Escape from recognition of SARS-CoV-2 variant spike epitopes but overall preservation of T cell immunity

Abstract

SARS-CoV-2 variants that escape neutralization and potentially affect vaccine efficacy have emerged. T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is incompletely understood. We assessed neutralizing antibody and T cell responses in 44 South African COVID-19 patients either infected with the Beta variant (dominant from November 2020 to May 2021) or infected before its emergence (first wave, Wuhan strain) to provide an overall measure of immune evasion. We show that robust spike-specific CD4 and CD8 T cell responses were detectable in Beta-infected patients, similar to first-wave patients. Using peptides spanning the Beta-mutated regions, we identified CD4 T cell responses targeting the wild-type peptides in 12 of 22 first-wave patients, all of whom failed to recognize corresponding Beta-mutated peptides. However, responses to mutated regions formed only a small proportion (15.7%) of the overall CD4 response, and few patients (3 of 44) mounted CD8 responses that targeted the mutated regions. Among the spike epitopes tested, we identified three epitopes containing the D215, L18, or D80 residues that were specifically recognized by CD4 T cells, and their mutated versions were associated with a loss of response. This study shows that despite loss of recognition of immunogenic CD4 epitopes, CD4 and CD8 T cell responses to Beta are preserved overall. These observations may explain why several vaccines have retained the ability to protect against severe COVID-19 even with substantial loss of neutralizing antibody activity against Beta.

The Robustness of Cellular Immunity Determines the Fate of SARS-CoV-2 Infection

“…Furthermore, CD4+ and CD8+ SARS-CoV-2 spike-specific T cell responses triggered by prior infection with the original strain or BNT 162b2 vaccination, remain largely intact against the Omicron strain (282). This is due to the fact that the vast majority of T cell epitopes are fully conserved (279)(280)(281)(283)(284)(285)(286), which suggests that the continued evolution of variants has not been associated with increased viral escape from T cell responses at the population level, and HLA binding of the mutated epitopes has been well conserved for the majority of the epitopes in Alpha to Omicron variants (281). Furthermore, it has been proposed that the phenotype of memory and the helper subset distribution of SARS-CoV-2-specific CD4+ and CD8+ T cells responses elicited by second dose vaccine are similar to the ones detected in individuals who have gone through a natural SARS-CoV-2 infection (250).…”

Fc effector activity and neutralization against SARS-CoV-2 BA.4 is compromised in convalescent sera, regardless of the infecting variant

“…In contrast, the ability of vaccines to prevent severe disease has been maintained (5,7,8). This is likely due to the preserved activity of T cells and Fc effector function, including antibody dependent cellular cytotoxicity (ADCC), against VOCs (9,10).…”

Serial infection with SARS-CoV-2 Omicron BA.1 and BA.2 following three-dose COVID-19 vaccination

“…While it is perhaps unsurprising that COVID-19 vaccines based on ancestral SARS-CoV-2 sequences will not generate sterilizing immunity against Omicron strains that have evolved to evade host immune responses (4,(38)(39)(40)(41)(42), various lines of evidence suggest that "hybrid" immunity resulting from vaccination plus infection provides greater protection against SARS-CoV-2 variants (5,43), due in part to maturation of Spike-specific antibodies (44)(45)(46) and expansion of antiviral T cells (47)(48)(49)(50)(51)(52). In light of this, we note that symptomatic BA.1 infection boosted vaccine-induced humoral responses against both BA.1 and BA.2 in our case participant, but the heightened response nevertheless failed to prevent subsequent symptomatic infection by BA.2.…”