Clonal diversity determines persistence of SARS-CoV-2 epitope-specific T cell response (preprint)

T cells play a pivotal role in reducing disease severity during SARS-CoV-2 infection and formation of long-term immune memory. We studied 50 COVID-19 convalescent patients and found that T cell response was induced more frequently and persisted longer than circulating antibodies. To identify epitopes that give rise to long-lived T cell memory, we performed ex vivo T cell expansion, MHC-tetramer cell-sorting, and high-throughput sequencing. We identified 756 clonotypes specific to nine known CD8+ T cell receptor (TCR) epitopes. Some epitopes were recognized by highly similar public clonotypes with restricted variable and joining segment usage. Receptors for other epitopes were extremely diverse, suggesting alternative modes of recognition. We also tracked persistence of epitope-specific response and individual clonotypes for a median of eight months after infection. The number of recognized epitopes per patient and quantity of epitope-specific clonotypes decreased over time, but the studied epitopes were characterized by uneven decline in the number of specific T cells. Epitopes with more clonally diverse TCR repertoires induced more pronounced and durable responses. In contrast, the abundance of specific clonotypes in peripheral circulation had no influence on their persistence. Our study demonstrates the durability of SARS-CoV-2-specific CD8+ memory, and offers important implications for vaccine design.

Immunogenicity and safety of a recombinant adenovirus type-5 COVID 19 vaccine in adults: data from a randomised, double-blind, placebo-controlled, single-dose, phase 3 trial in Russia (preprint)

BackgroundTo determine the immunogenicity, efficacy, reactogenicity, and safety of a single dose of recombinant adenovirus type-5 vectored COVID-19 vaccine (Ad5-nCoV, 5 x 1010 viral particles per 0.5 mL dose), we conducted a single-dose, randomised, double-blind, placebo-controlled, parallel group (3:1 Ad5-nCoV:placebo), phase 3 trial (Prometheus). MethodsFrom 11-September-2020 to 05-May-2021, across six sites in the Russian Federation, 496 participants were injected with either placebo or Ad5-nCoV expressing the full-length spike (S) protein from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ResultsSeroconversion (the primary endpoint) rates of 78.5% (95% CI: 73.9; 82.6) against receptor binding domain (RBD), 90.6% (95% CI: 87.2; 93.4) against S protein and 59% (95% CI: 53.3; 64.6) against neutralising SARS-CoV2 antibodies 28 days post-vaccination. Geometric mean titres (GMTs) were also elevated for antibodies against the RBD (405.32 [95% CI: 361.58; 454.46]) and S protein (678.86 [95% CI: 607.44; 754.40]) compared to the GMT of neutralising antibodies against SARS-CoV-2 (16.73 [95% CI: 15.36; 18.22]). Using an IFN-{gamma} ELISpot assay after stimulating the cells with full-length S protein we showed that the Ad5-nCoV vaccine induced the most robust cellular immune response on Days 14 and 28. Up to Day 28, the primary and all secondary endpoints of the Ad5-nCoV vaccine were statistically superior to the placebo ([p] <0.001). Systemic reactions were reported in 113 of 496 (22.8%) participants (Ad5-nCoV, 26.9%; Placebo, 10.5%), and local reactions were reported in 108 (21.8%) participants (Ad5-nCoV, 28.5%; Placebo, 1.6%). These were generally mild and resolved within 7 days after vaccination. Of the six serious adverse events reported, none of the events were vaccine related. There were no deaths or premature withdrawals. ConclusionA single-dose of Ad5-nCoV vaccine induced a marked specific humoral and cellular immune response with a favourable safety profile. Trial RegistrationClinicalTrials.gov: NCT04540419

Immunogenic epitope panel for accurate detection of non-cross-reactive T cell response to SARS-CoV-2 (preprint)

The ongoing COVID-19 pandemic calls for more effective diagnostic tools, and T cell response assessment can serve as an independent indicator of prior COVID-19 exposure while also contributing to a more comprehensive characterization of SARS-CoV-2 immunity. In this study, we systematically assessed the immunogenicity of 118 epitopes with immune cells collected from multiple cohorts of vaccinated, convalescent, and healthy unexposed and SARS-CoV-2 exposed donors. We identified seventy-five immunogenic epitopes, 24 of which were immunodominant. We further confirmed HLA restriction for 49 epitopes, and described association with more than one HLA allele for 14 of these . After excluding two cross-reactive epitopes that generated a response in pre-pandemic samples, we were left with a 73-epitope set that offers excellent diagnostic specificity without losing sensitivity compared to full-length antigens, which evoked a robust cross-reactive response. We subsequently incorporated this set of epitopes into an in vitro diagnostic 'Corona-T-test' which achieved a diagnostic accuracy of 95% in a clinical trial. When applied to a cohort of asymptomatic seronegative individuals with a history of prolonged SARS-CoV-2 exposure, this test revealed a lack of specific T cell response combined with strong cross-reactivity to full-length antigens, indicating that abortive infection had occurred in these individuals.

SARS-CoV-2 epitopes are recognized by a public and diverse repertoire of human T-cell receptors (preprint)

Understanding the hallmarks of the adaptive immune response to SARS-CoV-2 is critical for fighting the COVID-19 pandemic. We assessed the antibody and T-cell reactivity in COVID-19 convalescent patients and healthy donors sampled both prior to and during the pandemic. The numbers of SARS- CoV-2-specific T cells were increased in healthy donors examined during COVID-19. Combined with the absence of symptoms and humoral response across that group, this finding suggests that some individuals might be protected by T-cell cross-reactivity. In convalescent patients we observed public and diverse T-cell response to SARS-CoV-2 epitopes, revealing T-cell receptor motifs with germline- encoded features. Bulk CD4+ and CD8+ T-cell responses to Spike glycoprotein were mediated by groups of homologous T-cell receptors, some of them shared across multiple donors. Overall, our results demonstrate that T-cell response to SARS-CoV-2, including the identified set of specific T-cell receptors, can serve as a useful biomarker for surveying viral exposure and immunity.