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Essays on Vaccination

Vaccines essay topics and outline examples, essay title 1: "the vital role of vaccines in public health: debunking myths and upholding science".

Thesis Statement: Vaccines are a cornerstone of public health, and it is crucial to dispel misinformation and emphasize the overwhelming scientific evidence supporting their safety and efficacy.

Essay Outline:

• Introduction
• The History and Impact of Vaccines
• Common Vaccine Myths and Misconceptions
• Scientific Evidence Supporting Vaccines
• Vaccine Safety and Adverse Effects
• The Importance of Herd Immunity
• Addressing Vaccine Hesitancy

Essay Title 2: "Vaccination Mandates: Balancing Individual Rights with Public Health"

Thesis Statement: While respecting individual rights is essential, vaccination mandates are a legitimate measure to safeguard public health and prevent outbreaks of vaccine-preventable diseases.

• The Concept of Vaccination Mandates
• Individual Rights and Autonomy
• Public Health Concerns and Disease Prevention
• Legal and Ethical Considerations
• Case Studies of Vaccine Mandates
• Opposition and Challenges to Mandates

Essay Title 3: "The Impact of Vaccine Disinformation on Public Health: A Global Challenge"

Thesis Statement: The proliferation of vaccine disinformation poses a significant threat to public health, and addressing this challenge is vital to ensure widespread vaccine acceptance and disease control.

• The Spread and Impact of Vaccine Disinformation
• Factors Contributing to Vaccine Hesitancy
• The Role of Social Media and Online Platforms
• Countering Vaccine Disinformation Efforts
• Global Initiatives and Collaborations
• Case Studies on Successful Interventions

The Benefits of Vaccination

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The Issues Surrounding Vaccination and Its Importance

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The Use of Vaccination – a Choice for Every One

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The Importance of Vaccines to Prevent Infectious Diseases

Advantages and disadvantages of the various types of vaccines, chickenpox: history, symptoms and treatment, the importance of increasing hpv vaccination in children, why is vaccination of human papillomavirus significant, debate on vaccination and autism, impact of media on parents' acceptance of immunization, the use of vaccines in modern medicine and the vaccination delimma, legal and ethical issues about the mmr vaccine, an argument in favor of using vaccines, the urgent need for a vaccine against zika virus, report on the measles disease and vaccination, yellow fever disease - what problems are caused by mosquitoes, chasing polio eradication: vaccine development, the examination of human sciences in connection to the effectiveness of vaccines, the different types of vaccines, vaccine types, should vaccinations be mandatory: future safety for children, should parents vaccinate their child, should vaccines be required to attend public school.

Vaccination, also known as immunization, is a medical procedure that involves the administration of a vaccine to stimulate the immune system and provide protection against specific infectious diseases. It is a preventive measure designed to enhance the body's natural defenses by introducing harmless fragments of the disease-causing agent or weakened or inactivated forms of the pathogen.

The mechanism of vaccination involves introducing a weakened or inactivated form of a disease-causing agent, such as a virus or bacterium, into the body. This prompts the immune system to recognize and respond to the pathogen. When a vaccine is administered, it stimulates the immune system to produce an immune response, similar to what would happen during a natural infection. The immune system recognizes the foreign antigens present in the vaccine and mounts a defense by producing antibodies and activating immune cells. These immune responses help the body develop immunity against the specific pathogen. Vaccination can also involve the use of genetically engineered proteins or pieces of the pathogen to stimulate an immune response. These components are known as antigens and can be derived from the outer coats of viruses or the cell walls of bacteria. By introducing these harmless components of the pathogen into the body, vaccines help the immune system recognize and remember the specific pathogen. This way, if the individual is later exposed to the actual disease-causing agent, their immune system can mount a rapid and effective response to neutralize or eliminate the pathogen, preventing the development of the disease or reducing its severity.

1. Inactivated Vaccines 2. Live Attenuated Vaccines 3. Subunit, Recombinant, and Conjugate Vaccines 4. mRNA Vaccines 5. Viral Vector Vaccines

The origin of vaccination can be traced back to ancient times, although the concept was not fully understood at the time. The practice of vaccination, as we know it today, began with the discovery of immunization against smallpox by Edward Jenner in the late 18th century. Jenner, an English physician, observed that milkmaids who had contracted cowpox, a much milder disease, seemed to be protected against smallpox. In 1796, he conducted an experiment where he took material from a cowpox sore and inoculated it into an eight-year-old boy named James Phipps. Afterward, Jenner exposed the boy to smallpox, but he did not develop the disease. This groundbreaking experiment led to the development of the smallpox vaccine. The term "vaccination" itself comes from the Latin word "vacca," meaning cow, as the original smallpox vaccine was derived from cowpox. Jenner's work paved the way for the development of vaccines against other infectious diseases, and vaccination quickly became a widely accepted method for preventing and controlling the spread of deadly diseases.

Public opinion on vaccination varies across different societies and individuals. Overall, vaccination has been widely accepted and supported by the majority of the population, recognizing its significant role in preventing and controlling infectious diseases. Vaccines have been instrumental in eradicating or significantly reducing the impact of diseases such as smallpox, polio, measles, and more. However, there are also pockets of skepticism and opposition towards vaccination, driven by various factors such as misinformation, fear, religious beliefs, or concerns about vaccine safety. This has led to the emergence of anti-vaccine movements and vaccine hesitancy in some communities. Public opinion on vaccination is influenced by various factors, including access to accurate information, trust in healthcare professionals and scientific research, cultural and religious beliefs, personal experiences, and the influence of social media and other communication channels. Efforts to promote vaccination and address vaccine hesitancy involve public health campaigns, education, and communication strategies to provide accurate information about vaccines, address concerns, and emphasize the importance of vaccination in protecting individual and public health.

1. Disease prevention 2. Herd immunity 3. Public health impact 4. Safety and effectiveness 5. Global impact

1. Vaccine safety concerns 2. Personal freedom and choice 3. Misinformation and skepticism 4. Religious or philosophical objections 5. Perception of low disease risk

1. According to the World Health Organization (WHO), vaccines prevent between 2-3 million deaths worldwide every year. 2. Smallpox is the only disease that has been totally eradicated through vaccination. 3. Vaccines have significantly reduced the global burden of infectious diseases. For instance, measles deaths decreased by 73% worldwide between 2000 and 2018. 4. The influenza vaccine helps reduce the risk of severe illness and hospitalization. In the United States, annual flu vaccination prevented an estimated 7.5 million flu illnesses during the 2019-2020 season. 5. The average vaccine takes around 10-15 years of research and development before it is widely available.

The topic of vaccination is of paramount importance when considering the impact it has had on public health. Writing an essay about vaccination provides an opportunity to explore the profound significance of this medical intervention. Vaccination has played a pivotal role in preventing and controlling infectious diseases, saving countless lives worldwide. By delving into the subject, one can highlight the historical development of vaccines, their mechanisms of action, and the scientific evidence supporting their effectiveness. Furthermore, examining the topic of vaccination allows for an exploration of the public health implications, including the concept of herd immunity and the role of vaccination in disease eradication efforts. It also provides a platform to address the various arguments surrounding vaccine hesitancy and vaccine refusal, shedding light on the importance of accurate information, education, and communication. Moreover, the essay can delve into the ethical considerations surrounding vaccination policies, such as balancing individual autonomy with the collective responsibility for public health. By exploring these aspects, one can foster a deeper understanding of the challenges, controversies, and potential solutions in promoting vaccination uptake.

1. American Academy of Pediatrics. (2018). Immunization information for parents. https://www.healthychildren.org/English/safety-prevention/immunizations/Pages/default.aspx 2. Centers for Disease Control and Prevention. (2021). Vaccines & immunizations. https://www.cdc.gov/vaccines/index.html 3. Gust, D. A., Darling, N., Kennedy, A., & Schwartz, B. (2008). Parents with doubts about vaccines: Which vaccines and reasons why. Pediatrics, 122(4), 718-725. https://doi.org/10.1542/peds.2007-0538 4. Larson, H. J., de Figueiredo, A., Xiahong, Z., Schulz, W. S., Verger, P., Johnston, I. G., Cook, A. R., Jones, N. S., & the SAGE Working Group on Vaccine Hesitancy. (2016). The state of vaccine confidence 2016: Global insights through a 67-country survey. EBioMedicine, 12, 295-301. https://doi.org/10.1016/j.ebiom.2016.08.042 5. MacDonald, N. E., Hesitancy SAGE Working Group. (2015). Vaccine hesitancy: Definition, scope and determinants. Vaccine, 33(34), 4161-4164. https://doi.org/10.1016/j.vaccine.2015.04.036 6. Offit, P. A., Quarles, J., Gerber, M. A., Hackett, C. J., & Marcuse, E. K. (2002). Addressing parents' concerns: Do vaccines cause allergic or autoimmune diseases? Pediatrics, 110(6), 1113-1116. https://doi.org/10.1542/peds.110.6.1113 7. Omer, S. B., Salmon, D. A., Orenstein, W. A., deHart, M. P., & Halsey, N. (2009). Vaccine refusal, mandatory immunization, and the risks of vaccine-preventable diseases. New England Journal of Medicine, 360(19), 1981-1988. https://doi.org/10.1056/NEJMsa0806477 8. Smith, P. J., Humiston, S. G., Parnell, T., Vannice, K. S., & Salmon, D. A. (2011). The association between intentional delay of vaccine administration and timely childhood vaccination coverage. Public Health Reports, 126(Suppl 2), 135-146. https://doi.org/10.1177/00333549111260S219 9. World Health Organization. (2019). Ten threats to global health in 2019. https://www.who.int/news-room/spotlight/ten-threats-to-global-health-in-2019 10. World Health Organization. (2021). Immunization coverage. https://www.who.int/news-room/fact-sheets/detail/immunization-coverage

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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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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.

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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

NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK

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Correspondence to Andrew J. Pollard .

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Competing interests.

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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Related links

Advisory Committee on Immunization Practices (ACIP): https://www.cdc.gov/vaccines/acip/index.html

Coalition for Epidemic Preparedness Innovations (CEPI): https://cepi.net/

Gavi, the Vaccine Alliance: https://www.gavi.org/

Joint Committee on Vaccination and Immunisation (JCVI): https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-immunisation

Nature Milestones in Vaccines: https://www.nature.com/immersive/d42859-020-00005-8/index.html

The Green Book, information for public health professionals on immunisation, Public Health England : https://www.gov.uk/government/collections/immunisation-against-infectious-disease-the-green-book

Vaccine Knowledge Project: https://vk.ovg.ox.ac.uk/vk/

Vaccines 101: How new vaccines are developed: https://www.youtube.com/watch?v=2t_mQwTY4WQ&feature=emb_logo

Vaccines 101: How vaccines work: https://www.youtube.com/watch?v=4SKmAlQtAj8&feature=emb_logo

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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Types of COVID-19 Vaccines

This primer outlines key terms and concepts related to COVID-19 vaccines and is intended for members of the general public, policy makers, educators, and key stakeholders.

International Vaccine Access Center

This primer on Covid-19 vaccines consists of a series of brief reports on vaccine development, allocation, and deployment in the United States and globally. The intended audience is the general public as well as policymakers, educators, and key stakeholders interested in a concise guide to Covid-19 vaccines. Topics to be addressed include ensuring the safety and efficacy of Covid-19 vaccines, principles for vaccine allocation, strategies for deployment and delivery of Covid-19 vaccines, vaccine confidence and demand, and the economics of Covid-19 vaccines.

Types of Covid-19 Vaccines

Several different types of vaccines against SARS-CoV-2, the virus that causes the disease Covid-19, are in development. Some are based on traditional methods for producing vaccines and others use newer methods.

Vaccines stimulate the human body’s own protective immune responses so that, if a person is infected with a pathogen, the immune system can quickly prevent the infection from spreading within the body and causing disease. In this way, vaccines mimic natural infection but without actually causing a person to become sick.

For SARS-CoV-2, antibodies that bind to and block the spike protein on the virus’s surface are thought to be most important for protection from disease because the spike protein is what attaches to human cells, allowing the virus to enter. Blocking this entrance prevents infection and thus disease and transmission to others.

Desired vaccine characteristics

The ideal SARS-CoV-2 vaccine would:

• be safe and associated with only mild, transient side effects (e.g. soreness and low-grade fever);
• confer long-lasting protection (more than a season) in a high proportion of vaccine recipients (e.g. >80%), particularly in vulnerable populations such as the older adults and those with other underlying medical conditions or risk factors such as obesity;
• protect not only against disease but prevent virus transmission to others;
• be administered as a single dose;
• be able to be produced quickly and in large quantities;
• be easily stored (e.g., not at ultra-low temperatures, in packaging that does not require a lot of space);
• can be easily transported (e.g., outside of the cold-chain or even through the mail); and
• can be easily administered (does not require special devices, self-administered or administered by those who do not require much training).

The initial SARS-CoV-2 vaccines will not have all of these characteristics and we may never have a vaccine that does. Different types of vaccines will have different characteristics with different tradeoffs. The most important characteristics are that a SARS-CoV-2 vaccine be safe, shortly after vaccination and in the long term, and protect a substantial proportion of those vaccinated against moderate to severe disease, particularly those in the most vulnerable groups.

Inactivated virus vaccines

Several inactivated SARS-CoV-2 vaccines have been developed, including those by Sinovac Biotech, Sinopharm, the Wuhan Institute of Biological Products, and Bharat Biotech. Inactivation of viruses is a well-established method to produce vaccines and several inactivated virus vaccines are widely used, including vaccines against influenza, polio, hepatitis A, and rabies viruses. The virus is inactivated so that it can no longer replicate or multiply. The immune system is exposed to viral proteins but the inactivated virus cannot cause disease. The inactivated virus stimulates the body’s immune system to produce antibodies so when a person is exposed to the natural virus, antibodies are called to action to fight the virus.

Production of inactivated virus vaccines requires the ability to cultivate or grow the virus in large quantities. Because viruses cannot replicate outside of host cells, vaccine viruses need to be cultured in continuous cell lines or tissues. Influenza virus, for example, is typically grown in eggs to produce the inactivated influenza vaccine. The virus is then purified and concentrated before inactivation with chemicals. Inactivated vaccines typically do not provide immune responses as strong as attenuated (i.e., modified or weakened viruses so they do not cause disease) viral vaccines and may require booster doses to achieve and sustain protection.

Inactivated virus vaccines have been produced for many decades and the manufacturing procedures are well established and relatively straightforward, although there are challenges to producing safe and effective inactivated virus vaccines. First, the inactivation process has to sufficiently inactivate all of the virus without changing viral proteins so much that they induce weak immune responses. Second, the inactivation process cannot alter the virial proteins in a way that results in an abnormal or altered immune response and enhanced disease after exposure to the natural virus. As with all vaccines, the immunogenicity of new inactivated virus vaccines must be rigorously tested to ensure safety and efficacy.

Protein-based vaccines

Many vaccines for SARS-CoV-2 in development include only viral proteins and no genetic material, including those by Novavax, Sanofi and GlaxoSmithKline, SpyBiotech, and others. Some use whole viral proteins and others just pieces of viral proteins. For SARS-CoV-2 vaccines, this means either the spike protein on the surface of the virus or a portion of the spike protein called the receptor-binding domain, which binds to host cells (i.e., the cells where viruses can replicate). These protein-based, or subunit, vaccines work much like inactivated vaccines by exposing the immune system to viral proteins and inducing protective immune responses without causing disease. In the case of protein-based vaccines, this is because no genes necessary for virus replication are included in the vaccine.

Protein-based vaccines have been widely used and have a long history of safety and effectiveness. Examples include vaccines for hepatitis B virus, shingles, and the bacteria that cause whooping cough (pertussis). There are different ways of producing recombinant viral proteins, including production of the virus protein in yeast or insect cells. Protein-based vaccines also can be packaged in different ways and combined with vaccine adjuvants (additives in small quantities) that improve or enhance immune responses. The Novavax SARS-CoV-2 vaccine, for example, uses nanoparticles of cholesterol, phospholipid, and saponins from the soap bark tree to deliver viral proteins to cells of the immune system and stimulate strong immune responses.

The addition of adjuvants to vaccines is another common way of enhancing the immune responses to virus proteins. Protein-based vaccines sometimes do not induce strong CD8 T cell responses, the cells that destroy virus-infected cells, and adjuvants can help correct this. Aluminum-containing adjuvants have been used in vaccines since the 1930s in small enough quantities to not cause any harm. Other adjuvants include different lipid formulations and a synthetic form of DNA that mimics bacterial and viral genetic material. Vaccine adjuvants will likely be important to induce strong and durable protection in older adults whose immune systems are less responsive as they age. Vaccines with adjuvants can cause more local reactions, such as redness, swelling, and pain at the injection site, and more systemic reactions such as fever, chills, and body aches, than non-adjuvanted vaccines.

Viral vector vaccines

Viral vector vaccines use another non-replicating virus to deliver SARS-CoV-2 genes, in the form of DNA, into human cells where viral proteins are produced to induce protective immune responses. This viral DNA is not integrated into the host genome (i.e.., all of the body’s DNA) but is transcribed or copied into messenger RNA and translated into proteins. Current SARS-CoV-2 viral vectored vaccines use non-replicating human or chimpanzee adenoviruses, including those by AstraZeneca with the University of Oxford, Johnson & Johnson, CanSino Biologics, and the Gamaleya Research Institute, part of Russia’s Ministry of Health.

Adenoviruses are a group of approximately 50 common viruses that can cause cold-like symptoms, fever, sore throat, diarrhea, and pink eye. The human adenovirus vectors used for SARS-CoV-2 are weakened forms of adenovirus 5 and adenovirus 26. The weakened vectors do not replicate because important genes have been deleted. These vaccines will likely require at least two doses, although there is some hope that a single dose may induce protective immune responses.

Viral vectors have been studied for several decades for gene therapy, to treat cancer, and for research into molecular biology as well as for vaccines. Viral vectors other than adenoviruses include retroviruses and the vaccinia virus that was used to prevent smallpox. In July 2020, the European Commission approved use of an adenovirus 26 vaccine for Ebola that was manufactured by Johnson & Johnson, the first adenovirus vectored vaccine approved for use in humans, and the same vaccine platform used by Johnson & Johnson for their SARS-CoV-2 vaccine. Large-scale production of viral vector vaccines requires cultivation of the viral vector, such as adenovirus, in cell cultures and virus purification.

Most people have been exposed to multiple adenoviruses and thus have pre-existing immunity that could impair vector entry into host cells. This is a potential limitation of viral vector vaccines using human adenoviruses. The AstraZeneca and University of Oxford vaccine uses a chimpanzee adenovirus as vector, thus minimizing the risk of pre-existing immunity to the vector that might reduce vaccine efficacy.

Genetic vaccines

Instead of using a viral vector to deliver SARS-CoV-2 virus genes to human cells, the genes can be administered directly as either DNA or RNA. Several of the SARS-CoV-2 vaccines furthest along in phase 3 trials are messenger RNA (mRNA) vaccines that deliver the spike protein gene, including those by Moderna, BioNTec with Pfizer, CureVac, and Imperial College London. Once the genetic sequence of the SARS-CoV-2 virus was known in January 2020, it was relatively straightforward to generate genetic vaccine candidates. mRNA vaccines are easier to develop and manufacture compared to other vaccine types as they do not require cultivating viruses in cells. This is why they were some of the first SARS-CoV-2 vaccines to enter human trials. However, no mRNA vaccine has previously been licensed and approved for humans and most experience with this technology in humans has been for the treatment of cancer.

mRNA vaccines are taken up into cells, but do not need to enter the nucleus to trick the body into producing viral proteins, which then induce immune responses. RNA is particularly potent at inducing innate immune response, the earliest type of response to a pathogen that prevents spread within the body. mRNA is used by the cell as a template to build a protein through the process of translation.

Early phase 1 and 2 studies of SARS-CoV-2 mRNA vaccines show these vaccines induce immune responses likely to be protective, including in older adults. However, until phase 3 clinical trials are completed, the safety, efficacy, and duration of protection from mRNA vaccines will not be known and at least two doses will be required.

Advantages and disadvantages of different vaccine types

Until completion of the phase 3 clinical trials, we will not know the safety and efficacy of the different types of SARS-CoV-2 vaccines and their relative advantages and disadvantages. It will be important to not only monitor short-term vaccine safety, such as soreness and fever, but the risk of long-term adverse events such as enhanced disease following exposure to natural infection and autoimmune diseases. Of particular interest will be vaccine effectiveness in vulnerable populations such as older adults and those with underlying medical conditions, including diabetes, HIV infection, and chronic heart, kidney, and lung diseases. Protein-based vaccines with adjuvants may be the most likely to induce protective immune responses in elderly adults with weakened immune systems. These different vaccine types will not be interchangeable. Once a vaccine is selected, the same vaccine must be used for a second dose if required.

Many of the vaccines furthest along in development are those for which vaccine delivery platforms existed. mRNA vaccines were developed rapidly after the SARS-CoV-2 genome was sequenced and manufacturing capacity can be rapidly scaled-up. However, some mRNA vaccines have stringent cold chain requirements. The Pfizer and BioNTech mRNA will need to be stored at -70oC until about 48 hours prior to use, when it can be refrigerated, because of the instability of RNA, while the Moderna mRNA vaccine may require storage at -20oC until about one week prior to use. Freezers with the capacity to hold large volumes of vaccine at this temperature will be needed and are not currently part of the existing vaccine supply cold chain.

Lois Privor-Dumm, Director of Adult Vaccines and Senior Advisor for Policy, Advocacy & Communications

Lois Privor-Dumm, IMBA, is Director of Adult Vaccines and Senior Advisor for Policy, Advocacy & Communications at the International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health

William Moss, Executive Director, International Vaccine Access Center, JHU

William Moss, MD, MPH, is Executive Director of the International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health.

Fighting Viruses: How Do Vaccines Work?

This article was reviewed by a member of Caltech's Faculty .

Vaccines are powerful and effective tools for preventing and slowing the spread of disease.

When the body is invaded by a pathogen, such as SARS-CoV-2, the immune system typically responds by attacking it with the help of white blood cells. Several types of white blood cells exist and play different roles in the immune response. For example, B lymphocytes, or B cells, produce proteins called antibodies, which bind to the pathogen and help to neutralize it. Cytotoxic T lymphocytes, or "killer" T cells, are responsible for destroying infected cells to prevent the virus from spreading.

The human immune system has evolved to remember pathogens it has fought off in the past. If the same viruses or bacteria reinvade , the immune system can often attack them quickly.

This also explains how vaccination protects us: vaccines usually contain dead, weakened, or partial versions of the pathogens that cause a particular disease—enough to stimulate the immune response and create immunological memory but not enough to trigger harmful symptoms. In this way, vaccination allows us to develop immunity to a disease without having first been infected.

What level of immunity should we expect from vaccines?

Two main considerations associated with infection are (1) whether or not the infection will lead to disease and (2) whether or not the infection can be transmitted to others. Vaccines do not always address both.

"Sterilizing immunity" has been held up as an ideal outcome, in which immunity as a result of previous infection or vaccination completely prevents a pathogen from replicating in the body. Because the pathogen cannot replicate, it will not cause disease or be transmitted to others.

"Functional immunity" means that a person may get infected (or reinfected) by a pathogen, but their immune system will be able to respond quickly enough to keep disease from occurring or becoming severe. An infected person with functional immunity may still be able to transmit the pathogen to others, even if they show no symptoms.

Sterilizing immunity is extremely rare and may even be impossible to demonstrate. This is because it is difficult to identify people who have been infected when they do not show any symptoms. Sterilizing immunity also is not associated with viruses that attack the mucous membranes (the tissue lining body cavities such as respiratory passages), like SARS-CoV-2. Thus, as vaccines against SARS-CoV-2 are being developed, the focus has been on preventing COVID-19 rather than achieving sterilizing immunity.

Why do we get some vaccines just once and others multiple times?

Vaccine dosages and administration schedules depend, in part, on how many strains of a virus exist and on the body's immunological memory of specific pathogens.

For example, each year, researchers predict which strains of influenza will be prevalent that season and design a vaccine to target them. This is necessary because the flu virus has a relatively high mutation rate, meaning that the virus changes as it replicates itself. Some new strains are different enough from older versions that the immune system no longer recognizes them. Viruses such as HIV mutate so rapidly that vaccine development is particularly challenging.

The body's ability to remember how to fight a pathogen also may diminish over time. For the common cold coronavirus, for example, immunological memory tends to be shorter, which is why many people get colds once a year or more often. Conversely, the immune system remembers the measles, which is why the measles vaccine or infection gives lifelong protection.

While SARS-CoV-2 does not mutate as rapidly as HIV, multiple new strains have emerged, including the Delta and Omicron variants . Immunological memory for SARS-CoV-2 also seems to vary widely among individuals.

The Centers for Disease Control and Prevention (CDC) recommend that individuals get a COVID-19 vaccine primary series and boosters as soon as they are eligible. Four vaccines are authorized or approved in the U.S., including the Pfizer-BioNTech, Moderna, Johnson & Johnson's Janssen, and Novavax vaccines.

Read more about antibodies and how vaccines teach the body to make antibodies on the Caltech Science Exchange >

Read more about COVID-19 boosters on the Caltech Science Exchange >

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What do Vaccines do?

Different Types of Vaccines

Last updated 18 April 2022

The first human vaccines against viruses were based on using weaker or attenuated viruses to generate immunity, while not giving the recipient of the vaccine the full-blown illness or, preferably, any symptoms at all. For example, the smallpox vaccine used cowpox, a poxvirus similar enough to smallpox to protect against it, but usually didn’t cause serious illness. Rabies was the first virus attenuated in a lab to create a vaccine for humans.

Vaccines are made using several processes. They may contain live viruses that have been attenuated (weakened or altered to not cause illness); inactivated or killed organisms or viruses; inactivated toxins (for bacterial diseases where toxins generated by the bacteria, and not the bacteria themselves, cause illness); or merely segments of the pathogen (this includes both subunit and conjugate vaccines). Live, attenuated vaccines currently recommended as part of the U.S. Childhood Immunization Schedule include those against measles, mumps, and rubella (via the combined MMR vaccine), varicella (chickenpox), and influenza (in the nasal spray version of the seasonal flu vaccine). In addition to live, attenuated vaccines, the immunization schedule includes vaccines of every major type.

The different vaccine types each require different development techniques. Each section below addresses one of the vaccine types.

Live, Attenuated Vaccines

Attenuated vaccines can be made in several ways. Some of the most common methods involve passing the disease-causing virus through a series of cell cultures or animal embryos (typically chick embryos). Using chick embryos as an example, the virus is grown in different embryos in a series. With each passage, the virus becomes better at replicating in chick cells, but loses its ability to replicate in human cells. A virus targeted for use in a vaccine can be grown through—“passaged” through—upwards of 200 different embryos or cell cultures. Eventually, the attenuated virus will not replicate well (or at all) in human cells, and can be used in a vaccine. All the methods that involve passing a virus through a non-human host produce a version of the virus that can still be recognized by the human immune system, but cannot replicate well in a human host.

When the resulting vaccine virus is given to a human, it will not replicate enough to cause illness, but will still provoke an immune response that can protect against future infection.

One concern that must be considered is the potential for the vaccine virus to revert to a form capable of causing disease. Mutations that can occur when the vaccine virus replicates in the body may lead to a more virulent strain. This is unlikely, as the vaccine virus’s ability to replicate is limited. However, possible mutations are considered when developing an attenuated vaccine. It is worth noting that mutations are somewhat common with the oral polio vaccine (OPV), a live vaccine that is ingested instead of injected. The vaccine virus can mutate into a virulent form and lead to rare cases of paralytic polio. For this reason, OPV is no longer used in the United States, and has been replaced on the Recommended Childhood Immunization Schedule by the inactivated polio vaccine (IPV).

Protection from a live, attenuated vaccine typically outlasts the protection provided by a killed or inactivated vaccine.

Killed or Inactivated Vaccines

One alternative to attenuated vaccines is a killed or inactivated vaccine. Vaccines of this type are created by inactivating a pathogen, typically using heat or chemicals such as formaldehyde or formalin. This destroys the pathogen’s ability to replicate, but keeps it “intact” so that the immune system can still recognize it. (“Inactivated” is generally used rather than “killed” to refer to viral vaccines of this type, as viruses are generally not considered alive.)

Because killed or inactivated pathogens can’t replicate at all, they can’t revert to a more virulent form capable of causing disease (as discussed above with live, attenuated vaccines). However, they tend to provide shorter protection than live vaccines, and are more likely to require boosters to create long-term immunity. Killed or inactivated vaccines on the U.S. Recommended Childhood Immunization Schedule include the inactivated polio vaccine and the seasonal influenza vaccine (injectable).

Some bacterial diseases are not directly caused by a bacterium, but by a toxin produced by the bacterium. One example is tetanus: the Clostridium tetani bacterium does not cause its symptoms, a neurotoxin it produces (tetanospasmin) does. Immunizations for this type of pathogen can be made by inactivating the toxin that causes disease symptoms. As with organisms or viruses used in killed or inactivated vaccines, this can be done via treatment with a chemical, such as formalin, or by using heat or other methods.

Immunizations created using inactivated toxins are called toxoids . Toxoids can actually be considered killed or inactivated vaccines, but are sometimes given their own category to highlight that they contain an inactivated toxin, not an inactivated form of bacteria.

Subunit and Conjugate Vaccines

Both subunit and conjugate vaccines contain only pieces of the pathogens they protect against.

Subunit vaccines use only part of a target pathogen to provoke a response from the immune system. This can be done by isolating a specific protein from a pathogen and presenting it as an antigen on its own. The acellular pertussis vaccine and influenza vaccine (in shot form) are examples of subunit vaccines.

Another type of subunit vaccine can be created via genetic engineering. A gene coding for a vaccine protein is inserted into another virus, or into producer cells in culture. When the carrier virus reproduces, or when the producer cell metabolizes, the vaccine protein is also created. The end result of this approach is a recombinant vaccine: the immune system will recognize the expressed protein and provide future protection against the target virus. The Hepatitis B vaccine currently used in the United States is a recombinant vaccine.

Another vaccine made using genetic engineering is the human papillomavirus (HPV) vaccine. Two types of HPV vaccine are available—one provides protection against two strains of HPV, the other four—but both are made in the same way: for each strain, a single viral protein is isolated. When these proteins are expressed, virus-like particles (VLPs) are created. These VLPs contain no genetic material from the viruses and can’t cause illness, but prompt an immune response that provides future protection against HPV.

Conjugate vaccines are somewhat similar to recombinant vaccines: they’re made using two different components. Conjugate vaccines, however, are made using pieces from the coats of bacteria. These coats are chemically linked to a carrier protein, and the combination is used as a vaccine. Conjugate vaccines are used to create a more powerful, combined immune response: typically the “piece” of bacteria presented would not generate a strong immune response on its own, while the carrier protein would. The piece of bacteria can’t cause illness, but combined with a carrier protein, it can generate immunity against future infection. The vaccines currently used for children against pneumococcal bacterial infections are made using this technique.

mRNA Vaccines

In 2020, as the COVID-19 pandemic was well underway, the United States and other countries around the world raced to create a vaccine against the SARS CoV-2 virus, the virus causing the pandemic. In the United States, “Operation Warpspeed” provided billions of dollars in funding to numerous pharmaceutical companies to develop a successful vaccine and take it to market. Under normal circumstances, the vaccine trials would have happened subsequently (i.e. phase I, phase II, phase III, etc.). Because of the public health emergency, vaccine trials occurred consecutively (phases I, II and III simultaneously).

Two vaccines were authorized for emergency use by the end of 2020 in the United States, both based on mRNA technology. (A third vaccine would be authorized early in 2021, based on viral vectors, which will be discussed in the next section.) This technology uses mRNA enveloped in a lipid (fat) sphere. The vaccine is then introduced into the body, where the body’s immune cells take up the vaccine particles and reveal the mRNA. The mRNA gives the cell “code” to create a protein similar to the “spike” protein on the coronavirus’ surface. The immune cell then releases that protein to other immune cells, triggering an immune response that includes antibody production and activation of specialized cells to find and kill coronaviruses bearing that spike protein and any host cells infected.

Viral Vector

In early 2021, a third vaccine for the COVID-19 pandemic was authorized for use in the United States. That vaccine used a simian adenovirus that was basically hollowed out and the mRNA for coding a coronavirus spike protein was put inside. Like the mRNA vaccines, the mRNA in the viral vector is introduced into immune cells after those immune cells take up the simian adenovirus after recognizing it as a pathogen. The immune cell then creates the spike protein and triggers the ensuing immune response.

More Information

Researchers continue to develop new vaccine types and improve current approaches. For more information about experimental vaccines and delivery techniques, see our article .

• Plotkin, S.A., Mortimer, E. Vaccines . New York: Harper Perennial; 1988.
• Plotkin, S.A., Orenstein, W.A., Offit, P.A., eds. Vaccines. 6th. ed. Philadelphia: Elsevier; 2013.
• Understanding mRNA COVID-19 Vaccines.  Centers for Disease Control and Prevention. Available at: 

Explaining How Vaccines Work

There are different types of vaccines. Learn about how COVID-19 vaccines work .

Getting Vaccinated Is Safer Than Getting Sick

Vaccines work by imitating an infection, many vaccines require more than one dose, everyone should get recommended vaccines on schedule, vaccines strengthen the body’s natural defenses.

Vaccines help the body learn how to defend itself from disease without the dangers of a full-blown infection. The immune response to a vaccine might cause tiredness and discomfort for a day or two, but the resulting protection can last a lifetime.

Infections are unpredictable and can have long-term consequences. Even mild or symptom-less infections can be deadly. For example, most people infected with the human papillomavirus (HPV) never show any sign of infection. But for some, the sign appears years later as an aggressive, life-threatening cancer. By then, it’s too late to get vaccinated.

Vaccines work by imitating an infection —the presence of a disease-causing organism in the body—to engage the body’s natural defenses. The active ingredient in all vaccines is an antigen , the name for any substance that causes the immune system to begin producing antibodies. In a vaccine, the antigen could be either

• Weakened or killed bacteria or viruses
• Bits of their exterior surface or genetic material, or
• Bacterial toxin treated to make it non-toxic.

Antibodies are proteins produced by white blood cells to identify and neutralize foreign substances. White blood cells are created in the bone marrow but dispersed throughout the body in low numbers, ready to begin multiplying and attacking microbes and substances not native to the body. After they have eliminated an infection, white blood cells stop multiplying and their numbers dwindle until only a few are left to keep watch. At that point, a person is considered immunized.

Because immunity can take weeks to develop after vaccination, it is possible to become infected in the weeks immediately following vaccination. Even after that, vaccinated people can and sometimes do get infected. But a vaccinated person is far less likely to die or become seriously ill than someone whose immune system is unprepared to fight an infection.

A single dose of vaccine provides only partial protection. The number of doses needed to achieve immunity depends on whether the antigen in a vaccine is alive or not. Because they contain living bacteria or viruses, live-attenuated vaccines can provide enduring protection with only two doses. By contrast, non-live vaccines typically require at least three doses to achieve protection that fades over time and must be restored with booster doses.

Live-attenuated vaccines

• Offer long-lasting, even lifetime protection.
• Could cause a life-threatening infection in someone with a weak or suppressed immune system.
• Require two doses to achieve maximum immunity.
• Examples include the chickenpox vaccine and the MMR (measles, mumps, and rubella) combined vaccine , which children should receive around their first and fifth birthdays.

Non-live vaccines

• Protection fades over time.
• Safer for people with weak immune systems.
• Require three or more doses to achieve maximum immunity.
• Infants receive doses at 2 months, 4 months, 6 months, and 18 months of age.
• Children get one booster dose around the time they first enter school and another when they begin middle school.
• Adults should get a tetanus booster once every 10 years or during each pregnancy.

Certain vaccines must be updated periodically to protect against mutation-prone viruses that cause waves of infections months or years apart. To stay protected, people must get the updated vaccines even if they got an earlier version.

• The seasonal flu vaccine is reformulated each year to target the four strains expected to be most common and most dangerous.
• The updated COVID-19 vaccines were developed to deal both with fading immunity and a fast-evolving virus.

History shows that vaccines are the safest, most effective way to protect yourself and your family from many preventable diseases.

Everyone should get all recommended vaccines at the recommended times. It is especially important for children and adolescents to get catch-up doses of any missed vaccines or vaccine doses as soon as they can. Adults should get all recommended vaccines for their age or other risk factors such as health condition or occupation. All adults should get tetanus boosters, seasonal flu and COVID-19 vaccines, and any vaccines missed in childhood.

To be immune is to be partially or fully resistant to a specific infectious disease or disease-causing organism. A person who is immune can resist the bacteria or viruses that cause a disease, but the protection is never perfect.

Immunization is the process of being made resistant to an infectious disease, usually by means of a vaccine.

Immunity is protection against a disease, and it can be passive or active, natural or vaccine induced.

Active immunity  comes from being exposed to a disease-causing organism.

• Natural immunity  results from being infected by a disease-causing organism, whether the infection is symptomatic or not.
• Vaccine-induced immunity  results from being exposed to killed or weakened bacteria or viruses—or even just important pieces of them—through vaccination.

Either way, active immunity takes longer to develop but lasts longer than passive immunity.

Passive immunity is provided by antibodies produced by another human being or animal.

• Full-term babies acquire passive immunity from their mother’s antibodies during the final months of pregnancy.
• Patients can acquire passive immunity through antibody-containing blood products derived from human or animal sources.

Passive immunity provides protection that is immediate but fades within weeks or months.

Additional information on how to improve your clinic’s practices to encourage vaccination .

For more information on vaccines call 800-CDC-INFO (800-232-4636) or visit  www.cdc.gov/vaccines .

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• For Parents: Vaccines for Your Children

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Vaccine Types

There are several different types of vaccines. Each type is designed to teach your immune system how to fight off certain kinds of germs—and the serious diseases they cause.

When scientists create vaccines, they consider:

• How your immune system responds to the germ
• Who needs to be vaccinated against the germ
• The best technology or approach to create the vaccine

Based on a number of these factors, scientists decide which type of vaccine they will make. There are several types of vaccines, including:

Inactivated vaccines

Live-attenuated vaccines.

• Messenger RNA (mRNA) vaccines

Subunit, recombinant, polysaccharide, and conjugate vaccines

Toxoid vaccines, viral vector vaccines.

Inactivated vaccines use the killed version of the germ that causes a disease.

Inactivated vaccines usually don’t provide immunity (protection) that’s as strong as live vaccines. So you may need several doses over time (booster shots) in order to get ongoing immunity against diseases.

Inactivated vaccines are used to protect against:

• Hepatitis A
• Flu (shot only)
• Polio (shot only)

Live vaccines use a weakened (or attenuated) form of the germ that causes a disease.

Because these vaccines are so similar to the natural infection that they help prevent, they create a strong and long-lasting immune response. Just 1 or 2 doses of most live vaccines can give you a lifetime of protection against a germ and the disease it causes.

But live vaccines also have some limitations. For example:

• Because they contain a small amount of the weakened live virus, some people should talk to their health care provider before receiving them, such as people with weakened immune systems, long-term health problems, or people who’ve had an organ transplant.
• They need to be kept cool, so they don’t travel well. That means they can’t be used in countries with limited access to refrigerators.

Live vaccines are used to protect against:

• Measles , mumps , rubella (MMR combined vaccine)
• Yellow fever

Messenger RNA vaccines—also called mRNA vaccines

Researchers have been studying and working with mRNA vaccines for decades and this technology was used to make some of the COVID-19 vaccines. mRNA vaccines make proteins in order to trigger an immune response. mRNA vaccines have several benefits compared to other types of vaccines, including shorter manufacturing times and, because they do not contain a live virus, no risk of causing disease in the person getting vaccinated.

mRNA vaccines are used to protect against:

Subunit, recombinant, polysaccharide, and conjugate vaccines use specific pieces of the germ—like its protein, sugar, or capsid (a casing around the germ).

Because these vaccines use only specific pieces of the germ, they give a very strong immune response that’s targeted to key parts of the germ. They can also be used on almost everyone who needs them, including people with weakened immune systems and long-term health problems.

One limitation of these vaccines is that you may need booster shots to get ongoing protection against diseases.

These vaccines are used to protect against:

• Hib ( Haemophilus influenzae type b) disease
• Hepatitis B
• HPV (Human papillomavirus)
• Whooping cough (part of the DTaP combined vaccine)
• Pneumococcal disease
• Meningococcal disease

Toxoid vaccines use a toxin (harmful product) made by the germ that causes a disease. They create immunity to the parts of the germ that cause a disease instead of the germ itself. That means the immune response is targeted to the toxin instead of the whole germ.

Like some other types of vaccines, you may need booster shots to get ongoing protection against diseases.

Toxoid vaccines are used to protect against:

For decades, scientists studied viral vector vaccines. Some vaccines recently used for Ebola outbreaks have used viral vector technology, and a number of studies have focused on viral vector vaccines against other infectious diseases such as Zika, flu, and HIV. Scientists used this technology to make COVID-19 vaccines as well.

Viral vector vaccines use a modified version of a different virus as a vector to deliver protection. Several different viruses have been used as vectors, including influenza, vesicular stomatitis virus (VSV), measles virus, and adenovirus, which causes the common cold. Adenovirus is one of the viral vectors used in some COVID-19 vaccines being studied in clinical trials. Viral vector vaccines are used to protect against:

The future of vaccines

Did you know that scientists are still working to create new types of vaccines? Here are 2 exciting examples:

• DNA vaccines are easy and inexpensive to make—and they produce strong, long-term immunity.
• Recombinant vector vaccines (platform-based vaccines) act like a natural infection, so they're especially good at teaching the immune system how to fight germs.

Learn more about:

• Types of vaccines
• Types of vaccines routinely given to children
• Research on new vaccines
• Understanding How COVID-19 Vaccines Work

Get Immunized

Getting immunized is easy. Vaccines and preventive antibodies are available at the doctor’s office or pharmacies — and are usually covered by insurance.

Find out how to get protected .

Want to learn about the journey of your child’s vaccine?

See how vaccines are developed, approved, and monitored .

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• Iran J Public Health
• v.50(7); 2021 Jul

A Brief Overview of COVID-19 Vaccines

Dariush d. farhud.

1. School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

2. Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran

3. Farhud Genetics Clinic, Tehran, Iran

Shaghayegh Zokaei

4. School of Advanced Medical Sciences, Tehran Medical Branch, Islamic Azad University, Tehran, Iran

Since the initiation of the covid-19 pandemic, efforts have been made to provide acquired immunity against covid-19. Prior to Covid-19 vaccines manufacture and authorization, there was established knowledge about the structure and function of coronaviruses that accelerated the capability to produce vaccines ( 1 , 2 ). After the sharing of genetic sequencing data and the major commitment of the global pharmaceutical industry to address COVID-19, the production of vaccines began. The high efficacy of various COVID-19 vaccines in preventing symptomatic COVID-19 infections was found in large-scale phase III trials ( 3 ). During the entire development path of these vaccines, several steps were evaluated including the safety and acceptable toxicity of the vaccine, duration of protective immunity, stability characteristics of each vaccine, heat stability and storage conditions outside the required temperature range, delivery system like injection, oral, and nasal, dosing schedules for COVID-19 vaccines (a single-dose regimen or multiple divided doses), and probable side effects of vaccines ( 4 – 12 ).

So far, billions of vaccine doses had been preordered by various countries and about half of the doses purchased by developed countries with high income ( 13 ). Vaccination has been prioritized for those at the highest risk of complications, such as the elderly, health care workers, and people with chronic diseases such as heart diseases, cancer, and diabetes ( 14 ). Two doses of different vaccines may work better to protect against COVID-19 and trigger stronger immune responses. For instance, mixing and matching two-dose COVID-19 Pfizer-BioNTech and AstraZeneca vaccines elicit a potent immune response against coronavirus, but target different parts of the virus spike ( 15 ). These vaccines have so far been suitable for people aged 18 yr and over, but the recent research by Pfizer on teens aged 12 to 15 yr has shown that the vaccine was effective for this age group and has no significant side effects. The Pfizer-BioNTech COVID-19 vaccine has been approved for this age group, and they can now receive it ( 16 ).

Until 19 June, 2021, about 21% of the world’s population have been vaccinated with at least one dose, however, only 0.8% of people in low-income countries have received at least one dose of a COVID-19 vaccine ( 17 ). Of all the countries, the United States leads with the highest number of injectable doses. After the United States, India, Brazil, the United Kingdom, Germany, France, Italy, Mexico, Canada, and Israel received the most injections, respectively ( Fig. 1 ) ( 18 ). Moreover, Canada ranks first in the number of vaccinated people among other countries ( Fig. 2 ) ( 19 ). The total number of vaccination doses administered per 100 people in the total population has so far been the highest in Israel, followed by the United Kingdom, the United States, Canada, Germany, Italy, and France ( Fig. 3 ) ( 20 ). Among the total population of countries that have received all doses prescribed by the vaccination protocol, Israel ranks first with more than 50% of its population vaccinated. The United Kingdom, the United States, Germany, Italy, France, and Canada are next in line ( Fig. 4 ) ( 21 ). Among all countries, Iran has one of the lowest rates of vaccination with only about 5 million doses of vaccine ( Fig. 1 ) ( 18 ). Besides, China has been excluded from the calculations due to the unclear vaccination data.

Total number of single dose vaccine administered in the countries with the highest injection rates until June19, 2021. Due to the specific dose regime, it does not represent the total number of people vaccinated (e.g. people receive multiple doses). Iran is included in the chart just for comparison ( 18 )

Share of people vaccinated against COVID-19, which is only available for countries that administered both first and second doses until June19, 2021. The countries with the highest injection rates are listed, and Iran is included in the chart just for comparison ( 19 )

The total number of administered COVID-19 vaccine per 100 people in the general population until June19, 2021, which is counted as a single dose and does not represent the total number of people vaccinated (e.g. people receive multiple doses). The countries with the highest injection rates are listed, and Iran is included in the chart just for comparison ( 20 )

Share of the population that is fully vaccinated prescribed by the vaccination protocol until June19, 2021. This data is only available for countries that administered both first and second doses. The countries with the highest injection rates are listed, and Iran is included in the chart just for comparison ( 21 )

Different types of vaccines are designed to stimulate your immune system and fight against the novel coronavirus. Based on the best approach and technology available in the production of vaccines, scientists will determine their type. There are different categories of vaccines including messenger RNA (mRNA), live-attenuated, inactivated, subunit, and viral vector vaccines. Each of them has its advantages and disadvantages over the others ( Table 1 ) ( 18 , 19 , 21 , 22 ).

Understanding various types of vaccines, advantages and disadvantages ( 22 – 25 )

Altogether, it is critical that roughly 70% to 85% of the population must be immune and get vaccinated, but till the end of the pandemic, people still need to keep on wearing masks, ensuring physical distancing, and controlling ventilation in buildings and public spaces. Although some immune responses for example against rhinovirus, the predominant cause of the common cold in humans, triggers an interferon response and blocks SARS-CoV-2 replication ( 23 ), vaccines can provide long-term and more effective immunity. Vaccines teach the body to protect against diseases and stimulate the immune system. Immunization against diseases including influenza, polio, pertussis, diphtheria, measles, and tetanus can prevent the death of millions of people each year, therefore, it is a fundamental human right and an essential element of primary health care.

Conflict of interest

The authors declare that there is no conflict of interests.

Types of vaccines for COVID-19

On this page, you will find infographics to explain how different types of vaccines work, including the Pfizer/BioNTech vaccine, the Moderna vaccine and the Oxford/AstraZeneca vaccine. Scroll down to discover more, click the download link to print the graphic or share on social media tagging  @britsocimm  to help strengthen public understanding.

As the UK COVID-19 vaccine approval and roll out continues to evolve, these infographics will be updated. They are accurate as of March 2023. 

Vaccines train your immune system using a harmless form of the virus, SARS-CoV-2, which causes COVID-19. Vaccines stimulate an immune response without causing illness. Each type of vaccine for COVID-19 works differently to introduce antigens, which are unique features of the SARS-CoV-2 virus, to your body. The antigen triggers a specific immune response and this response builds immune memory, so your body can fight off SARS-CoV-2 in future. 

Viral vector vaccines for COVID-19

The University of Oxford/AstraZeneca vaccine uses this technology to protect against COVID-19. This type of vaccine uses an unrelated harmless virus (the viral vector) to deliver SARS-CoV-2 genetic material. When administered, our cells use the genetic material to produce a specific viral protein, which is recognised by our immune system and triggers a response. This response builds immune memory, so your body can fight off the virus in future.

Genetic vaccines for COVID-19

The Moderna and Pfizer/BioNTech COVID-19 vaccines use this type of technology to train the immune system. The vaccines contains a segment of genetic material of the SARS-CoV-2 virus, which causes COVID-19. The genetic material, RNA in the case of Moderna and Pfizer/BioNTech vaccine, codes for a specific viral protein. When administered, your cells use the genetic material from the vaccines to make the protein, which is recognised by your immune system and triggers a specific response. This response builds immune memory, so your body can fight off SARS-CoV-2 in future.

Inactivated vaccines for COVID-19

This type of vaccine contains the killed SARS-CoV-2 virus, which is recognised by the immune system to trigger a response without causing COVID-19 illness. This response builds immune memory, so your body can fight off SARS-CoV-2 in future.

Attenuated vaccines for COVID-19

This type of vaccine contains the weakened SARS-CoV-2 virus, which is recognised by the immune system to trigger a response without causing COVID-19 illness. This response builds immune memory, so your body can fight off SARS-CoV-2 in future.

Protein vaccines for COVID-19

This type of vaccine contains proteins from the SARS-CoV-2 virus, which are recognised by the immune system to trigger a response. This response builds immune memory, so your body can fight off SARS-CoV-2 in future.

If you are interested in translating these resources into another language, please email  [email protected] . Please do not translate these resources without our permission

ORIGINAL RESEARCH article

Vaccine hesitancy in patients presenting to a specialized allergy center: clinical relevant sensitizations, impact on mental health and vaccination rates.

• 1 Kepler University Hospital GmbH, Linz, Upper Austria, Austria
• 2 Johannes Kepler University of Linz, Linz, Upper Austria, Austria
• 3 Institute for Allergology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
• 4 Fraunhofer Institute for Translational Medicine und Pharmacology ITMP, Allergology and Immunology, Berlin, Baden-Württemberg, Germany

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Background: The COVID-vaccination program with new types of vaccinations and early reports of allergic reactions to vaccines led to vaccination hesitancy in patients with allergies. In this study, we aimed to characterize patients who present at an allergy center with specific questions regarding risk assessment to COVID vaccines in comparison to regular allergy center patients. Methods: 50 patient charts of patients with risk assessment for COVID vaccination (COV-group) and 50 regular allergy center patients (ALL-group) were assessed for documented allergies, comorbidities, total IgE and tryptase levels and hospital anxiety and depression score (HADS). Skin Prick-Testing (SPT) with additives of COVID-vaccines (polyethylenglycol (PEG), polysorbate) were performed if indicated based on medical history. Results: Patients who presented for examination prior to a possible COVID vaccination were mostly female (86%), had more frequently reported allergic reactions to drugs in the past, but only in a minor group (28%) reactions were qualifying as anaphylaxis. COV-group patients scored significantly higher in the HADS for anxiety and depression than regular ALL-group patients. The same trend was observed when data were corrected for gender. Of note, patient without any prior contact to COVID-vaccines scored comparable regarding anxiety to patients with prior reaction to COVID-vaccinations, but significantly higher in the depression score. In 19 patients (38%) who met the indications for SPT for the suspicious contents PEG and Polysorbate 80, tests did not show a positive result. 84% of patients who underwent Prick-Test but only 15% of patients who received consultation alone agreed to vaccination at our center. No vaccination related event was documented in these patients. Conclusion: In conclusion, vaccination hesitancy was frequently elicited by negative experiences with drugs and putative drug allergies. Females predominate in this patient group and anxiety and depression scores were significantly elevated. Allergological workup including SPT led to a high rate of subsequent vaccinations, whereas discussion with patients about risks and individualized advice for vaccination without testing only rarely resulted in documented vaccinations.

Keywords: allergy, COVID, Vaccine, Prick-test, HADS - Hospital Anxiety and Depression Scale

Received: 20 Oct 2023; Accepted: 24 Apr 2024.

Copyright: © 2024 Kogseder, Puxkandl, Hoetzenecker and Altrichter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Natalie Kogseder, Kepler University Hospital GmbH, Linz, Upper Austria, Austria Viktoria Puxkandl, Kepler University Hospital GmbH, Linz, Upper Austria, Austria Wolfram Hoetzenecker, Kepler University Hospital GmbH, Linz, Upper Austria, Austria Sabine Altrichter, Kepler University Hospital GmbH, Linz, Upper Austria, Austria

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Next pandemic likely to be caused by flu virus, scientists warn

Influenza is still the biggest threat to global health as WHO raises fears about the spread of avian strain

Influenza is the pathogen most likely to trigger a new pandemic in the near future, according to leading scientists.

An international survey, to be published next weekend, will reveal that 57% of senior disease experts now think that a strain of flu virus will be the cause of the next global outbreak of deadly infectious illness .

The belief that influenza is the world’s greatest pandemic threat is based on long-term research showing it is constantly evolving and mutating, said Cologne University’s Jon Salmanton-García, who carried out the study.

“Each winter influenza appears,” he said. “You could describe these outbreaks as little pandemics. They are more or less controlled because the different strains that cause them are not virulent enough – but that will not necessarily be the case for ever.”

Details of the survey – which involved inputs from a total of 187 senior scientists – will be revealed at European Society of Clinical Microbiology and Infectious Diseases (ESCMID) congress in Barcelona next weekend.

The next most likely cause of a pandemic, after influenza, is likely to be a virus – dubbed Disease X – that is still unknown to science, according to 21% of the experts who took part in the study. They believe the next pandemic will be caused by an as-yet-to-be-identified micro-organism that will appear out of the blue, just as the Sars-CoV-2 virus, the cause of Covid-19 , did, when it started to infect humans in 2019.

Indeed, some scientists still believe Sars-CoV-2 remains a threat, with 15% of the scientists surveyed in the study rating it their most likely cause of a pandemic in the near future.

Other deadly micro-organisms – such as Lassa, Nipah, Ebola and Zika viruses – were rated as serious global threats by only 1% to 2% of respondents. “Influenza remained – by a very large degree, the number one threat in terms of its pandemic potential in the eyes of a large majority of world scientists,” added Salmanton-García.

Last week, the World Health Organization raised fears about the alarming spread of the H5N1 strain of influenza that is causing millions of cases of avian flu across the globe. This outbreak began in 2020 and has led to the deaths or killing of tens of millions of poultry and has also wiped out millions of wild birds.

Most recently, the virus has spread to mammal species, including domestic cattle which are now infected in 12 states in the US, further increasing fears about the risks to humans. The more mammalian species the virus infects, the more opportunities it has to evolve into a strain that is dangerous to humans, Daniel Goldhill, of the Royal Veterinary College in Hatfield, told the journal Nature last week.

The appearance of the H5N1 virus in cattle was a surprise, added virologist Ed Hutchinson, of Glasgow University. “Pigs can get avian flu but until recently cattle did not. They were infected with their own strains of the disease. So the appearance of H5N1 in cows was a shock.

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“It means that the risks of the virus getting into more and more farm animals, and then from farm animals into humans just gets higher and higher. The more the virus spreads, then the chances of it mutating so it can spread into humans goes up and up. Basically, we are rolling the dice with this virus.”

To date, there has been no indication that H5N1 is spreading between humans. But in hundreds of cases where humans have been infected through contact with animals over the past 20 years, the impact has been grim. “The mortality rate is extraordinarily high because humans have no natural immunity to the virus”, said Jeremy Farrar, chief scientist of the World Health Organization.

The prospect of a flu pandemic is alarming, although scientists also point out that vaccines against many strains, including H5N1, have already been developed. “If there was an avian flu pandemic it would still be a massive logistical challenge to produce vaccines at the scale and speed that will be needed. However, we would be much further down that road than we were with Covid-19 when a vaccine had to be developed from scratch,” said Hutchinson.

Nevertheless, some lessons of preventing disease spread have been forgotten since the end of the Covid pandemic, said Salmanton-García. “People have gone back to coughing into their hands and then shaking hands with other people. Mask-wearing has disappeared. We are going back to our old bad habits. We may come to regret that.”

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What Sentencing Could Look Like if Trump Is Found Guilty

By Norman L. Eisen

Mr. Eisen is the author of “Trying Trump: A Guide to His First Election Interference Criminal Trial.”

For all the attention to and debate over the unfolding trial of Donald Trump in Manhattan, there has been surprisingly little of it paid to a key element: its possible outcome and, specifically, the prospect that a former and potentially future president could be sentenced to prison time.

The case — brought by Alvin Bragg, the Manhattan district attorney, against Mr. Trump — represents the first time in our nation’s history that a former president is a defendant in a criminal trial. As such, it has generated lots of debate about the case’s legal strength and integrity, as well as its potential impact on Mr. Trump’s efforts to win back the White House.

A review of thousands of cases in New York that charged the same felony suggests something striking: If Mr. Trump is found guilty, incarceration is an actual possibility. It’s not certain, of course, but it is plausible.

Jury selection has begun, and it’s not too soon to talk about what the possibility of a sentence, including a prison sentence, would look like for Mr. Trump, for the election and for the country — including what would happen if he is re-elected.

The case focuses on alleged interference in the 2016 election, which consisted of a hush-money payment Michael Cohen, the former president’s fixer at the time, made in 2016 to a porn star, Stormy Daniels, who said she had an affair with Mr. Trump. Mr. Bragg is arguing that the cover-up cheated voters of the chance to fully assess Mr. Trump’s candidacy.

This may be the first criminal trial of a former president in American history, but if convicted, Mr. Trump’s fate is likely to be determined by the same core factors that guide the sentencing of every criminal defendant in New York State Court.

Comparable cases. The first factor is the base line against which judges measure all sentences: how other defendants have been treated for similar offenses. My research encompassed almost 10,000 cases of felony falsifying business records that have been prosecuted across the state of New York since 2015. Over a similar period, the Manhattan D.A. has charged over 400 of these cases . In roughly the first year of Mr. Bragg’s tenure, his team alone filed 166 felony counts for falsifying business records against 34 people or companies.

Contrary to claims that there will be no sentence of incarceration for falsifying business records, when a felony conviction involves serious misconduct, defendants can be sentenced to some prison time. My analysis of the most recent data indicates that approximately one in 10 cases in which the most serious charge at arraignment is falsifying business records in the first degree and in which the court ultimately imposes a sentence, results in a term of imprisonment.

To be clear, these cases generally differ from Mr. Trump’s case in one important respect: They typically involve additional charges besides just falsifying records. That clearly complicates what we might expect if Mr. Trump is convicted.

Nevertheless, there are many previous cases involving falsifying business records along with other charges where the conduct was less serious than is alleged against Mr. Trump and prison time was imposed. For instance, Richard Luthmann was accused of attempting to deceive voters — in his case, impersonating New York political figures on social media in an attempt to influence campaigns. He pleaded guilty to three counts of falsifying business records in the first degree (as well as to other charges). He received a sentence of incarceration on the felony falsification counts (although the sentence was not solely attributable to the plea).

A defendant in another case was accused of stealing in excess of $50,000 from her employer and, like in this case, falsifying one or more invoices as part of the scheme. She was indicted on a single grand larceny charge and ultimately pleaded guilty to one felony count of business record falsification for a false invoice of just under $10,000. She received 364 days in prison.

To be sure, for a typical first-time offender charged only with run-of-the-mill business record falsification, a prison sentence would be unlikely. On the other hand, Mr. Trump is being prosecuted for 34 counts of conduct that might have changed the course of American history.

Seriousness of the crime. Mr. Bragg alleges that Mr. Trump concealed critical information from voters (paying hush money to suppress an extramarital relationship) that could have harmed his campaign, particularly if it came to light after the revelation of another scandal — the “Access Hollywood” tape . If proved, that could be seen not just as unfortunate personal judgment but also, as Justice Juan Merchan has described it, an attempt “to unlawfully influence the 2016 presidential election.”

History and character. To date, Mr. Trump has been unrepentant about the events alleged in this case. There is every reason to believe that will not change even if he is convicted, and lack of remorse is a negative at sentencing. Justice Merchan’s evaluation of Mr. Trump’s history and character may also be informed by the other judgments against him, including Justice Arthur Engoron’s ruling that Mr. Trump engaged in repeated and persistent business fraud, a jury finding that he sexually abused and defamed E. Jean Carroll and a related defamation verdict by a second jury.

Justice Merchan may also weigh the fact that Mr. Trump has been repeatedly held in contempt , warned , fined and gagged by state and federal judges. That includes for statements he made that exposed witnesses, individuals in the judicial system and their families to danger. More recently, Mr. Trump made personal attacks on Justice Merchan’s daughter, resulting in an extension of the gag order in the case. He now stands accused of violating it again by commenting on witnesses.

What this all suggests is that a term of imprisonment for Mr. Trump, while far from certain for a former president, is not off the table. If he receives a sentence of incarceration, perhaps the likeliest term is six months, although he could face up to four years, particularly if Mr. Trump chooses to testify, as he said he intends to do , and the judge believes he lied on the stand . Probation is also available, as are more flexible approaches like a sentence of spending every weekend in jail for a year.

We will probably know what the judge will do within 30 to 60 days of the end of the trial, which could run into mid-June. If there is a conviction, that would mean a late summer or early fall sentencing.

Justice Merchan would have to wrestle in the middle of an election year with the potential impact of sentencing a former president and current candidate.

If Mr. Trump is sentenced to a period of incarceration, the reaction of the American public will probably be as polarized as our divided electorate itself. Yet as some polls suggest — with the caveat that we should always be cautious of polls early in the race posing hypothetical questions — many key swing state voters said they would not vote for a felon.

If Mr. Trump is convicted and then loses the presidential election, he will probably be granted bail, pending an appeal, which will take about a year. That means if any appeals are unsuccessful, he will most likely have to serve any sentence starting sometime next year. He will be sequestered with his Secret Service protection; if it is less than a year, probably in Rikers Island. His protective detail will probably be his main company, since Mr. Trump will surely be isolated from other inmates for his safety.

If Mr. Trump wins the presidential election, he can’t pardon himself because it is a state case. He will be likely to order the Justice Department to challenge his sentence, and department opinions have concluded that a sitting president could not be imprisoned, since that would prevent the president from fulfilling the constitutional duties of the office. The courts have never had to address the question, but they could well agree with the Justice Department.

So if Mr. Trump is convicted and sentenced to a period of incarceration, its ultimate significance is probably this: When the American people go to the polls in November, they will be voting on whether Mr. Trump should be held accountable for his original election interference.

What questions do you have about Trump’s Manhattan criminal trial so far?

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Norman L. Eisen investigated the 2016 voter deception allegations as counsel for the first impeachment and trial of Donald Trump and is the author of “Trying Trump: A Guide to His First Election Interference Criminal Trial.”

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