Discussion
T-cell recall, infections, COVID-19 disease
DISEASE, INFECTIONS, VIRAL SHEDDING
The immune response to COVID-19 vaccination has been extensively studied in SARS-CoV-2-seronegative populations during randomized placebo-controlled studies (Retrospective case studies (ILL-D1 spike-binding and nAb titers in vaccinees were comparable to peak titers observed post-primary series (Real-world serological studies have demonstrated that spike-binding antibody titers begin to wane as early as 4–6 months post-primary series vaccination (ILL-D1 spike-binding and nAb IgG responses inversely correlated with virologic outcomes, with moderate correlations observed for viral shedding titers and for the duration of shedding in saliva – particularly in vaccinees. As SARS-CoV-2 is transmitted Frequencies of spike-specific CD4+ and CD8+ T cells were enhanced in vaccinees compared to placebo recipients at ILL-D1, likely due to pre-existing memory cells in vaccinees. Surprisingly, these enhanced responses were maintained 2 weeks post-ILL-D1. It is possible that vaccinee spike-specific memory T cells continued to expand over this period, however, it is also likely that the addition of Vaccinee T cells displayed a greater proportion of polyfunctional markers compared with placebo recipients. Polyfunctional T cells are most abundant in individuals with mild COVID-19 (One limitation to this study is that data were obtained prior to and during a global SARS-CoV-2 Alpha variant wave and thus breakthrough infections were caused by circulating SARS-CoV-2 variants that are no longer VoCs. Would the vaccinees have been imparted with a similar antiviral cellular advantage had they been infected by an Omicron variant? We and others have observed that primary series AZD1222 vaccination induces durable, diverse T-cell responses with minimal viral escape from VoC including Omicron BA.1 (Cellular immune responses inversely correlated with virologic outcomes, which is in line with observations that effective viral clearance by cellular immunity correlates with milder COVID-19 disease severity (Limitations of this analysis include the low numbers of participants >65 years of age who experienced breakthrough infection, and the small sample size for the T-cell correlative analyses. As described in Sobieszczyk et al. (In summary, breakthrough infection in AZD1222 vaccinees was characterized by a lower symptom burden, lower viral loads, and more robust humoral and cellular responses compared with unvaccinated participants. Our findings are intriguing in light of other studies with vaccinees who received primary series mRNA-based COVID-19 vaccines, wherein a similar attenuated disease profile with reduced viral loads (Although sample numbers were limited, cellular immune responses displayed strong inverse correlations with viral endpoints upon breakthrough infection, emphasizing the importance of cellular immunity in protective immune responses against COVID-19. Limiting SARS-CoV-2 viral transmission is a key step to overcoming the COVID-19 pandemic. Our data also indicate that the induction of T-cell recall responses early following breakthrough correlated with reduced viral loads in saliva compared to unvaccinated individuals. Of note, COVID-19 vaccines designed using the ancestral SARS-CoV-2 spike protein continue to confer protection against severe disease, likely arising from the conservation of T-cell epitopes in previous and contemporary VoCs (