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

A prospective study of the protective effect of SARS-CoV-2-specific antibodies and T cells in Moscow residents (preprint)

BackgroundCoronavirus disease COVID-19 has spread worldwide extremely rapidly. Although many individuals have been infected and have cleared the virus, developing virus-specific antibodies and effector/memory T cells, an important question still to be answered is what levels of T cell and antibody responses are sufficient to protect from the infection. MethodsIn 5,340 Moscow residents, we evaluated the anti-SARS-CoV-2 IgM/IgG titers and the frequencies of the T cells specific to the nucleocapsid, membrane, and spike proteins of SARS-CoV-2, using IFN{gamma} ELISpot, and we also evaluated the fractions of virus-specific CD4+ and CD8+ T cells using intracellular staining of IFN{gamma} and IL2 followed by flow cytometry. Furthermore, we analyzed the post-inclusion COVID-19 rates as a function of the assessed antibody and T cell responses using the Kaplan-Meyer estimator method. ResultsWe showed that T cell and antibody responses are closely interconnected and commonly are induced concurrently. Individuals positive for both antibody and T cell immunities demonstrated the highest levels of protectivity against the SARS-CoV-2 infection, indistinguishably from individuals with antibody response only. Meanwhile, individuals with T cell response only demonstrated slightly higher protectivity than individuals without both types of immunity, as measured from N-protein-specific or CD4+IL2+ T cells. However, these individuals were characterized by higher IgG titers than individuals without any immunity, although the titers were below the seropositivity cut-off. ConclusionsThe results of the study indicated the advantage of serology testing over the analysis of T cell responses for the prediction of SARS-CoV-2 infection rates on a populational level.

Structural basis for recognition of two HLA-A2-restricted SARS-CoV-2 spike epitopes by public and private T cell receptors (preprint)

T cells play a vital role in combatting SARS-CoV-2 and in forming long-term memory responses. Whereas extensive structural information is available on neutralizing antibodies against SARS- CoV-2, such information on SARS-CoV-2-specific T cell receptors (TCRs) bound to their peptide-MHC targets is lacking. We determined structures of a public and a private TCR from COVID-19 convalescent patients in complex with HLA-A2 and two SARS-CoV-2 spike protein epitopes (YLQ and RLQ). The structures revealed the basis for selection of particular TRAV and TRBV germline genes by the public but not the private TCR, and for the ability of both TCRs to recognize natural variants of YLQ and RLQ but not homologous epitopes from human seasonal coronaviruses. By elucidating the mechanism for TCR recognition of an immunodominant yet variable epitope (YLQ) and a conserved but less commonly targeted epitope (RLQ), this study can inform prospective efforts to design vaccines to elicit pan-coronavirus immunity.

Structural basis for recognition of two HLA-A2-restricted SARS-CoV-2 spike epitopes by public and private T cell receptors (preprint)

T cells play a vital role in combatting SARS-CoV-2 and in forming long-term memory responses. Whereas extensive structural information is available on neutralizing antibodies against SARS-CoV-2, such information on SARS-CoV-2-specific T cell receptors (TCRs) bound to their peptide–MHC targets is lacking. We determined structures of a public and a private TCR from COVID-19 convalescent patients in complex with HLA-A2 and two SARS-CoV-2 spike protein epitopes (YLQ and RLQ). The structures revealed the basis for selection of particular TRAV and TRBV germline genes by the public but not the private TCR, and for the ability of both TCRs to recognize natural variants of YLQ and RLQ but not homologous epitopes from human seasonal coronaviruses. By elucidating the mechanism for TCR recognition of an immunodominant yet variable epitope (YLQ) and a conserved but less commonly targeted epitope (RLQ), this study can inform prospective efforts to design vaccines to elicit pan-coronavirus immunity.

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.Funding: Mikhail Shugay was supported by RFBR grant No 19-34-70011. Alexander Ivanov was supported by the Ministry of Science and Higher Education of the Russian Federation [Agreement No. 075-15-2019-1660]. Conflict of Interest: The authors declare no conflicts of interest.Ethical Approval: All donors signed the informed consent approved by the National Research Center for Hematology ethical committee before the enrollment. Additionally, 10 healthy hematopoietic stem cell donor samples and 10 healthy donor serum samples were obtained from the blood bank with the approval of the local ethical committee.

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.