Can immune responses predict which vaccines work best?

 Summary

Other than a placebo-controlled, clinical trial lasting many months and involving tens of thousands of people, is there any way to be sure a COVID-19 vaccine will work? Many researchers say the vaccines already in use offers a shortcut: Simply gauge a vaccine's ability to elicit so-called neutralizing antibodies, which bind to the virus and prevent it from entering cells. But several recent studies point to other "correlates of protection": "binding" antibodies—which latch onto the virus but don't block entry—and another set of immune warriors called T cells. Vaccine decisions may soon depend on a better understanding of these supporting actors. Several manufacturers are developing updates of their COVID-19 vaccines tailored to protect against new viral variants that could be used as booster shots. The companies hope regulatory agencies won't require evidence of efficacy in big clinical trials, which are time-consuming, expensive, and increasingly ethically fraught because some of the participants receive a placebo even though proven vaccines are now available. 

Cellular immune responses to covid-19

T cells could be valuable allies in pandemic control

Protective and enduring immune responses to viral infections or vaccines usually arise from the combined actions of lymphocytes: B cells (responsible for humoral antibody immunity) and T cells (responsible for cellular immunity and helping B cell responses).

B cells produce detectable antibodies in classes IgM, IgG, and IgA along with lesser amounts of IgD and IgE. For SARS-CoV-2, the causative agent of covid-19, the focus is mainly on IgM, IgG, and IgA antibodies that can neutralise the virus by binding to the spike and other membrane proteins and thus preventing infection.1 Understanding the lesser known roles of T cells and cellular immunity will deepen our insights into covid-19 pathogenesis and help inform both vaccine development and pandemic containment strategies.

An effective immune response to SARS-CoV-2 involves four types or subsets of T cells: T helper cells (CD4) are responsible for cellular immunity and for helping B cells to produce neutralising antibodies; cytotoxic or killer T cells (CD8) directly kill infected cells—aided by helper T cells2; other T cells (including T-17 (Th17) cells) drive the inflammatory responses that help to control infections3; and regulatory T cells (T regs) help to contain the immune response, to prevent over-reaction and damage to tissues.

CD4 T cells ensure all these components work together by secreting small short acting cytokines that bind to receptors on target cells. Importantly, all B and T cell types have immunological memory after a first encounter with a pathogen. This enables a faster effective response after a second encounter with the same pathogen or one that is closely related (cross reaction).

Preliminary studies from the US and Europe recently documented T cells specific to SARS-CoV-2 in people with acute covid-19 and in those recovering from infection.456 They report helper and killer T cells specific to SARS-CoV-2 in people with and without antibodies.6 More unexpectedly, they found specific T cells in people with no history of exposure to SARS-CoV-2—individuals who had repeatedly swabbed negative for the virus.4 These cells have even been found in stored blood taken before the pandemic (2015-18). Finally, the studies identified strong T cell memory responses in people recovering from covid-19. Memory cells are critical for protective and enduring immunity.

What are the implications of these early findings? Principally, these studies show that a good T cell immune response and immunological memory accompany natural exposure to or infection with SARS-CoV-2, that evidence of these responses is present in some people who have apparently never encountered the virus, and that T cell immune responses can exist in the absence of detectable antibodies.

Collectively, these features suggest that candidate vaccines7 should aim to stimulate both B cell (neutralising) antibodies and T cell antiviral responses.8 Early phase clinical trials of candidate vaccines developed in Oxford, UK, and in China do show concomitant B cell neutralising antibodies and antiviral T cells in vaccinated healthy volunteers,910 improving prospects for protective immunity. This combined response is a feature of many successful vaccines, including vaccines against varicella (chickenpox), influenza, measles, and hepatitis B.

Immune memory

That some “virus naive” participants in early studies had pre-existing memory helper (50% of participants) and killer T (20%) cells with potential activity against SARS-CoV-2 is intriguing. These cells might arise from cross reactions to other circulating coronaviruses, such as some common cold viruses, and might be a welcome hint of possible background immunity to covid-19 in populations at risk—even in the absence of antibodies.

Any cellular immune memory for SARS-CoV-2 in the population could enhance responses to vaccines and might also give a vaccination programme a head start towards herd immunity. Herd immunity is population resistance to spread of an infection, achieved when a high enough proportion of individuals are immune, usually through vaccination.1112

Pre-existing memory helper T cells specific to SARS-CoV-2 could boost the production of neutralising IgG antibodies in the blood of newly exposed people and could also enhance antibody protection at mucosal surfaces through IgA in saliva, tears, or nasal secretions.131415 Such IgA antibodies act as a protective barrier at common viral entry points. Research is now required to further characterise these possible immune pathways including memory B and T cells in mucosal tissues.

Research should also explore the role of regulatory T cells in severe covid-19, particularly cytokine storm syndrome16 and the documented association between high titres of IgG antibodies and poorer disease outcomes including death.17 Both might reflect ineffective control of inflammation by regulatory T cells.

Recent findings on the role of T cells in covid-19 give us cause to be cautiously optimistic that cellular immune responses could be a valuable ally in global efforts to control this and future pandemics.