REVIEWS A guide to vaccinology: from basic principles to new developments Andrew J. Pollard 1,2 ✉ and Else M. Bijker1,2 Abstract | 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. Antigens Vaccines have transformed public health, particularly on infectious diseases to provide insight into the key Parts of the pathogen (such as since national programmes for immunization first issues facing immunologists today. We also provide proteins or polysaccharides) became properly established and coordinated in the some perspectives on current and future challenges that are recognized by the 1960s. In countries with high vaccine programme cov- in continuing to protect the world’s population from immune system and can be used to induce an immune erage, many of the diseases that were previously respon- common pathogens and emerging infectious threats. response by vaccination. sible for the majority of childhood deaths have essentially Communicating effectively about the science of vacci- disappeared1 (FIg. 1). The World Health Organization nation to a sceptical public is a challenge for all those Protection (WHO) estimates that 2–3 million lives are saved each engaged in vaccine immunobiology but is urgently The state in which an individual year by current immunization programmes, contributing needed to realign the dialogue and ensure public health8. does not develop disease after being exposed to a pathogen. to the marked reduction in mortality of children less than This can only be achieved by being transparent about 5 years of age globally from 93 deaths per 1,000 live births what we know and do not know, and by considering the in 1990 to 39 deaths per 1,000 live births in 2018 (REF.2). strategies to overcome our existing knowledge gaps. Vaccines exploit the extraordinary ability of the highly evolved human immune system to respond to, What is in a vaccine? and remember, encounters with pathogen antigens. A vaccine is a biological product that can be used to However, for much of history, vaccines have been devel- safely induce an immune response that confers protection oped through empirical research without the involve- against infection and/or disease on subsequent exposure ment of immunologists. There is a great need today for to a pathogen. To achieve this, the vaccine must contain improved understanding of the immunological basis antigens that are either derived from the pathogen or for vaccination to develop vaccines for hard-to-target produced synthetically to represent components of the pathogens (such as Mycobacterium tuberculosis, the bac- pathogen. The essential component of most vaccines 3 1Oxford Vaccine Group, terium that causes tuberculosis (TB)) and antigenically is one or more protein antigens that induce immune 4 Department of Paediatrics, variable pathogens (such as HIV) , to control outbreaks responses that provide protection. However, polysac- University of Oxford, that threaten global health security (such as COVID-19 charide antigens can also induce protective immune Oxford, UK. or Ebola)5,6 and to work out how to revive immune responses and are the basis of vaccines that have been 2NIHR Oxford Biomedical responses in the ageing immune system7 to protect developed to prevent several bacterial infections, such Research Centre, Oxford the growing population of older adults from infectious as pneumonia and meningitis caused by Streptococcus University Hospitals Trust, 9 Oxford, UK. diseases. pneumoniae, since the late 1980s . Protection conferred ✉e-mail: andrew.pollard@ In this Review, which is primarily aimed at a broad by a vaccine is measured in clinical trials that relate paediatrics.ox.ac.uk scientific audience, we provide a guide to the history immune responses to the vaccine antigen to clinical end https://doi.org/10.1038/ (BOx 1), development, immunological basis and remark- points (such as prevention of infection, a reduction in s41577-020-00479-7 able impact of vaccines and immunization programmes disease severity or a decreased rate of hospitalization). NATURE REVIEWS | IMMUNOLOGY VOLUME 21 | FEBRUARY 2021 | 83 REVIEWS a Diphtheria b Capsular group C meningococcus Introduction of 1,800 1,600 80,000 vaccination (1940) Introduction of 70,000 1,400 vaccination (1999) 60,000 1,200 50,000 1,000 40,000 800 30,000 600 Notifications 20,000 Number of cases 400 10,000 200 0 0 1914 1924 1934 1944 1954 1964 1974 1984 1994 2003 Year 1998/19991999/20002000/20012001/20022002/20032003/20042004/20052005/20062006/20072007/20082008/20092009/20102010/20112011/20122012/2013 Year c Polio d Haemophilus influenzae type B 1,000 Introduction of 900 vaccination (1992) 800 7,000 700 Introduction of 600 6,000 vaccination (1956) 5,000 500 4,000 400 3,000 300 Laboratory reports Laboratory 2,000 200 Notifications 1,000 100 0 0 1912 1922 1932 1942 1952 1962 1972 1982 1992 2006 1990199119921993199419951996199719981999200020012002200320042005 Year Year e Measles f Pertussis 900,000 800,000 Introduction of 200,000 700,000 vaccination (1968) 180,000 600,000 160,000 140,000 Introduction of vaccination (1950s) 500,000 120,000 Notifications 400,000 100,000 300,000 Notifications 80,000 60,000 200,000 40,000 100,000 20,000 0 0 1940 1944 1948 1952 1956 1960 1964 1968 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 1950 1953 1956 1959 1962 1965 1968 1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 2010 2013 2016 Year Year Fig. 1 | The impact of vaccination on selected diseases in the UK. 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. Finding an immune response that correlates with pro- The distinction between live and non-live vaccines tection can accelerate the development of and access to is important. The former may have the potential to repli- new vaccines10 (BOx 2). cate in an uncontrolled manner in immuno compromised Vaccines are generally classified as live or non-live individuals (for example, children with some pri- Attenuated (sometimes loosely referred to as ‘inactivated’) to distin- mary immunodeficiencies, or individuals with HIV A reduction in the virulence attenuated of a pathogen (through either guish those vaccines that contain replicating infection or those receiving immunosuppressive drugs), 11 deliberate or natural changes strains of the relevant pathogenic organism from those leading to some restrictions to their use . By contrast, in virulence genes). that contain only components of a pathogen or killed non-live vaccines pose no risk to immunocompromised whole organisms (Fig. 2). In addition to the ‘traditional’ individuals (although they may not confer protection in Virus-like particles live and non-live vaccines, several other platforms have those with B cell or combined immunodeficiency, as Particles constructed of viral proteins that structurally mimic been developed over the past few decades, including viral explained in more detail later). the native virus but lack the vectors, nucleic acid-based RNA and DNA vaccines, and Live vaccines are developed so that, in an immuno- viral genome. virus-like particles (discussed in more detail later). competent host, they replicate sufficiently to produce a 84 | FEBRUARY 2021 | VOLUME 21 www.nature.com/nri REVIEWS Adjuvant strong immune response, but not so much as to cause the portfolio of adjuvants is steadily expanding, with An agent used in a vaccine to significant disease manifestations (for example, the liposome-based adjuvants and oil-in-water emulsions enhance the immune response vaccines for measles, mumps, rubella and rotavirus, being licensed in the past few decades14. The mech- against the antigen. oral polio vaccine, the Mycobacterium bovis bacillus anism of action of aluminium salts (alum), although Danger signals Calmette–Guérin (BCG) vaccine for TB and live atten- extensively used as an adjuvant for more than 80 years, 15 Molecules that stimulate a uated influenza vaccine).