What does correlates of vaccine-induced immunity really mean?

A review paper summarising how scientists define correlates of protection for vaccines

Figure showing how the innate and adaptive immune responses can interact synergistically after vaccination to confer protection against viral infection and diseases. It is critical to define which of these components are correlates or cocorrelates of protection. Drawing by BioRender.

There are generally 4 categories of immune functions that relate to vaccine-induced protection:

Correlate: A specific immune response to a vaccine that is closely related to protection against infection, disease or other defined end point

Absolute correlate: A quantity of a specific immune response to a vaccine that always provide near 100%

Relative correlate: A quantity of a specific immune response to a vaccine that usually (not always) provides protection

Cocorrelate: A quantity of a specific immune response to a vaccine that is 1 of >=2 correlates of protection, and that must be synergistic with other correlatesSurrogateA quantified specific immune response to a vaccine that is not itself protective but that substitutes for the true (perhaps unknown) correlate

What have researchers learnt about correlates of protection? There are some important pointers that I learnt from the article published by Stanley Plotkin, CID, 2008:

1. The correlate of protection induced by vaccination may not necessarily be the same correlate that operates to close off infection. An example of this principle is measles vaccine. Titers <200 mIU/mL of antibody after vaccination are protective against infection, whereas titers between 120 and 200 mIU/mL protect against clinical signs of disease but not against infection. Titers <120 mIU/mL are not protective at all. Another consideration is the cellular immunity to measles, which is critical in recovery from disease, as CD8+ cells are needed to control viremia and consequent infection of organs. Another example is cytomegalovirus, where antibodies are a correlate of protection against infection, whereas T cell immunity is a correlate of protection against disease.

2. Correlate of protection may be either absolute and relative. Examples of absolute correlates (situations in which a certain level of response almost guarantees protection) include diphtheria, tetanus, measles, rubella and hepatitis A. While absolute correlation is highly desired, many correlates are relative. In these cases, although protection is usually conferred at a certain level of responses, breakthrough infections are possible. An example is the influenza vaccine, where a hemagglutination-inhibition antibody titer of 1/40 is associated with 70% clinical efficacy.

3. While antibodies are often used as measures of correlates of protection, not all antibodies neutralise infections in the same way. An example is the Meningococcal polysaccharide vaccines which give notoriously poor protection in young children, although children do have significant ELISA antibody responses. Other functions, including opsonophagocytosis, ADCC and complement activation could also be important for protection.

4. In some cases, antibodies are surrogates, rather as a true correlate of protection. This means that the antibodies could be indirectly related to the true correlate of protection. Examples provided were the rotavirus and varicella vaccine, where cell-mediated immunity is clearly required for protection against viral infection and disease.

5. Emerging evidence suggest the possibility of organ-specific correlates. Based on experimental studies, it appears that CD4+ cells are key to the prevention of brain pathology after measles and in helping CD8+ cells to close off West Nile virus CNS infection. More work will be needed to define correlates of protection that are organ-specific.

6. Correlates of immunity may differ between different age groups. An example is the influenza vaccine, where antibody production is critical to prevent primary influenza infection in the young, but CD4+ cells may be more important for immunologically experienced individuals undergoing heterosubtypic infection.

7. Cellular responses are increasingly recognised as correlates or cocorrelates of protection. Given that CD4+ cells must be present to help antibodies to develop, and CD8+ cells are needed for virus clearance, emerging evidence now suggest that cellular responses are critical in limiting viral pathogenesis and dissemination. However, more work will be needed to uncover the parameters that are essential for cell-mediated protection.

When doing systems vaccinology, these are certainly some aspects that are worth noting. Hope you will like the compilation of systems vaccinology papers that I have curated here.

Thanks for reading!