Suboptimal SARS-CoV-2-specific CD8+ T-cell response associated with the prominent HLA-A*02:01 phenotype

An improved understanding of human T-cell-mediated immunity in COVID-19 is important if we are to optimize therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T-cell memory to shared peptides presented by common HLA types like HLA-A2. Following re-infection, cross-reactive CD8+ T-cells enhance recovery and diminish clinical severity. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from SARS-CoV-2 Spike, Nucleocapsid and Membrane proteins led to the clonal expansion of SARS-CoV-2-specific CD8+ and CD4+ T-cells in vitro, with CD4+ sets being typically robust. For CD8+ T-cells taken directly ex vivo, we identified two HLA-A*02:01-restricted SARS-CoV-2 epitopes, A2/S269-277 and A2/Orf1ab3183-3191. Using peptide-HLA tetramer enrichment, direct ex vivo assessment of the A2/S269+CD8+ and A2/Orf1ab3183+CD8+ populations indicated that the more prominent A2/S269+CD8+ set was detected at comparable frequency ([~]1.3x10-5) in acute and convalescent HLA-A*02:01+ patients. But, while the numbers were higher than those found in uninfected HLA-A*02:01+ donors ([~]2.5x10-6), they were low when compared with frequencies for influenza-specific (A2/M158) and EBV-specific (A2/BMLF1280) ([~]1.38x10-4) populations. Phenotypic analysis ex vivo of A2/S269+CD8+ T-cells from COVID-19 convalescents showed that A2/S269+CD8+ T-cells were predominantly negative for the CD38, HLA-DR, PD-1 and CD71 activation markers, although the majority of total CD8+ T-cells were granzyme and/or perforin-positive. Furthermore, the bias towards naive, stem cell memory and central memory A2/S269+CD8+ T-cells rather than effector memory populations suggests that SARS-CoV2 infection may be compromising CD8+ T-cell activation. Priming with an appropriate vaccine may thus have great value for optimizing protective CD8+ T-cell immunity in COVID-19.

Distinct systems serology features in children, elderly and COVID patients

SARS-CoV-2, the pandemic coronavirus that causes COVID-19, has infected millions worldwide, causing unparalleled social and economic disruptions. COVID-19 results in higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive coronavirus immunological responses, induced by circulating human coronaviruses, is critical to understand such divergent clinical outcomes. The cross-reactivity of coronavirus antibody responses of healthy children (n=89), adults (n=98), elderly (n=57), and COVID-19 patients (n=19) were analysed by systems serology. While moderate levels of cross-reactive SARS-CoV-2 IgG, IgM, and IgA were detected in healthy individuals, we identified serological signatures associated with SARS-CoV-2 antigen-specific Fc{gamma} receptor binding, which accurately distinguished COVID-19 patients from healthy individuals and suggested that SARS-CoV-2 induces qualitative changes to antibody Fc upon infection, enhancing Fc{gamma} receptor engagement. Vastly different serological signatures were observed between healthy children and elderly, with markedly higher cross-reactive SARS-CoV-2 IgA and IgG observed in elderly, whereas children displayed elevated SARS-CoV-2 IgM, including receptor binding domain-specific IgM with higher avidity. These results suggest that less-experienced humoral immunity associated with higher IgM, as observed in children, may have the potential to induce more potent antibodies upon SARS-CoV-2 infection. These key insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.

Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19

We report the kinetics of the immune response in relation to clinical and virological features of a patient with mild-to-moderate coronavirus disease-19 (COVID-19) requiring hospitalisation. Increased antibody-secreting cells, follicular T-helper cells, activated CD4+ and CD8+ T-cells and IgM/IgG SARS-CoV-2-binding antibodies were detected in blood, prior to symptomatic recovery. These immunological changes persisted for at least 7 days following full resolution of symptoms, indicating substantial anti-viral immunity in this non-severe COVID-19.