing of seven vaccine doses routinely given to children younger than two. This is consistent with results reported in a previous study [ 41 ] in which an immunization knowledge questionnaire administered at the Children's Hospital in Boston produced a mean score of 76% on questions relating to the schedule and administration of childhood vaccines.

In question 10, more than 55% of parents answered correctly that vaccination is potentially harmful. It shows that most of the parents acknowledged vaccine side effects. Parents in this study seem to be more aware of vaccine risk/benefit than parents in another study [ 22 ] in which 36.1% of parents believed that vaccines could be potentially harmful after vaccination.

Positively finding was found in the first and second questions in the part of practice questionnaire (Q11, Q12), approximately 94% of parents favored vaccination for their children and 96% of parents recommended immunization to other parents [ 42 ]. That means the parents have good immunization practice and adequate information about the benefits of vaccination in the future and they have great trust in the immunization programme. This finding is similar to other findings in a study in Pakistan [ 22 ] in which 96% of parents were in favour of vaccination for their children, but the percentage of parents (57.7%) that recommended the vaccination to others was lower than the percentage of Iraqi parents, and this difference could be related to the different environment and socioeconomic status prevailing in each country.

In addition, most parents correctly answered question 13, which related to the first immunization dose in the first week of life; the highest frequency of parents (451 parents) was referred to a good experience in immunization field and this was drawn from older children's experience or that of friends or relatives.

The majority received information about vaccines from physicians and other medical staff. Further work is needed to increase physicians' and immunization providers' knowledge in this area [ 43 ]. In this study, parents are noted as one of the important sources of immunization information but their immunization knowledge needs to be strengthened. According to question 14, 77.5% of parents were informed about vaccination and these parents are one of immunization’s information sources, a finding similar to another study [ 22 ] in which most parents were informed about immunization and noted as another information source.

According to the parents’ answers to questions 15, 16, 17, and 18, about 59.5% of parents collected the information from literature by reading, approximately 70% of parents preferred information from the television, less than 41% of parents heard about vaccination from radio, and about 25% of parents received vaccination information from the internet. The above results suggest television is the best source for immunization information because television is freely available at home and it is more convenient for parents to watch medical programmes than use the internet: not all parents know how to use the internet or obtain information by reading. However, this result was inconsistent with other studies [ 22 , 44 ] which consider internet as the main source of information on vaccination.

The last two questions (Questions 19 and 20) in the practice questionnaire assessed and evaluated the antenatal clinic and maternity hospital as immunization information providers. The result showed that parents received the information from clinics (65.9%) more than from hospitals (40.2%). Parents visit health clinics for routine child health care but visit the hospital for child delivery only and do not visit it again. Other studies in India and Bangladesh [ 45 , 46 ] showed that nurses and other medical workers were considered the main sources of immunization information for mothers, and other study in India found that mothers received weak information from medical staff owing to the poor communication between them [ 47 ].

The levels of KP among parents were positively associated with their children’s immunization rate was found in this study. The finding of this study is consistent with other studies’ findings [ 48 , 49 ] in which knowledge regarding vaccination is correlated with immunization rates. In addition, the results are supported by an Italian study of mothers [ 35 ] which showed that mothers’ lack of knowledge regarding vaccination is an important reason for failure to complete the immunization schedule. Another study [ 34 ] revealed that parents' good knowledge could not explain the low immunization rate of their children.

There is a need to increase awareness and knowledge about the benefits and importance of vaccination, as well as the harmful consequences of non-complete immunization. A planned educational programme is needed; the educational level of the parents needs to be taken into consideration when the programme is planned, especially as regards those with a lower educational level.

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Acknowledgment

I would like to acknowledge the institute of postgraduate’s studies “IPS”/ Universiti Sains Malaysia “USM” for their support in achieving this work through the USM fellowship program.

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School of Pharmacy, Faculty of Medical sciences, University of Duhok (UOD), Duhok, Iraq

Omer Qutaiba B Al-lela

Faculty of Pharmacy, AIMST University, Kedah, Malaysia

Mohd Baidi Bahari

College of Pharmacy, University of Mosul, Mosul, Iraq

Harith Khalid Al-Qazaz

Pharmacy Department, Al-Rashed University College, Baghdad, Iraq

Muhannad RM Salih

International Islamic University Malaysia, Kulliyyah of Pharmacy, Pahang, Malaysia

Shazia Q Jamshed & Ramadan M Elkalmi

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All authors have made substantial contributions to the conception of the study, drafting the article, and final approval of the version to be submitted. OQ, MB, and HQ conceived and designed the study. OQ and MR did the electronic search for the relevant articles and drafted the manuscript. MR and RM analyzed the data. OQ and SJ revised and edited the manuscript. RM and SJ prepared the manuscript for publication. All authors have read and approved the final submitted manuscript.

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Qutaiba B Al-lela, O., Bahari, M.B., Al-Qazaz, H.K. et al. Are parents' knowledge and practice regarding immunization related to pediatrics’ immunization compliance? a mixed method study. BMC Pediatr 14 , 20 (2014). https://doi.org/10.1186/1471-2431-14-20

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Childhood vaccine refusal and what to do about it: a systematic review of the ethical literature

• Kerrie Wiley 1 ,
• Maria Christou-Ergos 1 ,
• Chris Degeling 2 ,
• Rosalind McDougall 3 ,
• Penelope Robinson 1 ,
• Katie Attwell 4 ,
• Catherine Helps 1 ,
• Shevaun Drislane 4 &
• Stacy M Carter 2  

BMC Medical Ethics volume  24 , Article number:  96 ( 2023 ) Cite this article

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Parental refusal of routine childhood vaccination remains an ethically contested area. This systematic review sought to explore and characterise the normative arguments made about parental refusal of routine vaccination, with the aim of providing researchers, practitioners, and policymakers with a synthesis of current normative literature.

Nine databases covering health and ethics research were searched, and 121 publications identified for the period Jan 1998 to Mar 2022. For articles, source journals were categorised according to Australian Standard Field of Research codes, and normative content was analysed using a framework analytical approach.

Most of the articles were published in biomedical journals (34%), bioethics journals (21%), and journals that carry both classifications (20%). Two central questions dominated the literature: (1) Whether vaccine refusal is justifiable (which we labelled ‘refusal arguments’); and (2) Whether strategies for dealing with those who reject vaccines are justifiable (‘response arguments’). Refusal arguments relied on principlism, religious frameworks, the rights and obligations of parents, the rights of children, the medico-legal best interests of the child standard, and the potential to cause harm to others. Response arguments were broadly divided into arguments about policy, arguments about how individual physicians should practice regarding vaccine rejectors, and both legal precedents and ethical arguments for vaccinating children against a parent’s will. Policy arguments considered the normative significance of coercion, non-medical or conscientious objections, and possible reciprocal social efforts to offset vaccine refusal. Individual physician practice arguments covered nudging and coercive practices, patient dismissal, and the ethical and professional obligations of physicians. Most of the legal precedents discussed were from the American setting, with some from the United Kingdom.

Conclusions

This review provides a comprehensive picture of the scope and substance of normative arguments about vaccine refusal and responses to vaccine refusal. It can serve as a platform for future research to extend the current normative literature, better understand the role of cultural context in normative judgements about vaccination, and more comprehensively translate the nuance of ethical arguments into practice and policy.

Peer Review reports

Introduction

Vaccine rejection has existed for as long as vaccines [ 1 ]. Despite the significant contribution of childhood vaccination to reductions in global child morbidity and mortality [ 2 ], some parents continue to reject vaccines for their children. Parents’ reasons for rejection vary widely, and often depend on their social settings. For example, in high-income settings where around 2–3% of parents reject routine childhood vaccines [ 3 , 4 ], reasons can include previous bad experiences with vaccines or the medical system, concerns about vaccine safety, doubt about the effectiveness or necessity of vaccines, alternative health approaches, and participation in particular social groups or communities. These reasons can be grounded in deeply held religious beliefs or general philosophical approaches to health, views on freedom of choice, or mistrust in government and/or the vested interests of vaccine producers, among other things [ 5 , 6 , 7 , 8 ].

Vaccination plays a dual role in disease prevention: it serves to protect the vaccinated individual from disease, and when vaccination rates reach a high enough threshold for some diseases, also protects the broader community—including those who remain unvaccinated—by disrupting disease transmission through herd immunity. This dual role of vaccination, providing benefit to both the individual and community, complicates ethical questions regarding vaccine refusal, specifically, whether vaccine rejection is ethically justifiable.

Health care providers, communities, and governments encourage uptake and discourage vaccine rejection by various means, and the dual role of vaccination is also relevant to an evaluation of these practice and policy responses. Vaccine acceptance is encouraged with interventions like incentives, health provider recommendations and “nudges” directed at individual families, as well as by facilitating easier access to vaccination through strategies such as cost reduction and making clinic locations and opening times convenient, with many of these interventions supported by varying levels of evidence [ 9 ]. Governments often discourage vaccine rejection via the imposition of mandates that can vary in type and severity [ 10 ] and are not always well-supported by evidence [ 11 ]. These can include punitive measures, such as limiting unvaccinated children’s access to early childhood education or daycare. A thorough understanding of the ethical dimensions of childhood vaccine rejection and responses to it is important when navigating vaccine rejection in the clinical setting, and when formulating policy [ 12 ]. Systematic reviews of the evidence are considered best practice for informing vaccine practice and policy however, to our knowledge there have not yet been any published systematic reviews of the literature on the ethics of childhood vaccine rejection despite there being a broad literature on the subject. We sought to systematically explore and characterise the normative arguments made about parental refusal of routine vaccination, with the aim of better informing vaccine policy and practice.

We searched nine databases for literature that discussed normative positions on childhood vaccine rejection. Refer to the PRISMA flow chart (Fig.  1 .)

PRIMSA Flow Diagram of Review

Search strategy

We searched Medline, Embase, Philosophers Index, Philpapers, Project Muse, Cinahl, The Global Digital Library on Ethics (globethics.net), The Bioethics Literature Database (BELIT), and Pubmed using the general search strategy listed in Fig.  2 for articles published between January 1998 and March 2022.

Inclusion criteria

We included any publication which provided a substantive normative argument about parental refusal of routine vaccines for children aged five and under. We used a broad definition of ‘normative’ to mark anything that goes beyond mere description to consider right and wrong, good and bad, justifiable and unjustifiable, or legitimate and illegitimate actions or ways of being in the world. Our broad conception included textual forms such as ethical reflections, prudential and legal norms, and accounts of rationality. We used ’substantive’ to mark publications where the authors’ main purpose was to make an argument about whether vaccine refusal is morally justifiable. This included empirical research that explicitly examined normative dimensions of vaccine refusal. We were limited to reviewing publications published in English.

Exclusion criteria

We excluded publications where authors made a normative claim in passing, but the publication’s main purpose was to report non-normative empirical findings. We also excluded: publications on adult vaccination (including COVID vaccination) and the HPV vaccine (which is administered in adolescence, not childhood); empirical research such as surveys or interviews, unless they expressly explored normative arguments; and descriptive publications about the characteristics of the anti-vaccination movement that provided no normative position.

Screening and data extraction

After search execution and duplicate removal, a screening triangulation exercise was undertaken to ensure consistency among the screeners. A set of 20 titles and abstracts were independently screened by six authors, and the results compared. The inclusion and exclusion criteria were refined in a subsequent group discussion, and a sub-set of full text articles were then screened and evaluated by the same group of people, and results again compared. A discussion of this second triangulation step resulted in a refined and standardized screening approach.

The authorship group were then divided into four pairs, and the remaining titles and abstracts divided among the pairs. Each individual screened titles and abstracts against inclusion criteria, and then met with their screening partner to compare results and discuss and resolve any differences.

Full text was sought for each record screened for inclusion, and a second screening then removed articles which didn’t meet the inclusion criteria once the full text was read, articles that could not be sourced, and duplicates not identified in the initial screening.

The final list of full text publications was then divided among four authors (SC, RM, CD and KW) for data extraction using the concept of “information units” described by Mertz and colleagues [ 13 ]. In this context an information unit was defined as a normative issue or argument, and each of the four ‘extracting’ authors summarized each of the relevant information units in the papers they were assigned.

For included journal articles, Australian Standard Field of Research (FoR) codes for the journal that each article appeared in were sourced as a proxy for the disciplinary location of the article (e.g. bioethics, medicine, law). We used the Australian and New Zealand Standard Research Classification (ANZSRC) 2008, as this was the current standard when analysis commenced [ 14 ]. We used two digit FoR codes (division codes) to identify the source journal as either being Medical and Health Sciences (code 11), Ethics and Philosophy (code 22) Law (code 18) or other codes grouped as “other”. In some cases, the journal was assigned a combination of these codes (refer to Fig.  3 ).

Respective percentages of included articles falling under various ANZSRC FoR Codes (2008)

Quality assessment in systematic reviews of normative literature remains a contested area, with various options and no established best practice approach [ 15 ]. In this review, we took a satisficing approach to quality appraisal [ 16 ]: publication in a peer-reviewed journal or by a reputable academic publisher was taken as a sufficient level of quality to justify inclusion in the review. The peer review process undergone by PhD theses was also taken to be a sufficient indictor of quality to justify inclusion. Further quality appraisal of individual publications was not undertaken. This aligns with the purpose of the review which was to map and synthesize the current literature on this topic.

A framework approach was used to organise and synthesise the data [ 17 ]. The extracted information units were read by one author (KW), and a coding frame inductively developed to summarise and classify the information units extracted by the group. The publications were then independently coded according to this framework by two authors (KW and PR). Following this, the two authors met and compared their coding, discussing any differences and resolving them by consensus. The data were then synthesized into themes. In addition, for journal articles, the ANZSRC Field of Research codes for the journal each article appeared in were descriptively analysed to assess the distribution of the included literature across various disciplines.

Search results

Five thousand, two hundred and thirty-one publications were returned by the searches (see Fig.  1 ). Eight hundred and twenty-two duplicates were removed in the first instance, leaving 4409 records to be screened by title and abstract. During this screening process 4058 records were excluded, leaving 351 full text publications to be assessed. Of these a further 230 records were excluded (due to not meeting the inclusion criteria, previously unidentified duplicates, or inability to source the full text), leaving 121 publications for inclusion in the review. These included 117 journal articles, three theses and one book.

Literature source type

Analysis of the ANZSRC Field of Research codes of the source journals of included articles revealed three main areas, or a combination of them (Fig.  3 ). Around half were coded to medicine (63%); of these, just over half were dual coded to ethics (20%) or another code (9%). 21% of articles were from the philosophy or ethics literature alone; another 25% were from ethics and medicine or ethics and law. Law was the least dominant discipline, with only 12% of articles being coded to law (alone or in combination with other disciplines). This pattern suggests active concern within medicine regarding non-vaccination, but also widespread overlap in concern between medicine, ethics, and law.

Main themes found in the literature

Articles addressed two central questions (see Table  1 ):

Whether vaccine refusal was justified (henceforth ‘refusal’ arguments).

Whether various policy or practice responses to those who reject vaccines are justified (henceforth ‘response’ arguments).

Descriptive analysis of content

The literature was dominated by papers focused on ‘response’ arguments (61%). A smaller group of papers address ‘refusal’ arguments (19%), and about 18% considered both ‘refusal’ and ‘response’, usually making normative arguments about vaccine refusal as background to arguments regarding ‘response’ (See Fig.  4 ). Less than 2% of papers had a different focus.

Comparative frequencies of themes occurring among included articles

‘Response’ arguments were more common in the medical and health sciences literature (ERA FoR code 11, see Fig.  5 ). Although the ethics/philosophy (FoR code 22) and law literatures (FoR code 18) were also dominated by ‘response’ arguments, these journals—unlike medical journals—were more likely to include ‘refusal’ arguments.

Comparative frequency of overarching themes across the different disciplines of the included articles

As would be expected, authors made ‘response’ and ‘refusal’ arguments in different ways. In the following sections we consider the detail of how arguments were made. We refer to each included article by its unique reference listed in Table  1 .

‘Refusal’ arguments: whether or not vaccine rejection by individual parents is justifiable

Arguments about whether vaccine refusal by individual parents is justifiable included consideration of parents’ rights, the interests of the child (including the legal ‘best interests of the child standard’), the value of herd immunity, the epistemic basis for ethical claims, and the relevance of religious views. Our sampling period included a special issue of Narrative Inquiry in Bioethics which published narratives written by parents to communicate their normative positions on vaccination. Most of these were written by non-vaccinating parents, and they make up over one third of all arguments in the identified literature that support refusal. On balance, most of the literature argues that it is not justifiable for parents to refuse routine vaccination for their children.

Some arguments within the literature were absolute in their position on whether vaccine rejection is justifiable; others weighed competing values in a situation-specific approach. Irrespective of the arguments used to justify a position, most of the literature frames the question of whether vaccine rejection is justifiable based on three key areas of concern: (i) Respect for autonomy, the doctrine of informed consent and the value of liberty, (ii) Consequences for the child and others, and/or (iii) The normative significance of parental trust, distrust, and uncertainty. We explore the main arguments within these concepts below. As the discussion shows, these concepts are not discrete – they are often weighed against one another, linked by causal claims, or held in tension in the arguments made. Figure  6 represents proportionally the ’refusal’ arguments made in the reviewed literature.

‘Refusal’ arguments made in the literature on the ethics of vaccine refusal

Respect for autonomy, the doctrine of informed consent and the value of liberty

Fifteen papers from this sample present arguments that vaccine refusal is justified based on respect for parental autonomy, rights, or liberties (21, 23, 25, 31, 32, 35, 36, 39, 68, 71, 75, 80, 94, 100, 121). Some argue that vaccine refusal is justified on the basis of preserving legal rights (31, 80) or expression of religious freedom [ 23 ]. Opposing positions (including from four of the authors who also offer arguments justifying refusal) argue that, on balance, considerations regarding respect for autonomy are, or can be, outweighed by the potential harm caused to the child and others by not vaccinating though the increased risk of vaccine preventable diseases (21, 36, 20, 23, 110). This includes legal perspectives arguing that the freedom to choose is not unfettered [ 25 ] and that courts can override parental autonomy if this is in the child’s best interest (75, 85), as well as arguments from religious perspectives that the freedom to exercise religious beliefs needs to be weighed against harm caused to others (21,91). Those who argue that vaccine refusal is justified counter that disrespecting parental autonomy can also cause harm to the child through loss of trust and possible disengagement of the child from the healthcare system (100), and that the increased risk of disease is a price worth paying to ensure that political values are preserved (71). Of note: non-vaccinating parents also assert a right to make choices for their children in support of their refusal [ 14 , 18 ], but unlike others, their arguments are based primarily on epistemic claims about vaccine effectiveness, necessity and safety rather than moral or ethical positions. However, they assert that these doubts necessitate respect for their decision.

Consequences for others and the child

Most of the literature argues for or against the justifiability of vaccine refusal based on consequences. These include potential harms from vaccine preventable diseases or vaccines themselves, or conversely, potential benefits from herd immunity. The concept of herd immunity is deployed in different ways. Those justifying vaccine refusal in certain circumstances argue that in settings where there is a high level of herd immunity, the risk posed by an unvaccinated child is not great enough to override respect for parental autonomy (62, 65, 94, 98), and that the benefits of community protection do not justify the individual risk posed by the vaccine and borne by the child who is already protected through herd immunity (72, 96, 97, 17, 93, 108). Perspectives of non-vaccinators echo these ideas by asserting that some diseases are not harmful enough to proscribe vaccine refusal [ 14 ] and that vaccine injury contributes to and justifies refusal [ 16 ].

In contrast, those who argue that refusal is not justifiable propose a duty to contribute to herd immunity because it is a public good (7,80, 19,120, 33, 48, 68,115), or that free-riding (allowing one’s child to enjoy the benefits of herd immunity provided by others, while avoiding the risk of vaccinating) is unfair (37,46, 48). On this account, the vaccine refusal of a few may undermine herd immunity and thus cause harm to the many by increasing disease risks (9, 11, 26, 37, 59, 76, 81, 86); further, these risks are borne by the most vulnerable (43). These arguments about harm to others include those made by authors writing from religious perspectives (8, 81, 84, 92, 98). Finally, an account by a vaccinating parent suggests that harms resulting from non-vaccination are blameworthy because they are an intentional act of aggression against vaccinated children [ 19 ].

The concept of the child’s interests arises frequently in these publications. Pursuing or protecting these interests generally combines concern about the consequences of non-vaccination for the child with concern for autonomy, in the broad sense of being able to direct one’s life in accordance with one’s values or aims. Authors write about the interests of the child in both a general sense (i.e. the interests of the child outside of a legal context) and in a legal sense (the formal ‘best interests of the child standard’). The legal construction is used both to support (31, 6, 93) and to oppose vaccine refusal. Arguments that receiving a vaccine is in the legal ‘best interests of the child’ (21,39) posit that any deviation from a widely accepted legal view of the interests of a child should weigh the risk of harm to the child (68) irrespective of the parent’s beliefs (78), or that non-vaccination constitutes negligence or child endangerment [ 28 ]. On the other hand, some authors argue that, from a legal perspective, parents have the right to consent to or refuse vaccination ostensibly using the ‘child’s best interests standard’(93) and that there is insufficient legal precedent to argue that non-vaccination constitutes medical neglect [ 6 ].

Arguing from distrust and uncertainty

As previously noted, the sample included a set of papers written from the perspective of non-vaccinating parents. Most of these contributions seek to justify vaccine refusal, and many justifications were grounded in distrust. They call into question vaccine safety and effectiveness [ 12 , 13 , 14 , 18 ], and the accuracy of the reporting of adverse events following immunization (96). They claim financial conflicts, constructing clinicians, clinical medicine, and/or regulatory agencies as untrustworthy or non-credible [ 12 , 14 , 16 ]. They cite empirical studies of non-vaccinators to support parental preferences for natural infection over a vaccine (97). Non-vaccinating parents were not the only authors to make arguments in this vein. Some other authors cite the lack of absolute certainty of vaccine safety as justification for parents refusing vaccines in the interests of their children (28,76), especially regarding newer vaccines for which efficacy is not well-established (34). This line of argument depicts vaccine proponents as driven by commercial interests, thus justifying parental mistrust and refusal (34). Contra this, one paper asserts that refusal on the grounds of mistrust of government or medicine is not justifiable, as it is inconsistent with the scientific evidence and the well-established regulatory processes in place, such as the rigorous clinical testing required to develop and approve vaccines, and the systems established to report adverse events and ensure safety [ 8 ].

‘Response’ arguments: claims regarding the justifiability of different responses to non-vaccination

The literature examines four main responses to non-vaccination (i) government mandate policies (such as legal ramifications for refusing vaccination and vaccination as a school entry requirement), and other coercive policies, (ii) exemptions to mandate policies, (iii) individual practitioner and medical practice responses (including patient dismissal from practice for vaccine refusal, vaccinating against parents’ will, and nudging), and (iv) withholding health resources. The literature includes authors who argue that these responses are justifiable and others who argue that they are not. Much like the refusal arguments, some response arguments are absolute in their position, while others advocate weighing competing values in a context -specific way. Like refusal arguments, most arguments for and against particular responses to non-vaccinating parents draw from respect for autonomy, the doctrine of informed consent and the value of liberty, as well as considering consequences for the child and others. Other concepts appearing in these arguments include inequity, and the duties of governments and practitioners. Figure  7 represents proportionally the ’response’ arguments made in the reviewed literature.

‘Response’ arguments made in the literature on the ethics of vaccine refusal

As in the literature on refusal, many arguments about policy or practice responses to non-vaccinating parents depend on the interrelated concepts of respect for autonomy, informed consent and liberty. Five papers engage with the issue of practitioners vaccinating against parents’ will with respect to these concepts. They argue that forced vaccination by healthcare providers violates parents’ autonomy and/or the ethical requirement for informed consent, because vaccination carries risks (80,119), and clinicians have legal obligations to obtain valid consent for procedures (94). Some authors propose alternatives to forced vaccination, including focusing on rebuilding trust (rather than violating negative liberty) (32), and accepting that views on vaccination derive from plural and culturally-specific values [ 29 ]. On the other hand, proponents of forced vaccination do not engage with these concepts, instead deploying the harm principle and the legal ‘best interests of the child standard’ to justify their position. We explore this argument in the following section “Consequences for the child and others”.

Another set of papers make arguments about vaccine mandates that also draw on autonomy or liberty justifications, often weighing these against harm or risk of harm. Arguments justifying mandates are often legal in nature and use, for example, the harm principle or case law to argue that the freedom or liberty to choose not to vaccinate is limited by the risk of ill health and/or death to the child or others in the community, including vulnerable persons (83,91). One author argues that legal actions should be brought against those who harm others by refusing vaccination, as this would both discourage refusal and, in the case of any successful claims, compensate victims (55). Some authors argue that mandates are justifiable if the exercise of liberty rights poses a threat to public health (53,82,83,91,119). While those arguing that mandates are not justifiable sometimes rely on arguments about risk of harm—i.e. that in a low-incidence (and therefore low-risk) setting mandates cannot be justified (45, 87,104)—most make their arguments from autonomy, informed consent, and personal liberty and do not weigh these against the potential for harm (12,16,61,82,89,107,114). One author argues that even if mandates improve vaccination rates, they damage trust with parents and make refusers more steadfast in their decision (121), so are not sustainable. Finally, some authors present middle-ground positions that—in their view—are more autonomy- or liberty-preserving, including persuasion (121) or weakly enforced mandates (71), or argue that policy responses should take the least coercive approach that is feasible and effective to balance the needs of the individual with public health (117).

Those supporting conscientious objection to mandates argue that such provisions contribute to the collective good of a culture of respect for autonomy (82), or reflect the “American ideal” of personal freedom (66). Contra this, those opposed to conscientious objection provisions argue that challenges to mandates based in religious freedom have failed in case law, as the right to practice religion freely does not include the liberty to expose children or communities to disease (20,92). One author provides a qualified view of conscientious objection on religious grounds, arguing that such liberties could be justified only while high vaccination rates are maintained (109).

Authors disagree about whether certain policy or practice responses do, or do not, respect autonomy or uphold important liberties. For example, authors disagree on the effect of both nudges and conscientious objection policies on parental autonomy or liberty. With respect to nudges, some argue they are autonomy-preserving because they steer parents in a certain direction while allowing choice (106), do not override or challenge the strong views of deeply opposed opponents (42, 44) and uphold informed consent (121). Some supporters of nudging weigh multiple normative considerations, arguing that nudges that appeal to social responsibilities in a medical practice setting are justified because they appropriately balance parental autonomy against the practitioner’s responsibility to promote trust and collective benefits (3,80). Those opposed to nudges for vaccination decisions argue that the invasive nature of immunization increases the need for independent and informed decision making (60,113). These authors argue against a presumptive consultation style in general practice, proposing participatory clinical encounters (114), and using persuasion (42), as alternatives to more coercive approaches.

Consequences for the child and others

Many of the arguments in this literature consider individual and collective consequences—benefits, harms, burdens, and costs to society — and propose that these may override other normative considerations. The risk and prevention of harm is particularly pertinent here. For example, a parental decision can be overruled in cases where there is a significant risk of harm to the child (78), or nudges become more justifiable when the risk of harm to others is higher (3, 75).

Arguments about mandates often include concern about consequences, since it is inherent in a vaccine mandate that there will be some costs associated with non-vaccination. Mandate proponents argue that mandates ensure high vaccination rates, thus preventing disease outbreaks (39) and associated harms (97), so are in the best interest of individual children (28, 73, 111) and serve the greater good (4,28,73,79). Some justify mandates by proposing a duty to contribute to herd immunity, including under the “clean hands principle”, that is, an obligation not to participate in collectively harmful activities [ 1 , 5 ]. Conversely, some authors argue that mandates are not necessary to achieve high levels of population immunity, so state coercion is unjustified at a collective level or at the level of the individual child because each child receives limited benefit (94). Those opposing mandates also argue that vaccine safety is not absolute (88) and that mandates are a disutility, carrying associated costs with surveillance and enforcement (95). Other authors sought to balance these kinds of consequences against other normative considerations with respect to mandates, including the level of herd immunity, the risks of non-vaccination to the child and/or society, and respect for parental autonomy (32,53,88,119). One author argues that mandates protect ‘victims’ of the anti-vaccination movement from harms so long as certain conditions are met (43): that the vaccine can prevent infection and transmission, that individuals minimize their risk of exposure, and that the right of self-defense is preserved (e.g. in the case of allergy to vaccines).

Consequences are also important to arguments about conscientious objection, but here it is generally concerns about the impact on the collective. Some argue that exemptions should not be allowed because they may increase rates of disease or undermine individual or community health (20, 87, 118); others argue that if disease risk is low, exemptions are justified because those few individuals with exemptions do not pose a risk to others or herd immunity (20, 82, 105).

Consequences to the child and others are used to justify whether responses should be applied in general practice settings. As mentioned in the previous section, some authors justify healthcare workers vaccinating against a parent’s will using both the harm principle (69) and the legal ‘best interests of the child standard’ [ 25 ]; others suggest it is against the legal best interests of an older child to be forcibly vaccinated, as this may have a more detrimental impact than being unvaccinated (25,51). The best interests of the child are also invoked extensively to argue that non-vaccinating families should not be dismissed from medical practices (98,104, 26, 75). Here authors note that an unvaccinated child is more vulnerable to vaccine preventable diseases (9, 49), practice dismissal limits opportunities to access health care (31,52, 56,79,116) and the increased risk of harm from vaccine preventable diseases is transferred to other practices (9,47,49). One paper makes an argument about the consequences of treating non-vaccinating families for general practitioners, suggesting that practices caring for unvaccinated children should disclose this to other patients to minimize medicolegal risks, and should receive legal protection to account for the increased liability and risk of caring for these patients (40).

A small body of literature employs claims about who is responsible for the consequences of non-vaccination to make arguments about responses to non-vaccination. For example, one article seeks to justify discriminating against unvaccinated children with a vaccine preventable disease by limiting their access to health resources, relying on precedents such as coronary bypass surgery being withheld from obese people and smokers, and arguing that those who contribute to their own ill-health (in this case by not vaccinating) do not deserve healthcare (80). A related argument focuses on managing refugee camps during outbreaks that pose a direct and imminent threat of harm, proposing that the state is justified in withholding humanitarian aid from non-vaccinating refugees because the state is responsible for setting conditions that provide protection to (or prevent harm to) aid givers and public health [ 30 ].

Some critiques of policy or practice responses to non-vaccination emphasise that these responses can have inequitable effects and argue that this is unjustifiable. Exemption policies are a key focus here. Five papers argue against exemptions to vaccine mandates on the grounds that these unevenly distribute the risks and benefits of vaccinations (27,61,66, 73,118). These authors propose that the inaction of a few compromises the health of the most vulnerable community members (118) and disenfranchises those with medical contraindications for vaccines [ 27 ]. One author particularly focuses on home-schooled children, arguing that exempting them from vaccine mandates exposes both those children and society to harm, and that it is in the interests of these children and society that they be protected through vaccination (73). Some authors suggest that policy exemptions could be made justifiable by imposing conditions that offset potential inequities. On this view, exemptions could be justified so long as the refuser is prepared to make a financial or other contribution to help offset the potential financial burden of the diseases they may cause, or to otherwise contribute to social good [ 2 , 22 ].

Similarly, some opponents of coercive mandates or practice dismissal for non-vaccination critique these responses for having inequitable effects. It is argued that coercion risks creating a group of disenfranchised people (113) and that different people have different capacities to resist coercive policies (114). Similarly, dismissal leaves vulnerable children without advocacy (64), leads to patients not being treated equally (63) and marginalizes children from health care (74). One paper argues that family dismissal should be strongly discouraged, and an alternative mutually beneficial solution sought after considering the interests of the patient, physician, family, community, and society at large (74).

The duty of practitioners and the state

Some papers address the duties of practitioners and the duties of the state to respond to non-vaccination, in ways that go beyond simply weighing up consequences, implications for autonomy or freedom, or equity of impacts.

A variety of duties of practitioners are proposed. The first of these is to protect a child from their parent’s beliefs if those beliefs are likely to cause significant harm, which is used to justify initiating child protection proceedings to vaccinate against a parent’s will (67). Another is to protect patients in the waiting room from the risks posed by non-vaccinating patients, which is used to justify dismissing non-vaccinating patients from practice (9,26,38, 40,45). Counter-obligations are used to argue against practice dismissal. These include a health professional’s obligation to provide healthcare in the best interest of the child despite the parent’s decisions, and to deal with infectious disease as a part of their role (9,26,45,47, 56,101). Authors also argue that physicians’ obligations exclude enforcing parental accountability through dismissal, especially if that means the child is held accountable for the actions of their parents (47), and that continuing to provide care to a non-vaccinating family does not make the physician complicit in their decision (116).

It is sometimes asserted that the state is obliged to discourage non-vaccination on a number of grounds. This includes a fundamental duty of states to protect society [ 21 ], a responsibility of states to protect herd immunity as a common good or to reduce social and financial burdens and costs (53,119), and the state’s role to protect the common good in the face of risks to public health and the fallibility of individuals’ risk perception (54). Some of these arguments focus on exemptions from mandatory vaccination policies, proposing that states can not justify such exemptions because the government’s interest in protecting society outweighs the individual’s interest [ 21 ] or because vaccination is a social and moral good owed by a society to its children (118).

This review systematically explored and characterised the normative arguments made about parental refusal of routine childhood vaccination. Included publications addressed two types of arguments (i) ‘Refusal’ arguments (whether vaccine refusal is justified) and (ii) ‘Response’ arguments (whether various policy or practice responses to those who reject vaccines are justified). There were more ‘response’ arguments than ‘refusal’ arguments in the literature. On balance, most of the literature on ‘refusal’ arguments contended that it is not justifiable for parents to refuse vaccination for their children. Most of the ‘response’ argument literature argued against the various responses to non-vaccination put forward. However, compared to ‘refusal’ arguments, ‘response’ arguments were more varied and nuanced, and often came with caveats (e.g. exemptions to mandates are permissible if the disease burden is low).

The included articles predominantly originated from medical journals: these accounted for most of the papers focused on ‘response’ arguments. This may arise from the broader distribution of academic literature – there are more papers published in medicine than in the other disciplines represented in this review. It may also reflect the needs of readers of medical literature for guidance on how they should respond to non-vaccinating parents, highlighting the importance of making literature addressing the ethical dimensions of vaccine refusal accessible to immunization practitioners. Although there were some interdisciplinary perspectives, the dominance of the medical literature relating to ‘response’ arguments suggests that knowledge in this field may be advanced by incorporating more voices with expertise in ethics, law, and policy. This is especially important for deciding how to implement policy and practice responses to non-vaccination.

‘Refusal’ arguments were more common in the comparatively smaller collection of ethics/philosophy literature identified by this search, which may be, in part, a product of the differences in disciplinary traditions. While ethics/philosophy texts explore counterarguments and reach conclusions that are nuanced, and often with caveats, medical disciplines are primarily guided by practical considerations and a tradition of arguing from evidence rather than from ethical or philosophical principles. This privileging of evidence over principles may make it difficult to explore differing vaccination positions within the medical arena, potentially contributing to the adversarial clinical immunisation encounters described by vaccine-refusing parents and clinicians alike [ 7 , 18 , 19 ]. This pattern needs attention if ethical arguments are to have an impact in practice. As shown, most ethical arguments pay attention to evidence, as most ethical arguments include consequences in some way (see below). Ethical arguments can add nuance to biomedical thinking about consequences (e.g. consequences for individuals vs. the collective) and also about competing values (e.g. balancing consequences against concerns regarding autonomy, consent and liberty). The challenge for ethicists is to provide these arguments in an accessible and compelling form.

In fact, (i) consequences for the child and others, and (ii) respect for autonomy, the doctrine of informed consent and the value of liberty were dominant themes in both ‘refusal’ and ‘response’ arguments. Arguments were guided by common concepts such as the value of herd immunity, the prospect of harm to the child or others in the community and legal perspectives and precedents. The normative significance of parental trust, distrust, and uncertainty was a consideration unique to the ‘refusal’ arguments literature, driven in part by the five parental accounts from the special issue of Narrative Inquiry in Bioethics included in our sample. The concepts of inequity, and the duties of governments and practitioners only appeared in ‘response’ arguments. This is unsurprising: it reflects the purpose and perspective of these writers. An analysis of policy options is often required to bring inequity into view, and both clinicians and policymakers have obligations by virtue of their roles that can inform thinking about the right thing to do.

Many of the arguments justifying vaccine refusal aligned with the wider literature on the perspectives of non-vaccinating parents who value the freedom to make health decisions as caregivers, in what they perceive to be the best interest of their children [ 20 , 21 ]. These decisions are often based on doubts about vaccine safety or efficacy and are commonly initiated by a negative experience [ 19 , 20 , 22 ]. Unsurprisingly, arguments against rejecting childhood vaccines reflected the broader literature on how vaccine-supporting people view non-vaccination— including views that non-vaccinators are misinformed and disrupt social order, and that their actions are not based on reason or shared social values [ 23 ]. Common negative descriptors such as “anti-vaxxer” have similar valence in social discourse [ 24 ]. Those writing about vaccination should be aware of the potential for stigmatization and “othering” that can result by framing non-vaccination as a failure of parents [ 25 ]. When such arguments are used to inform policy and practice responses to non-vaccination, it introduces the potential for negative psychosocial impacts and further alienation of non-vaccinating parents.

Most ‘response’ arguments dealt with the justifiability of mandates and coercive policy. Generally, authors in favour of mandates prioritised the good of society; those against mandates prioritised individual choice. The large number of papers we found on mandates is unsurprising, given that these policies have been contentious. In Australia, federal and most state governments have mandates that require children to be vaccinated to be enrolled in childcare and for their families to be eligible for government financial assistance [ 26 ] Key political, academic and industry stakeholders argue that these mandates are designed to increase vaccination rates for the benefit of society [ 27 ]. On the other hand, Australian non-vaccinating parents express a belief that their children do not pose a threat to society, that all children should be treated in the same way, and that all parents should be able to make decisions for their children, regardless of vaccination status [ 28 ]. These perceptions of policy makers and non-vaccinating parents broadly represent the opposing arguments about mandates presented in this review. Facilitating a middle-ground approach to policy implementation may require closer attention to the values underlying these opposing views, and using a procedurally just approach to weigh them against one another.

In the context of an increasing number of systematic reviews in the field of bioethics, there has been recent criticism emerging about the use of these methods in bioethics. For example, Birchley and Ives (2022) argue that such methods are designed and therefore better suited to aggregation of quantitative data and not the complex and subjective nature of bioethical concepts and the theory-generating and interpretive approaches they require [ 29 ]. We argue that our application of the framework systematic review method - one of many well-established methods for systematic review and synthesis of qualitative and conceptual data - is appropriate for this research question and the application of our findings. Vaccine policy and practice requires a synthesis of what is known on relevant issues, and a systematic approach such as that used here provides a useful summary of the breadth of relevant ethical issues in a format that is accessible to policymakers. Our review has some limitations. Our aim was to map the range of normative arguments about vaccination refusal and policy. We did not have scope to present a novel ethical argument in response to our findings; this is an aim for future empirical and theoretical research. Most of the included literature focuses on high-income settings, predominantly the United States and the United Kingdom. In low-income settings, health services are often harder to access and levels of and reasons for vaccine rejection also differ in these settings. For example, political and cultural factors have been implicated in polio vaccine rejection in Nigeria [ 30 ], while low literacy, unemployment, and owning a mobile phone have been associated with polio vaccine refusal in Pakistan [ 31 ]. Our sampling period included a special issue of Narrative Enquiry in Bioethics which published narratives written by parents to communicate their normative positions on vaccination. These were mostly written by non-vaccinating parents and made up over one third of all arguments in the literature that support refusal. This is a strength in that it expanded the range of views represented in the review. However, it is also a limitation in that if this special issue had not been published within our sampling period, the range of arguments would have been more strongly skewed against vaccine refusal. These papers artificially increased the proportion of arguments in the scholarly domain that argue for vaccine refusal. It is a strength of our methodology that we were able to identify the unique perspective from which they were written and position them separately in our literature synthesis so that our representation of the literature distribution is not artificially skewed.

This review highlights an opportunity for interdisciplinary collaboration to widen the scope and reach of normative arguments about non-vaccination. Such collaboration can facilitate a broader understanding of and engagement with the ethical issues that may be relevant for practitioners, policymakers, and researchers in deciding how to respond to non-vaccinating parents. Arguments about the justifiability of non-vaccination and what should be done about it have the potential to positively influence routine childhood vaccination rates but can also alienate non-vaccinating families if not deployed with their perspectives in mind. There is an avenue for future work to further understand the influence of cultural context on normative arguments, especially within low- and middle-income settings. Moreover, there is an opportunity to further explore the influence and translation of scholarly ethical arguments into policy and practice responses to childhood non-vaccination.

Data Availability

The datasets generated and/or analysed during the current review are not publicly available, however the search terms used to generate the dataset are included in this published article.

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This review was funded by the Australian National Health and Medical Research Council, grant number GNT1126543.

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KW contributed to study design and search strategy development, ran the searches, managed the screening and inclusion process, screened articles for inclusion, extracted data, analysed and interpreted data and co-led manuscript drafting; MC ran updated searches, screened articles for inclusion and extracted data, assisted with analysis and interpretation and co-led manuscript drafting; CD contributed to study design and search strategy development, provided technical guidance, screened articles for inclusion and contributed to manuscript drafts; RM contributed to study design and search strategy development, provided technical guidance, screened articles for inclusion and contributed to manuscript drafts; PR screened articles for inclusion, extracted data, assisted with analysis and contributed to manuscript drafts; KA contributed to search strategy development, screened articles for inclusion and contributed to manuscript drafts; CH screened articles for inclusion and contributed to manuscript drafts; SD screened articles for inclusion and contributed to manuscript drafts; SMC contributed to study design and search strategy development, provided technical guidance, screened articles for inclusion and contributed to manuscript drafts.

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Wiley, K., Christou-Ergos, M., Degeling, C. et al. Childhood vaccine refusal and what to do about it: a systematic review of the ethical literature. BMC Med Ethics 24 , 96 (2023). https://doi.org/10.1186/s12910-023-00978-x

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• Vaccination
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BMC Medical Ethics

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Comprehensive literature review on COVID-19 vaccines and role of SARS-CoV-2 variants in the pandemic

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• 2 School of Medicine, National University of Ireland, Galway, University Road, Galway H91 TK33, Ireland.
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• DOI: 10.1177/25151355211059791

Since the outbreak of the COVID-19 pandemic, there has been a rapid expansion in vaccine research focusing on exploiting the novel discoveries on the pathophysiology, genomics, and molecular biology of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although the current preventive measures are primarily socially distancing by maintaining a 1 m distance, it is supplemented using facial masks and other personal hygiene measures. However, the induction of vaccines as primary prevention is crucial to eradicating the disease to attempt restoration to normalcy. This literature review aims to describe the physiology of the vaccines and how the spike protein is used as a target to elicit an antibody-dependent immune response in humans. Furthermore, the overview, dosing strategies, efficacy, and side effects will be discussed for the notable vaccines: BioNTech/Pfizer, Moderna, AstraZeneca, Janssen, Gamaleya, and SinoVac. In addition, the development of other prominent COVID-19 vaccines will be highlighted alongside the sustainability of the vaccine-mediated immune response and current contraindications. As the research is rapidly expanding, we have looked at the association between pregnancy and COVID-19 vaccinations, in addition to the current reviews on the mixing of vaccines. Finally, the prominent emerging variants of concern are described, and the efficacy of the notable vaccines toward these variants has been summarized.

Keywords: AstraZeneca; BioNTech/Pfizer; COVID-19 vaccine; Moderna; SARS-CoV-2 variants.

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Serious neurological adverse events following immunization against SARS-CoV-2: a narrative review of the literature

Sara eslait-olaciregui.

Histology and Embriology Unit, Department of Biomedica Science, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia

Applied Biomedical Sciences Research Group (UR BioMed), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia

Kevin Llinás-Caballero

Institute for Immunological Research, University of Cartagena, Cartagena, Colombia

David Patiño-Manjarrés

Thomas urbina-ariza, juan fernando cediel-becerra, camilo alberto domínguez-domínguez.

School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 #63C-69, 111221 Bogotá, Colombia

Amid the coronavirus disease 2019 (COVID-19) pandemic, massive immunization campaigns became the most promising public health measure. During clinical trials, certain neurological adverse effects following immunization (AEFIs) were observed; however, acceptable safety profiles lead to emergency authorization for the distribution and use of the vaccines. To contribute to pharmacovigilance and lessen the potential negative impact that vaccine hesitancy would have on immunization programs, we conducted a review of the scientific literature concerning the epidemiological data, clinical presentation, and potential mechanisms of these neurological AEFIs. There is some epidemiological evidence linking COVID-19 vaccines to cerebral venous sinus thrombosis, arterial ischemic stroke, convulsive disorder, Guillain–Barré syndrome, facial nerve palsy, and other neurological conditions. Cerebral venous sinus thrombosis has been associated with a thrombotic thrombocytopenia induced by the vaccine, similar to that induced by heparin, which suggests similar pathogenic mechanisms (likely involving antibodies against platelet factor 4, a chemokine released from activated platelets). Arterial ischemic stroke is another thrombotic condition observed among some COVID-19 vaccine recipients. Vaccine-induced convulsive disorder might be the result of structural abnormalities potentially caused by the vaccine or autoimmune mechanisms. Guillain–Barré syndrome and facial nerve palsy may also be linked to the immunization event, possibly due to immune mechanisms such as uncontrolled cytokine release, autoantibody production, or bystander effect. However, these events are mostly uncommon and the evidence for the association with the vaccine is not conclusive. Furthermore, the potential pathophysiological mechanisms remain largely unknown. Nevertheless, neurological AEFIs can be serious, life-threatening or even fatal. In sum, COVID-19 vaccines are generally safe and the risk of neurological AEFIs does not outweigh the benefits of immunization. However, early diagnosis and treatment of neurological AEFIs are of utmost importance, and both health professionals and the public should be aware of these conditions.

Plain language summary

A review of undesired effects involving the nervous system following the administration of COVID-19 vaccines

Among the range of complications that can occur after a vaccine, some of them can affect the nervous system and its vasculature. This narrative review aims to evaluate some serious neurological conditions following COVID-19 vaccination. We searched biomedical journal databases where physicians around the globe reported different complications after the administration of different COVID-19 vaccines. Besides reports of cases in individual patients or small groups, we reviewed studies that included bigger groups of patients (e.g. vaccinated versus non-vaccinated) and compared the occurrence of these events between them. We found that after the administration of a certain type of vaccine (e.g. ChAdOx1-S/Oxford, AstraZeneca vaccine), serious neurological complications were rare, with abnormal clot formation involving cerebral blood vessels being one of the most important among them. Nonetheless, other conditions have been observed after the administration of the vaccines; however, it is not certain yet if the vaccines are the actual cause of these complications.

There are some hypotheses that could explain why these adverse reactions take place after a vaccine. For instance, an abnormal immune response to the vaccine leads to the production of antibodies (i.e. proteins made by the immune system in response to the presence of a foreign substance). These antibodies trigger a response that could eventually result in clot formation. Besides, the immune response can also produce other adverse effects, including convulsive disorder, Guillain–Barré syndrome, and facial nerve palsy.

Scientific evidence suggests that vaccines are safe overall. While mild complications, such as pain at the site of injection or bruising might occur, more serious events remain rare. Furthermore, the complications derived from COVID-19 are far more likely in non-vaccinated individuals than the complications associated with the vaccine. Thus, vaccination continues to be the safest and most effective strategy to control the ongoing pandemic. However, both health professionals and the public should be aware of the possibility of serious neurological adverse reactions occurring after vaccination to allow early diagnosis and treatment.

Introduction

Vaccines are one of the most effective approaches for preventing infectious diseases and have helped eradicate conditions, such as smallpox and reduce the incidence of several other infections. 1 The outbreak of the coronavirus disease 2019 (COVID-19) pandemic, which has infected and killed millions of people, imposed an urgent need for vaccines. As a result, multiple vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), the virus that causes COVID-19, have been developed in record time and billions of people have been immunized all around the globe. Different platforms have been used for COVID-19 vaccines that are currently being administered, such as replication-deficient viral vectors (e.g. ChAdOx1-S developed by Oxford/AstraZeneca, Jcovden Ad26.COV2.S developed by Janssen, Gam-COVID-Vac or rAd26-rAd25 developed by Gamaleya, and Ad5-nCoV developed by CanSino), inactivated viruses (e.g. CoronaVac developed by Sinovac), and novel mRNA-based vaccines (e.g. BNT162b2 developed by Pfizer/BioNTech and mRNA-1273 developed by Moderna). 2

Adverse effects of COVID-19 vaccines are mild in most cases, consisting of local reaction in the site of injection and/or minor systemic effects like fatigue or headache. These are most likely the result of the initial immune response, characterized by the production of antiviral cytokines, particularly interferons. 3 On the other hand, severe COVID-19 vaccine adverse reactions, such as anaphylaxis, are rare. Although uncommon, there are reports of neurological complications following vaccination against SARS-CoV-2 in some people. 2 Here, we aim to review the evidence regarding serious neurological adverse effects of COVID-19 vaccines, including epidemiological studies and experimental evidence that sheds light on the potential mechanisms.

We present a narrative review of the literature regarding the serious neurological complications of COVID-19 vaccines. We searched international biomedical journal databases, such as MEDLINE (PubMed) using the following Medical Subject Headings (MeSH) terms and their synonyms: (‘adverse effects’ OR ‘Drug-Related Side Effects and Adverse Reactions’) AND ‘COVID-19 Vaccines’ AND (‘Neurologic Manifestations’ OR ‘Nervous System’). This search included evidence published until August 2022. To identify potential additional studies for inclusion, we manually looked up the references of the articles found by the search strategy described above. Three reviewers screened the identified records based on title and abstract and then selected those to be included in this review based on the full text. A fourth reviewer was consulted in cases in which eligibility was unclear. After that, three researchers extracted the relevant information from the selected articles. Any discrepancies or missing information were resolved by consensus.

Cerebral venous sinus thrombosis

Following the Food and Drug Administration (FDA) emergency use authorization for COVID-19 vaccines and the rapid onset of immunization campaigns around the world, a concerning number of adverse effects following immunization (AEFI) cases arose. For instance, a Mexican study reported an AEFI rate of 0.5% among BNT162b2 recipients, of which only 0.005% were serious AEFI 4 (Most (90.9–97%) of the Vaccine Adverse Event Reporting System (VAERS) reports were classified as nonserious events. 5 , 6

Particularly, the scientific community focused on the emerging cases of a rare hematological syndrome with a clinical presentation similar to heparin-induced thrombotic thrombocytopenia (HITT). These thrombotic events and the accompanying thrombocytopenia in recently vaccinated individuals would soon be named vaccine-induced thrombotic thrombocytopenia (VITT). 7 VITT is a consumption coagulopathy that can present with cerebral venous sinus thrombosis (CVST) and/or splanchnic thrombosis. 8 – 11 Although these complications imply significant risk per se, the fact that VITT might be associated with CVST increases its fatal potential and the clinician’s concerns.

Aiming to determine whether the risk–benefit ratio is affected by this AEFI, epidemiological studies have been carried out. A population-based cohort study compared the rate of thrombotic events between the recipients of the ChAdOx1-S vaccine and the general population. A higher-than-expected rate of CVST was detected in the immunized cohort: 11 excess venous thromboembolic events, including 2.5 excess CVST per 100,000 vaccinations. Furthermore, a 20.25 [95% confidence interval (CI): 8.14–41.73] standardized morbidity ratio for CVST was obtained. 12 Based on the results, CVST could be considered a rarely occurring complication of ChAdOx1-S and potentially other adenoviral vector vaccines (e.g. Ad26.COV2.S, rAd26-rAd2, and Ad5-nCoV). Although results are based on a true population study, interpretation should be cautious because there is not sufficient evidence to determine whether a specificity criterion (i.e. that the vaccine is the only cause of the event) is met. 13 In addition to this, the vaccinated cohort was fundamentally composed of health care workers, 12 a sample that might not accurately represent the general population that is being immunized and its risk factors, becoming a potential source of bias.

In respect to mRNA-based vaccines (i.e. BNT162b2 or mRNA-1273), Dias et al. 14 reported two cases of CVST following administration of BNT162b2. One of these patients had iron deficiency anemia, a condition that is considered a rare cause of thrombosis by some authors. 15 In addition to that, she was taking combined oral contraceptives, which are well-known prothrombotic risk factors 16 and thus might have also contributed to thrombogenesis in this case. However, the common use of these medications makes their contributory role arguable. The other patient had been diagnosed with multiple conditions that could have contributed to clot formation, such as hypertension, diabetes, and dyslipidemia. 14

Furthermore, a retrospective cohort study compared the absolute risk of CVST following a COVID-19 diagnosis with the absolute risk of CVST following immunization with an mRNA vaccine against COVID-19. The incidence of CVST following infection was significantly higher than the incidence observed in the immunized cohort [relative risk (RR) = 6.33, 95% CI: 1.87–21.40, p  = 0.00014]. The risk for thrombocytopenia, a cornerstone in the diagnosis of VITT, was also compared between cohorts. An RR of 23.96 (95% CI: 21.49–26.73, p  = 0.0001) supports the fact that thrombocytopenia is significantly more likely after the SARS-CoV-2 infection than following vaccination. 17 This evidence contributes to the risk–benefit analysis as it demonstrates that infection by the SARS-CoV-2 virus implies a significantly higher risk for CVST and thrombocytopenia than the potential risk associated with vaccination. Moreover, the observed incidence of CVST was compatible with the lowest estimate of the baseline rate in the United States. 17 These findings suggest that mRNA vaccines are not linked to an increased rate of CVST. However, CVST associated with VITT is a very rare syndrome. However, some patients could receive an inaccurate diagnosis and healthcare systems might not have a strong pharmacovigilance framework, leading to underreporting that could partially explain the low incidence.

Considering that VITT is a recently described clinical entity, it is necessary to elucidate the clinical spectrum of vaccine-associated CVST that enables early patient detection and further pharmacovigilance. CVST secondary to VITT presents a wide continuum of neurological manifestations, ranging from subtle and often disregarded complaints to more alarming symptomatology. For instance, some patients who received adenoviral vector vaccines, such as ChAdOx1-S or Ad26.COV2.S vaccine presented with headaches but no other neurological symptoms upon admission. 10 , 18 Conversely, some of these patients debut with remarkable neurological symptoms, such as vertigo, hemianopia, aphasia, seizures, hemiparesis, behavioral disturbances, and altered states of consciousness. 19 – 21 Of note, there seem to be no significant differences between the manifestations of CVST among patients who received mRNA-based vaccines versus those immunized with adenovirus-based vaccines. Persistent headaches, malaise, vomiting, and motor deficits were common symptoms to CVST associated with both vaccine technologies. 14 , 18 , 22 – 24

Regardless of the initial clinical presentation, a rapid neurological deterioration could be expected. For instance, a 32-year-old male developed thunderclap headache, left-sided incoordination, and hemiparesis 9 days after the ChAdOx1-S vaccine. In the span of 3 h, his Glasgow Coma Scale (GCS) decreased from 15 to 4, requiring intubation and ventilation; while pupillary responses deteriorated and became fixed and dilated. At that time, a computed tomography (CT) scan revealed clot, significant cortical edema, and evidence of cerebellar herniation and brainstem death. 25

In light of the above, CVST must be promptly identified. Both clinicians and patients should pay attention to any neurological symptoms, even those mild, that onset particularly 48 h after the administration of a vaccine and should be aware of the possibility of serious neurological AEFIs. In addition, low platelet counts should be considered as a warning sign since it is a hallmark feature of this condition. A complete hematology profile (complete blood count, reactive C protein, erythrocyte sedimentation rate, D-dimer, prothrombin time, and partial thromboplastin time) together with imaging studies might be enough to determine whether the clinical findings are in line with an expected vaccine reactogenicity or indicate a serious neurologic AEFI. Patients affected by VITT present with varying degrees of thrombocytopenia 11 , 21 , 25 – 28 elevated D-dimer levels, and low or borderline fibrinogen levels, associated in some cases with prolonged clotting times. 29 , 30 As stated before, there is a possibility of rapid deterioration. Therefore, further and thorough continuing clinical observation is warranted.

A detailed differential diagnosis allows a proper assessment of alternative explanations for the aforementioned hematologic disturbances. Considering that recent research has established COVID-19 as a prothrombotic condition, potentially inducing arterial and venous thrombosis, 31 an active SARS-CoV-2 infection must be ruled out. The time of onset of symptoms and vaccine administration should be carefully investigated, with the aim to determine a potential temporal association. Besides, although prothrombotic conditions – some of them highly prevalent – cannot fully explain the overall occurrence of CVST in the population, several other prothrombotic pathologies must be excluded in each case before associating CVST with the vaccination event.

Although a temporal relationship between the vaccination event and symptom onset has been consistently reported, there are reasonable alternative etiologies and predisposing factors that should be considered. Many patients have presented thrombotic events following vaccination, but aside from the vaccine, they usually present numerous pre-existing conditions that behave as risk factors associated with clot formation. For instance, in a report of three cases of VITT after the ChAdOx1-S vaccination, a 61-year-old woman diagnosed with bilateral pulmonary embolism also had a history of hypertension and a high body mass index (38 kg/m 2 ). 32 Both obesity and hypertension have been regarded as prothrombotic conditions. 29 , 30 Along the same line, a case of a 36-year-old female with diabetes mellitus on oral hypoglycemic therapy was diagnosed with CVST among other conditions. 29 They attributed the condition to the vaccine due to the temporal relationship, however, it is important to consider that diabetes mellitus is a disease that facilitates clot formation. 33 , 34 Nevertheless, CVST cases have been reported in patients that did not present overt prothrombotic pre-existing conditions. 30

In addition to the complete hematology profile, clinically oriented imaging studies are an essential component of the diagnostic workup. Several findings have been described in patients that developed VITT syndrome with central nervous system (CNS) compromise. In patients with focal neurological symptoms, there is a trend toward the thrombotic occlusion of sigmoid and transverse sinuses, as well as for the presence of hemorrhagic events involving the cerebellum and the frontal region of the brain. 18 , 21 , 25 – 27 , 32 In addition, the thrombotic events in VITT patients can also affect other venous sites besides the cerebral veins (e.g. superior ophthalmic vein), as well as arteries (resulting in concomitant arterial occlusions). 11 , 35

As for the treatment, several authors reported favorable clinical outcomes in VITT patients following therapies that included intravenous immunoglobulin (IVIG). 10 , 11 , 18 , 20 In line with this, IVIG has been demonstrated to be effective in ceasing platelet activation leading to a rapid platelet count increase in patients with spontaneous HITT, which is thought to share a common pathophysiological mechanism with VITT. 36 More specifically, spontaneous HITT is characterized by autoimmune platelet activation induced by heparin-independent antibodies in the absence of heparin exposure. This fits with our current comprehension of the pathogenesis of VITT, which will be expanded later on.

Regarding the mechanism of VITT secondary to ChAdOx1-S vaccination, it seems to be triggered by the synthesis of IgG antibodies against platelet factor 4 (PF4). The presence of serum immune complexes in VITT patients with a mixture of antibody specificities similar to what is observed in HITT patients suggested similar underlying mechanisms in both conditions. 18 In HITT, because of the positively charged PF4 binding to the negatively charged heparin, a PF4/heparin complex (also called PF4/polyanion) forms as a tetramer. 37 , 38 In response, the immune system of genetically predisposed patients produces antibodies against PF4/heparin complexes. The fragment antigen-binding (Fab) region of IgG binds to PF4/heparin complexes, while the fragment crystallizable (Fc) region of these antibodies binds to Fcγ receptor IIa (FcγRIIa) on platelets. This antigen–antibody–receptor interaction leads to the expression of P-selectin on the platelet surface and results in FcγRIIa cross-linking. As a consequence, platelet activation and consumption, together with the release of procoagulant factors from the platelet and the endothelium itself, might lead to thrombin formation and – potentially – life-threatening thrombotic events. 32 , 37 Similarly, in VITT, antibodies against PF4 recognize eight surface amino acids within its heparin-binding site, allowing PF4 tetramers to cluster and form immune complexes, which then activate platelets in a FcγRIIa-dependent fashion. 38

Procoagulant platelets are characterized by the expression of activation markers; namely, P-selectin (also called CD62 P) and phosphatidylserine (PS). 39 Compared with sera from healthy controls, sera from VITT patients induced significant changes in the distribution of CD62 P/PS positivity in platelets from healthy donors ( p  = 0.009). 40 The procoagulant effect of platelets is partially explained by the strictly regulated translocation of membrane phospholipids, including PS. Following platelet activation, the enzyme scramblase will mediate the translocation of PS from the inner to the outer membrane surface. Once PS is available in the outer leaflet, it will ease the formation of the intrinsic tenase and the prothrombinase complexes, thus favoring thrombin synthesis during the propagation phase of coagulation. 39 Furthermore, P-selectin plays a key role in the pathophysiology of thrombosis. This transmembrane protein is found inside the alpha granules of platelets and cellular activation leads to its transport to the platelet cell membrane. Surface-expressed P-selectin mediates platelet-leukocyte and platelet-platelet interaction, thus contributing to the formation of cellular aggregates, upregulation of tissue factor, and synthesis of procoagulant molecules. 41 Consequently, induction of procoagulant markers such as P-selectin and PS by anti-PF4 immunoglobulins could presumably explain thrombotic events observed in VITT.

Increased levels of anti-PF4 antibodies have been identified in patients with VITT, with or without CVST. 11 , 18 , 28 , 32 , 40 Consistent with other reports, high-titer anti-PF4 IgG was detected in the sera of 8 out of 8 patients diagnosed with VITT following ChadOx1-S vaccination, five of which exhibited clinical evidence of CVST. 40 IgG binding to platelets was higher after incubation with sera from VITT patients compared with sera from healthy controls ( p  = 0.026). Stronger binding of IgG antibodies against PF4 was also detected in the sera of VITT patients ( p  < 0.0001). 40 Collectively, these results point out that the anti-PF4 antibody-mediated platelet activation is a likely mechanism underlying VITT and, in turn, vaccine-related CVST.

The positive clinical response to IVIG in VITT patients is in line with the involvement of anti-PF4 antibodies and the FcγRIIa in the pathogenesis of VITT. The mechanism of action of IVIG seems to be related to the inhibition of the FcγRIIa receptor by monomeric IgG. 42 Consistently, an in vitro study demonstrated that platelet activation was completely inhibited by a monoclonal antibody that blocks the FcγRIIa and by high doses of IgG. 40

On the other hand, among a group of 41 healthy vaccinees, four individuals (9.8%) seroconverted with IgG antibodies against PF4 complexes within 14 days of vaccination. Moreover, the sera from these patients did not induce platelet activation. 40 This supports the possibility of asymptomatic seroconversion. Taking this into account, we could assume that a small fraction of vaccinees seroconverts to IgG against PF4 complex, and even a smaller fraction of such patients develops VITT. We hypothesize that genetic factors underlie the susceptibility to produce antibodies against PF4 and to develop VITT in consequence.

Furthermore, there is some experimental evidence supporting the involvement of RNA splicing resulting in spike protein solubilization as the underlying mechanism of VITT associated with vector-based vaccines ( Figure 1 ). Following the entry of adenoviral DNA, the gene encoding the SARS-CoV-2 spike protein is transcribed inside the nucleus. Subsequently, arbitrary splicing events occur within the open reading frame of this transcript, most – if not all – of them resulting in shorter protein variants, disrupting the spike protein upstream of the membrane anchor, thus rendering it soluble. 9 Most likely, when such soluble proteins are systemically available, they bind to angiotensin-converting enzyme 2 (ACE2) receptors in the endothelial cells, while the immune system starts to produce antibodies against this viral protein, inducing a massive inflammatory response, characterized by antibody-dependent cell-mediated cytotoxicity and/or complement-dependent cytotoxicity. 9 Both the endothelial activation and the immune response would then trigger the coagulation cascade, thus predisposing to clot formation. Besides, the spike protein could also disrupt the integrity of the blood–brain barrier (BBB) and enhance platelet activation. 43 , 44 Because of the non-unidirectional blood flow and the lack of typical venous valves in the CNS sinuses, the soluble spike protein stays in these vessels for a longer period, thus raising the probability of binding to endothelial cells expressing the ACE2 receptor. This could explain the increased frequency of thromboembolic events in this unusual site, compared with other regions in the body. 9

Proposed mechanism of VITT associated with vector-based vaccines.

Created with BioRender.com.

For details, please refer to the main text. Adenoviral vectors contain DNA encoding the spike protein, which is transcribed inside the nucleus. The resulting RNA undergoes posttranscriptional modifications, including splicing to remove introns. Unwanted splicing events might result in a truncated spike mRNA, which is later translated to produce a spike protein lacking the membrane anchor. This soluble spike protein would then bind to ACE2 receptors on the membrane of endothelial cells and activate the immune system, thus resulting in inflammation, platelet activation, and – overall – a prothrombotic state.

ACE2, angiotensin-converting enzyme 2; mRNA, messenger ribonucleic acid; ssDNA, single-stranded deoxyribonucleic acid.

Once we have discussed the potential mechanisms for VITT and CVST associated with adenoviral-based vaccines, it is worth contemplating aspects regarding mRNA vaccines. Studies in nonhuman primates have shown that mRNA-based vaccines skew the immune response toward a T helper (Th)1 profile, characterized by the production of cytokines, such as interferon-gamma, tumor necrosis factor (TNF), and interleukin (IL) 2 (IL-2). 45 , 46 Under normal circumstances, endothelial cells maintain a balance between a thrombogenic and non-thrombogenic state; whether thrombosis is favored or not depends partially on available cytokines. TNF, as well as other cytokines, favors endothelial tissue factor expression, 47 which is well known for being the main initiator of the coagulation cascade. Thus, it is reasonable to hypothesize that mRNA vaccines induce a Th1 cytokine profile, which could be linked to prothrombotic pathways.

Experimental evidence regarding the effects of the SARS-CoV-2 spike protein sheds light on the potential mechanisms underlying vaccine-associated CVST. First, the spike protein directly affects the BBB. Electric cell-substrate impedance and a three-dimensional (3D) microfluidic model showed that the spike protein disrupts the integrity and increases the permeability of the BBB. 43 The SARS-CoV-2 spike protein also induces a proinflammatory phenotype in cultured human brain endothelial cells, with increased expression of adhesion molecules, proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs). 43 MMPs are endopeptidases thought to digest tight junction proteins (i.e. claudin-1, claudin-5, occludin, and zonula occludens-1), as well as basement membrane proteins in the BBB, thus disrupting its integrity. 48 When integrity and permeability of the BBB are altered, inflammatory cell migration into the brain parenchyma could be favored. Furthermore, the heightened expression of surface adhesion molecules could contribute to the inflammatory cascade and cellular aggregation initiating prothrombotic pathways. In addition, spike glycoprotein interaction with the ACE2 receptor results in enhanced platelet activation, including an increased expression of procoagulant platelet markers. 44

Taken together, these results point out that mRNA-based vaccines might promote thrombotic events by the induction of a prothrombotic cytokine profile. Alterations in the BBB and platelet function could also be involved. However, more studies are needed to elucidate the potential mechanisms of VITT associated with these vaccines.

Arterial ischemic stroke

Besides CVST, another potential thrombotic AEFI compromising the nervous system is arterial ischemic stroke. Epidemiological data support that neurological thrombotic AEFIs are rare. For instance, the reported incidence of acute stroke in Mexico associated with six different vaccines (BNT162b2, ChAdOx1 nCov-19, Gam-COVID-Vac, CoronaVac, Ad5-nCoV, and Ad26.COV2-S) was 0.71 cases per 1,000,000 administered doses. 49 Additional studies are required to determine whether VITT has a predilection – if any, to cause venous or arterial thrombotic events. Arterial thrombosis as a manifestation of VITT appears to be less common than venous thrombosis. 50 In fact, cerebral arterial thrombosis accounts only for 12% of ischemic events related to VITT, compared with venous thrombosis that contributes at least with 50% of the cases. 51 In contrast, a large retrospective study found that the acute ischemic stroke corresponded to 75% of the overall stroke incidence, while cerebral venous thrombosis was present only in 3.6% of the cases. 49 Although more robust studies are missing, it seems that some vaccine technologies are more prone to cause arterial ischemic events than others. mRNA vaccines such as BNT162b2 and Moderna are related to a higher incidence of arterial events. In contrast, the proportion of arterial versus venous ischemic events following viral vector vaccines seems to be more evenly distributed. 52

Acute ischemic stroke observed after COVID-19 vaccines are predominantly due to large artery atherosclerosis (34.9%), as has been reported in Mexico- and Indonesia-based studies. 49 , 53 Moreover, arterial ischemic events following immunization were predominantly reported in females, who developed motor symptomatology associated with anterior cerebral circulation occlusion. For instance, a 42-year-old female developed left hemiplegia 2 weeks after a ChAdOx1-S dose. Imaging revealed bilateral anterior cerebral artery (ACA) and right middle cerebral artery (MCA) occlusion. 54 Left hemiparesis was also de clinical manifestation in a 79-year-old male, in whom brain magnetic resonance imaging (MRI) showed lacunar infarcts in anterior circulation territories. 53 Similarly, involvement of the proximal segment of MCA was observed in a 51-year-old female who developed right-sided hemiplegia, hemianopia, and global aphasia 7 days after a ChAdOx1-S vaccine. 55

This case study is compatible with the analysis of large retrospective studies in which almost two-thirds of the arterial events were observed in females, 52 almost 90% of patients presented an anterior circulation stroke mainly involving the MCA, and motor deficit was the most common symptom (75%) followed by language deficits. 50

Laboratory findings in patients who developed arterial stroke were similar to those in patients with CVST (i.e. thrombocytopenia, high D-dimer levels, low fibrinogen, and positive anti-PF4 IgG antibodies). 54 , 55

These similarities suggest a common pathological pathway related to a coagulopathy induced by the vaccine. Nevertheless, some patients exhibit different paraclinical findings. For instance, a female patient with left hemiparesis due to occlusion of the M1 segment of the right MCA had a reduced platelet count and elevated D-dimer levels but negative ELISA for anti-PF4 antibodies. 50

Among patients affected by acute ischemic stroke following immunization, pro-atherosclerotic risk factors are common, as well as a personal history of past ischemic strokes. 53 Hence, we hypothesize that such events could also be attributed to the vaccine recipients’ underlying conditions, such as hypertension, diabetes mellitus, smoking, and dyslipidemia. 53 , 56 Even so, we cannot rule out that vaccine administration further predisposed for such outcomes.

Despite the fact that cerebral ischemic events have been reported all over the world, it has been reported that recipients of ChAdOx1-S or BNT162b2 recipients do not show an increased short- or long-term risk of acute ischemic stroke, which supports the safety of COVID-19 vaccines. 52 , 57

Convulsive disorder

Among the adverse effects following COVID-19 vaccines, some authors reported patients presenting with convulsive disorder. Essentially, two etiological groups can be identified: first, seizures due to acquired structural etiologies (i.e. stroke) in which the vaccine is suspected to be the cause; and second, seizures secondary to an unknown etiology (in which an autoimmune mechanism could be hypothesized). Although temporality points to an association with the vaccine, some of these cases do not offer solid evidence to establish a causal connection.

Regarding the first category, some seizures occurred in the context of immune-related venous thrombosis or arterial occlusion. For instance, a 55-year-old female who developed ocular and neurological symptoms 10 days after the first dose of the ChAdOx1-S vaccine was diagnosed with secondary immune thrombocytopenia and bilateral superior ophthalmic vein thrombosis. Despite the treatment, she developed transient mild right-sided hemiparesis and aphasia, followed by right-sided focal seizures. The new-onset clinical presentation correlated to an ischemic stroke in the left parietal lobe, corresponding to MCA territory. 35 Similarly, another 55-year-old female experienced transitory aphasia, right-sided hemiparesis, generalized seizures, and coma 10 days after receiving the first dose of ChAdOx1-S vaccine. Laboratory findings were compatible with VITT, including elevated levels of antibodies against PF4/polyanion complexes. In addition, neuroimaging revealed occlusion of the right internal carotid artery terminus, as well as an obstruction of the left MCA. 11 Besides, a 22-year-old female developed self-limited generalized seizures 7 days after ChAdOx1-S vaccination. She was diagnosed with VITT associated with CVST. 19

Focal cerebral ischemia caused by thrombosis has been associated with metabolic dysfunction, local ionic shifts, and the release of excitotoxic neurotransmitters. As a result, the membrane potential is offset, producing a hyperexcitable state and a lower seizure threshold. 58 , 59 In addition, a sizable proportion of CVST patients present with seizures. 60 , 61 Therefore, it is likely that seizures in this category are not due to a direct epileptogenic effect of immunization but secondary to CVST or arterial occlusion probably associated with VITT.

Concerning the second category, one case that exemplifies this phenomenon is a 42-year-old female who presented with new-onset refractory status epilepticus 10 days after vaccination with ChAdOx1-S, characterized by generalized tonic–clonic seizure. She continued to experience these seizures without improvement despite antiepileptic treatment, thus requiring coma induction. Remarkably, the patient improved after antiepileptic dosage optimization, immunotherapy with pulse steroid therapy, and plasma exchange. 62 Considering that the status epilepticus was not febrile-related, no structural abnormalities besides post-ictal changes were identified via MRI, and considering that the patient resolved upon immunotherapy, the observed neurological manifestations might be immune-mediated.

Evidence of convulsive disorders following vector-based vaccines is restricted to case reports. No large epidemiological studies have explored this association so far. Regarding mRNA vaccines, a Mexican-based cohort study focusing on BNT162b calculated a ratio of 0.99 seizures per 100,000 doses. In addition, the lifetime prevalence of epilepsy in Latin America is similar to the prevalence observed in this study. This suggests that mRNA-based vaccines might not be associated with a higher frequency of new-onset seizures. 4

To the extent of our knowledge, there are no experimental studies that explore the relationship between hyperexcitable states and COVID-19 vaccines or the mechanisms that could be responsible for this association. Nevertheless, suboptimal therapeutic response with conventional antiepileptics, in contrast to the observed success of anti-inflammatory medications in this setting, suggests an involvement of the immune response in the pathogenesis of these seizures, given a proper exclusion of other etiologies. The immune-mediated convulsive syndrome is the articulated effect between infiltration by immune cells (i.e. Th cells, B cells, neutrophils, and monocytes) and inflammatory mediators, and the response of cerebral tissue resident cells. 63 Trauma, stroke, infection, or febrile status can cause neuroglial and endothelial cell activation. As a result, proinflammatory cytokines, such as IL-1β and TNF-α, are released. The subsequent inflammatory cascade increases intracellular calcium currents and provokes ion channel dysregulation, triggering epileptogenesis. 58 , 64 Similarly, during COVID-19, neuronal hyperexcitability is thought to be induced by reactive astrogliosis, activation of the microglia, cytokine storm, and BBB dysfunction. 65 However, it should be acknowledged that the scenario of an active SARS-CoV-2 infection is different from the post-immunization response.

Considering all this, immune-mediated epileptogenesis might be a plausible mechanism for the seizures following immunization against COVID-19. However, further experimental studies are needed to elucidate the pathophysiology of this vaccine-related condition. Until then, these ideas remain speculative.

Guillain–Barré syndrome

Guillain–Barré syndrome (GBS) is an immune-mediated polyradiculoneuropathy that occurs after some respiratory or gastrointestinal infections. Culprit pathogens such as Campylobacter jejuni and some viruses, such as the hepatitis E virus, have been associated with the development of the disease via a molecular mimicry mechanism. For instance, a subset of C. jejuni has lipo-oligosaccharides that can mimic the carbohydrate moiety of gangliosides in peripheral nerves triggering a humoral immune response that can result in nerve dysfunction. 66 GBS is often characterized by a rapidly progressive, symmetrical weakness of the limbs, usually with hyporeflexia or areflexia. Even though it can be self-resolving, it could be life-threatening in certain cases, as it causes respiratory muscle compromise. 66 , 67 Cerebrospinal fluid (CSF) analysis, nerve conduction study, as well as an MRI, are relevant for the diagnosis. Many patients with GBS are treated with IVIG, but some of them may require mechanical ventilation due to respiratory failure.

GBS has an incidence of 0.81–1.89 (median: 1.11) per 100,000 person-years, being more common in men than women (ratio 3:2). 66 Moreover, some rare cases have been reported following COVID-19 vaccination, but considering that it has life-threatening complications, such cases have raised public concern.

In a prospective observational study from Mexico after the first dose of BNT162b2, neurologic adverse effects among 704,000 vaccinees were assessed. Overall, three GBS cases (0.43 per 100,000 doses) were confirmed by clinical, laboratory, and electrophysiologic studies. Notably, all these patients had confirmed gastrointestinal infections and were negative for COVID-19. On the other hand, in the United Kingdom, a country with high vaccination rates, the Medicine and Health Care Products Regulatory Agency has reported that 491 patients developed GBS after the ChAdOx1-S vaccine between 1 January 2021 and 30 March 2022. 68 Some reports of this syndrome following COVID-19 immunization exhibit a temporal association with the vaccine and a classical clinical picture of GBS, including improvement upon IVIG administration in some cases. 67 , 69 However, to the best of our knowledge, the causality of this association has not yet been proven.

More recently, a report from surveillance data from the Vaccine Safety Datalink of the United States described the incidence of GBS following administration of Ad26.COV2.S, BNT162b2, or mRNA-1273 vaccines in 10,158,003 people (from 13 December 2020 to 13 November 2021). GBS was rare among those receiving these vaccines: GBS incidence after the mRNA vaccines was similar to the expected background rate while the incidence after Ad26.COV2.S was slightly greater. The adjusted RR of GBS during the 21 days following Ad26.COV2.S was 20.56 compared with mRNA vaccines ( p  < 0.001), corresponding to 15.5 excess cases per million Ad26.COV2.S recipients. 70 Thus, there was a small but significant increase in the risk of GBS after Ad26.COV2.S, which is consistent with previous reports. 71 Similar to these findings, a study conducted in Mexico that involved over 80 million doses of seven COVID-19 vaccines (mRNA-1273, BNT162b2, ChAdOx1-S, rAd26-rAd5, Ad5-nCoV, Ad26.COV2.S, and CoronaVac) found an overall incidence of 1.19 cases per million administered doses, the highest incidences were found among Ad26.COV2.S and BNT162b2 recipients. 72 Furthermore, an analysis of the World Health Organization pharmacovigilance database found a frequency of 0.13% of GBS and its variants following vaccination with either ChAdOx1 -S, BNT162b2, or mRNA-1273, which was low but higher when comparing it against the entire database. 73 However, it was not greater than the risk of GBS associated with influenza vaccine. 73 Overall, these data suggest that, although the risk for GBS may be higher after administration of certain COVID-19 vaccines, it is still low and similar to the background risk in most cases, therefore not surpassing the benefit of immunization.

A case series also reported two cases of GBS after receiving the BNT162b2 vaccine in two older women with a history of diffuse large B-cell lymphoma. The Adverse Drug Reaction Probability Scale (also called Naranjo scale) was calculated for these cases, and a score of 7 was obtained. Even though this is compatible with the GBS being a probable adverse drug reaction of the vaccine, the B-cell dysfunction presented by the patients is a potential predisposing factor for the disease. 74

A rare variant of GBS, characterized by bifacial weakness with paresthesia and facial diplegia as the only motor manifestation, has been reported in some of the cases of this syndrome following COVID-19 vaccination, particularly the ChAdOx1-S vaccine. 75 Interestingly, this GBS variant has also been described during SARS-CoV-2 infection, which suggests an involvement of the immune response to the spike protein. The observed latency period (11–22 days) supports the biological plausibility of this association, considering that the maximal immune response from vaccination is expected to occur in a similar window of time. 75

GBS has been linked to certain vaccines over the years. As mentioned before, some data indicate an association between influenza vaccine and GBS, but the evidence is not conclusive. 66 , 76 GBS secondary to the influenza vaccine is considered an immune-mediated event. Considering that GBS post-COVID-19 vaccination has a latency similar to GBS post-influenza (approximately 3 weeks), an immune-mediated mechanism is also suggested for the former. 77 There is no evidence regarding the precise mechanisms that underlie post-vaccination GBS. However, it is reasonable to hypothesize a role for the production of certain cytokines, like IL-6, IL-12, IL-15, and TNF-α, by macrophages and microglia cells, similar to what happens during an active SARS-CoV-2 infection. 67 This cellular activation and cytokine production can result in chronic inflammation and brain damage. In addition, vaccine product-related reaction can also play a role in vaccine-induced GBS, since certain contaminating proteins or other vaccine components could cause anti-ganglioside antibody production involved in the disease. 78

Facial nerve palsy

Facial nerve palsy (FNP) is a mononeuropathy that has been diagnosed among COVID-19 vaccine recipients. Therefore, it is currently being assessed as a possible AEFI. A similar phenomenon occurred following influenza and meningococcal vaccines, but a causal link has not yet been established. Overall, the cause of FNP is unknown in most cases (70% of cases), which is known as idiopathic FNP or Bell’s palsy (BP). 79

Epidemiological studies play a key role in the process of assessing causality; thus, a cautious interpretation of data is essential. An FDA briefing document regarding a meeting of the Vaccines and Related Biological Products Advisory Committee included the report of four BP cases among the recipients of the BNT162b2 vaccine versus none in the control group. 80 Although these results raised concerns given the imbalance of BP cases between vaccine and placebo groups, there is no certain causal relationship with the vaccine because the observed incidence in the group of vaccinees was not higher than the expected for the general population. 80 Similarly, in the mRNA-1273 phase 3 trial, four cases of BP were reported among 30,420 participants randomized on a 1:1 basis. It is important to note that three of the cases were in the vaccine arm and one of them was in the placebo arm. 81 In an Israeli case–control study, 37 patients with new-onset acute FNP were compared with matched controls. The study design aimed to minimize bias by controlling for variables, such as age, sex, and seasonality risk factors. Results showed that there was not an increase in the number of admissions due to FNP compared with previous years. Accordingly, the BNT162b2 vaccine was not identified as a risk factor for FNP in this study. 82 However, the possibility of an association between these vaccines and BP should be closely monitored.

FNP is characterized by very noticeable clinical features. The typical clinical presentation includes sudden onset of unilateral facial paralysis and other signs and symptoms, such as eyebrow ptosis, inability to close the eye, disappearance of the nasolabial fold, and ptosis at the affected corner of the mouth. The initial diagnostic approach should be meticulous due that it is considered an exclusion diagnosis and other pathologies (e.g. GBS, herpes zoster, sarcoidosis) should be pondered. 83 Prior to the establishment of FNP as an AEFI, it is necessary to consider pre-existing conditions as potential triggers or risk factors leading to the disease. Diabetes, obesity, hypertension, pre-eclampsia, and upper respiratory disease have been previously described as risk factors for FNP and should be taken into consideration. 79 However, these pre-existing conditions could not have triggered the condition by themselves in the absence of vaccine exposure.

The aforementioned considerations are depicted in a case series that included nine patients reported to have new-onset acute FNP. Among these, four patients had hypertension, a condition that could have contributed to the development of the disease. 84 Similarly, BP was described in a 57-year-old female who had a past medical history of three episodes of BP and hypertension secondary to corticosteroid administration. Interestingly, the latency periods from vaccine administration to FNP development described throughout the reviewed literature are highly variable, ranging from a few hours to 30 days after receiving a COVID-19 vaccine dose. 84 , 85

Several hypotheses aim to explain BP secondary to the COVID-19 vaccination: interferon production, molecular mimicry, bystander effect, among others. FNP has been reported as a rare possible complication of interferon therapy. Considering that COVID-19 vaccines, such as BNT162b2, have been demonstrated to induce an activation of the innate immune system, including the production of interferons, this mechanism is biologically plausible. 86 Moreover, molecular mimicry between vaccinal antigens and self-antigens present in the facial nerve could result in the production of cross-reactive antibodies. A bystander effect, in which self-antigens are presented at the site of the immune response elicited by the vaccine and the subsequent activation of dormant autoreactive lymphocytes, would trigger an immune response responsible for nerve inflammation. 82 , 86

Other reported neurological AEFIs are even less frequent than the ones discussed so far. Considering that vaccination campaigns are still being carried out and further vaccine boosters are expected to come, more AEFIs could arise. Therefore, clinicians should remain vigilant to worrisome signs and symptoms following COVID-19 vaccination. Hereon, we summarize some examples of rarely reported disorders that developed after immunization against COVID-19.

In the first place, a 51-year-old man with multiple comorbidities was being treated with clozapine for schizoaffective disorder. After receiving the BNT162b2 vaccine, he presented with delirium, normal pressure hydrocephalus, and a twofold increase in blood clozapine levels. This adverse reaction was attributed to inflammation-related CYP1A2 (i.e. the cytochrome enzyme responsible for clozapine metabolism) inhibition. 87 Several studies have reported a link between inflammation and elevated levels of clozapine. 88 In addition, inflammatory mediators are known to reduce CYP1A2 activity. 89 Inflammation has been proposed to block drug-metabolizing enzymes via three mechanisms: stimulation of transcriptional regulators, induction of nitric oxide-dependent proteasome proteolysis of enzymes, and epigenetic modifications resulting in lower gene expression. 88 However, the extent of the impact of inflammation on clozapine levels is not clear. Despite the temporality and biological plausibility of this observed effect following an mRNA-based vaccine, the patient’s pre-existing conditions may have played a significant role.

Other authors reported a patient with delirium and fever without meningeal irritation or neurological focal signs, accompanied by moderate widespread slowing on the electroencephalogram (EEG) after receiving the first dose of the ChAdOx1-S vaccine. 90 Increased BBB permeability was detected by lumbar punctures showing high levels of CSF protein. Initially, CSF and serum proinflammatory cytokines, together with serum C reactive protein, were elevated. Hence, an exaggerated innate immune response could have been involved in what the authors regard as a cytokine storm-associated encephalopathy. This condition has been linked to an immune effector cell-associated neurotoxicity syndrome in other circumstances, such as chimeric antigen receptor T-cell treatments, COVID-19 infection, and autoimmune diseases. 90

New-onset neuropathies following COVID-19 immunization are rare. In a case report, a 57-year-old female complained of intense burning dysesthesias in the extremities 1 week after receiving the BNT162b2 vaccine. Skin punch biopsies confirmed multifocal small fiber neuropathy. Having excluded other possible etiologies for the disease, the vaccine remains as a possible trigger. Previous reports have also described small fiber neuropathy following other vaccines. 91 A hypersensitivity reaction to polyethylene glycol was considered a possible mechanism for the pathogenesis in this case. 92

Finally, transverse myelitis (TM) is a rare immune spinal cord disorder often induced directly by infection or by autoimmune responses during or following an infection. 93 TM has been previously linked with systemic infections and vaccinations, as these can cause inflammation of the spinal cord. Other relevant etiologies include multiple sclerosis, autoimmune diseases and neuromyelitis optica spectrum disorder.

Although this disease remains rare after vaccination, some authors report cases of TM following COVID-19 vaccines after a proper exclusion of alternative causes, such as CNS infection or active SARS-CoV-2 infection. 93 , 94 Although more cases have been described in the literature, the lack of clinical information in many cases precludes adequate causality assessments. 93 During ChAdOx1-S clinical trials, three cases were reported among a 11,636 cohort: two in the ChAdOx1-S arm and one in the control group. However, two of these cases (one in the ChAdOx1-S group and one in the control group) were deemed unlikely to be related to the administered drug. 95 Nevertheless, the occurrence of TM cases has raised concern as it represents a very serious condition and should be carefully evaluated, including the exclusion of compressive and noninflammatory causes of myelitis.

Discussion, concluding remarks, and future perspectives

Throughout this review, we have summarized and discussed the scientific literature regarding neurological complications following COVID-19 vaccines. Immunization campaigns have successfully reduced mortality and morbidity due to COVID-19, proving to be an effective public health measure to battle the ongoing pandemic. Although acceptable vaccine safety was reported during clinical trials, public concern arose because of numerous reports of AEFIs that emerged around the globe. Henceforth, epidemiological studies were carried out, some of them showing that the risk of certain neurological AEFIs is not higher than the risk of neurological complications due to COVID-19 or than the basal risk of these conditions in the general population. This underpins vaccine safety and should encourage the continuation of immunization campaigns as needed. Despite several cases of these neurological AEFIs have been reported in the literature, the overall evidence does not support a true association in many cases. However, this issue remains yet unresolved and awaits further exploration. Meanwhile, clinicians should remain vigilant of early manifestations of potentially serious neurological AEFIs, so as to allow early diagnosis and treatment, thus reducing the probability of long-lasting sequelae or fatal outcomes.

While billions of people have been immunized against COVID-19 all over the world, only a small proportion of them develop neurological AEFIs. It is reasonable to hypothesize that genetic factors are responsible for an increased susceptibility to these neurological complications in a subset of individuals, while the vaccine acts as an environmental trigger. Genetic association studies and next-generation sequencing could help identify candidate genes for these complex traits. However, to the best of our knowledge, no studies have yet explored the genetic basis of these neurologic adverse reactions after COVID-19 vaccines.

Although rare, neurological complications following COVID-19 immunization should persist as a subject of pharmacovigilance and of epidemiological and biomedical research. Once vaccines were authorized by several regulatory entities, each country developed policies that prioritized certain population groups (e.g. healthcare workers, vulnerable age groups). Therefore, initial epidemiological studies were based on samples that might not accurately represent the entire population. Now that vaccines are massively available in most countries, larger epidemiological studies should be carried out and ongoing pharmacovigilance should be encouraged, aiming to eliminate potential sources of bias and provide the scientific community with more accurate frequency data for these neurological AEFIs.

Even though the precise pathophysiological mechanisms underlying neurological AEFIs mechanisms are not fully understood, these conditions can still be serious, life-threatening or fatal. Clinical data suggest that anti-PF4 antibodies are involved in the genesis of CVST after COVID-19 vaccines, similar to what occurs in HITT. However, how these antibodies are produced in response to the immunizing agents is not well understood. Currently, most of the evidence that has contributed to the elucidation of the mechanisms that might underlie neurological AEFIs comes from experimental studies focusing on the virus and not the vaccine itself. More experimental studies are required to increase our understanding of the potential link between vaccination and altered homeostasis in the nervous system.

Despite the pathophysiological similarities that were initially contemplated between HITT and VITT, some distinctions have been progressively unraveled. Compared with the typical HITT, anti-PF4/polyanion IgG titers were higher and platelet aggregation was less dependent on physiologic levels of heparin and less sensitive to inhibition with high-dose heparin in VITT patients. 18 However, the clinical implications of these differences are yet to be determined. Furthermore, considering the potential relevance of anti-PF4 antibodies in the pathophysiology of CVST, additional clinical research should clarify the significance of serological screening among populations at risk. More specifically, it is worth determining if the detection of anti-PF4 antibodies in patients with prothrombotic risk factors or in those with a history of autoimmunity has a predictive value that would justify prophylactic measures.

Acknowledgments

Not applicable.

Contributor Information

Sara Eslait-Olaciregui, Histology and Embriology Unit, Department of Biomedica Science, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia. Applied Biomedical Sciences Research Group (UR BioMed), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.

Kevin Llinás-Caballero, Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.

David Patiño-Manjarrés, Histology and Embriology Unit, Department of Biomedica Science, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia. Applied Biomedical Sciences Research Group (UR BioMed), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.

Thomas Urbina-Ariza, Histology and Embriology Unit, Department of Biomedica Science, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia. Applied Biomedical Sciences Research Group (UR BioMed), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.

Juan Fernando Cediel-Becerra, Histology and Embriology Unit, Department of Biomedica Science, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia. Applied Biomedical Sciences Research Group (UR BioMed), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.

Camilo Alberto Domínguez-Domínguez, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 #63C-69, 111221 Bogotá, Colombia.

Declarations

Ethics approval and consent to participate: Not applicable because this manuscript is a literature review and did not involve human participants, original human data, or human tissue.

Consent for publication: Not applicable because this manuscript is a literature review and did not involve human participants, original human data, or human tissue.

Author contributions: Sara Eslait-Olaciregui: Conceptualization; Data curation; Investigation; Visualization; Writing – original draft; Writing – review & editing.

David Patiño-Manjarrés: Conceptualization; Data curation; Investigation; Visualization; Writing – original draft; Writing – review & editing.

Thomas Urbina-Ariza: Data curation; Investigation; Visualization; Writing – original draft; Writing – review & editing.

Juan Fernando Cediel-Becerra: Conceptualization; Supervision; Writing – review & editing.

Camilo Alberto Domínguez-Domínguez: Conceptualization; Supervision; Writing – review & editing.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by Universidad del Rosario

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Availability of data and materials: Not applicable.