Although studies to date provide encouraging findings supporting both B and T cell responses to SARS-CoV-2, the forecast for long term immunity remains unclear. B cell responses to SARS-CoV-2's spike protein have received great attention, and evidence continues to emerge supporting the protective role of neutralizing anti-spike antibodies. However, with the levels of circulating neutralizing antibodies declining quickly for some, questions remain regarding the persistence of protective immunity (Cox et al. 2020).
Ultimately, immune memory to SARS-CoV-2 will be shaped by the quality of the combined responses from both the B cell and T cell compartments. Therefore, understanding the factors that induce and parameters that define an optimal first response, will enable identifying the best immunization regimes to ensure long-lasting protection.
"Adaptive Immunity", by Akiko Iwasaki, PhD, BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates
Based on recent studies, a consensus is emerging on antibody responses generally associated with COVID-19. First, individuals with confirmed SARS-CoV-2 infections, generally develop antibodies against the spike and nucleocapsid (N) proteins. Second, anti-spike neutralizing antibody level in convalescent plasma vary widely among individuals and correlate with disease severity. Finally, neutralizing antibody levels decline post symptoms onset (PSO) to varying degrees, according with disease severity.
In a recent and perhaps the longest longitudinal (Seow et al. 2020) study to date to analyze SARS-CoV-2 humoral responses, neutralizing antibody titers were evaluated up to 94 days PSO. Peak neutralizing antibody titers were generally seen at ~23 days PSO. In mild disease cases, neutralizing antibodies declined to undetectable levels within a period of ~50 days. In contrast, robust neutralizing antibody titers common in severe disease, could persist in some individuals for ~50-82 days . From these findings, investigators expect that higher antibody titers may provide, albeit for an unknown period, some level of protection from re-infection.
It remains to be determined, how the level, potency and duration of circulating neutralizing antibodies correlate with long lasting protection. Nevertheless, recent findings support that strong humoral immunity to SARS-CoV-2 may be characterized by the presence of spike specific-IgG neutralizing antibodies, -memory B cells, and –circulating T follicular helper cells (Tfh) (Juno et al. 2020). Notably, the proportion of both B cells and circulating Tfh cells reactive to spike predominated over those specific to the receptor binding domain (RBD), pointing to additional immunologically relevant spike epitopes.
In an effort to better understand SARS-CoV-2 immunity, researchers have focused on identifying relevant epitopes inducing T cell activation. In recent studies, COVID-19 T cell responses have been interrogated by stimulating peripheral blood mononuclear cells (PBMCs) ex vivo with pools of overlapping synthetic peptides. This approach allows the efficient screening of hundreds of protein sequences, and has led to the identification of various epitopes that may prove valuable for vaccine development and evaluation (Le Bert et al. 2020, Grifoni et al. 2020).
In one such study, COVID-19 convalescent samples allowed functional analysis of T cell responses, confirming the presence of IL-2 producing CD4+ T cells specific for spike and non-spike epitopes (Grifoni et al. 2020). Importantly, the SARS-CoV-2 derived peptides tested, elicited CD4+ T cell responses in all COVID-19 convalescent samples, while IFN-γ+ CD8+ T cell responses were seen in only 70% of samples.
In agreement with the critical role of CD4+ T cells for protective B cell responses, investigators noted a positive correlation between spike-CD4+ T cell and anti-spike IgG antibody responses. Finally, by stimulating T cells with overlapping peptide pools representing specific viral proteins, investigators found that CD4+ and CD8+ T cells were predominantly stimulated by viral proteins with high abundance, such as spike, membrane (M), and N proteins. Although, peptides from NSP6 (non-structural protein 6) and ORF8 also induced substantial CD8+ T cell reactivity.
Overall, a better picture of the elements defining an effective immune response to SARS-CoV-2 infection is emerging. These findings will not only prove critical for therapeutic strategies based on immunization, but will also inform other therapeutic modalities, such as the use of monoclonal antibody drugs to induce viral neutralization.
