What are the roles of antibodies versus a durable, high quality T-cell response in protective immunity against SARS-CoV-2?

Abstract

The first SARS-CoV-2 vaccine(s) will likely be licensed based on neutralizing antibodies in Phase 2 trials, but there are significant concerns about using antibody response in coronavirus infections as a sole metric of protective immunity. Antibody response is often a poor marker of prior coronavirus infection, particularly in mild infections, and is shorter-lived than virus-reactive T-cells; strong antibody response correlates with more severe clinical disease while T-cell response is correlated with less severe disease; and antibody-dependent enhancement of pathology and clinical severity has been described. Indeed, it is unclear whether antibody production is protective or pathogenic in coronavirus infections. Early data with SARS-CoV-2 support these findings. Data from coronavirus infections in animals and humans emphasize the generation of a high-quality T cell response in protective immunity. Yellow Fever and smallpox vaccines are excellent benchmarks for primary immune response to viral vaccination and induce long-lived virus-reactive CD8 T-cells, which are present and measurable within 1-4 months of vaccination. Progress in laboratory markers for SARS-CoV2 has been made with identification of epitopes on CD4 and CD8 T-cells in convalescent blood. These are much less dominated by spike protein than in previous coronavirus infections. Although most vaccine candidates are focusing on spike protein as antigen, natural infection by SARS-CoV-2 induces broad epitope coverage, cross-reactive with other betacoronviruses. It will be important to understand the relation between breadth, functionality and durability of T-cell responses and resulting protective immunity. It would be a public health and general trust-in-medicine nightmare - including a boost to anti-vaccine forces - if immune protection wears off or new disease patterns develop among the immunized. Data correlating clinical outcomes with laboratory markers of cell-mediated immunity, not only with antibody response, after SARS-CoV-2 natural infection and vaccines may prove critically valuable if protective immunity fades or if new patterns of disease emerge.

Keywords: Antibodies; Antibody-dependent enhancement; CD8 T-cells; COVID-19; Durable immunity; Protective immunity; SARS; SARS-CoV-2; T cell lifespan; T-cell epitopes; T-cells; Vaccines; Yellow Fever Vaccine.

Fig. 1

Long lifespan and mitotic quiescence of YFV-specific CD8 T-cells after vaccination (heavy water labeling shown in blue) (from [36]). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Protective and Pathologic Immunity in Coronavirus Infection: Humoral and Cellular Roles. Long-term survival and rapid proliferation with effector function on re-exposure are benchmarks of T-cells in highly effective infection- or vaccine-induced protective immunity against viral infections. Long-lifespan and maturation of CD8 T-cells is key for both quality and durability of immunity. In CoV infections, T-cells exhibit these features but antibodies and memory B-cells have not been durable. CD4 T-cells play critical helper roles for both CD8 T-cells and B-cells. Antibodies (by ADE or macrophage activation) and CD4 T-cells (by excessive cytokine production or Th2 eosinophilic immune damage) are concerns for potential contribution to tissue pathology in CoV infection. CD4 T-cells and tissue cytokines have shown a Th1 pattern in SARS-CoV-2. T-cells in CoV infections appear to have long lifespan and in both SARS-CoV-1 and -2 patients there cross-reactivity for betacoronavirus proteins. Abbreviations: CoV, coronavirus; Ab, antibodies; Ag, antigen; Cyto, cytokines; DC, dendritic cells; TCM, central memory T-cells; TRM, resident memory T-cells; T_fh, follicle helper T-cells; GC, germinal center; ADE, antibody-dependent enhancement; Fxns, functions; +, stimulatory effect.