A vaccine is a biological product that can be used to safely induce an immune response that confers protection against an 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. An antigen is a toxin or other foreign substance which induces an immune response, especially the production of antibodies. 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. 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.
Vaccines are generally classified as live attenuated or non-live (sometimes loosely referred to as ‘inactivated’) to distinguish those vaccines that contain live attenuated replicating strains of the relevant pathogenic organism from those that contain only components of a pathogen or killed whole organisms. 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.
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. 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.
Live attenuated 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, rotavirus, oral polio vaccine, and 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), 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).
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). 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. The mechanism of action of aluminum salts (alum), although extensively used as an adjuvant for more than 80 years, remains incompletely understood, but there is increasing evidence that immune responses and protection can be enhanced by the addition of newer adjuvants that provide danger signals from the pathogen to the innate immune system. The innate immune system is the bodies first line of defense against pathogens, providing rapid non-specific response to threats. Examples of these novel adjuvants are the oil-in-water emulsion MF59, which is used in some influenza vaccines; AS01, which is used in one of the shingles vaccines and the licensed malaria vaccine; and AS04, which is used in a vaccine against human papillomavirus (HPV).
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.
The adaptive immune response (to a specific pathogen) 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; are thought to mainly confer protection through the induction of antibodies. There is considerable supportive evidence that various types of functional antibodies are important in vaccine-induced protection, and this evidence comes from three main sources: immunodeficiency states, studies of passive protection and immunological data.
How do vaccines work?
What is 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. Dendritic cells are known as the most potent antigen Presenting Cells (APC’s, capable of capturing, processing, and presenting antigens to T cells, thereby bridging the inate and adaptive immune systems.
In the lymph node, the presentation of peptides of the vaccine protein antigen by Major Histocompatibility Complex MHC molecules on the dendritic cell activates T cells through their T cell receptor (TCR). In combination with signaling (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. CD8+ effector T cells also known as cytotoxic lymphocytes are a crucial part of the immune systems adaptive response, playing a key role in eliminating infected cells.
Infusion of exogenous antibodies can also 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, tetanus and influenza 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 and respiratory syncytial virus (RSV) 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.
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 programs, 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.
Sources
https://www.nature.com/articles/s41577-020-00479-7
https://publichealth.jhu.edu/2025/the-biology-of-vaccines
https://www.nature.com/articles/s41392-023-01557-7
https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-1-principles-of-vaccination.html
