Tissue-resident memory CD8 T-cell responses elicited by a single injection of a multi-target COVID-19 vaccine

Abstract

The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which enters the body principally through the nasal and larynx mucosa and progress to the lungs through the respiratory tract. SARS-CoV-2 replicates efficiently in respiratory epithelial cells motivating the development of alternative and rapidly scalable vaccine inducing mucosal protective and long-lasting immunity. We have previously developed an immunologically optimized multi-neoepitopes-based peptide vaccine platform which has already demonstrated tolerance and efficacy in hundreds of lung cancer patients. Here, we present a multi-target CD8 T cell peptide COVID-19 vaccine design targeting several structural (S, M, N) and non-structural (NSPs) SARS-CoV-2 proteins with selected epitopes in conserved regions of the SARS-CoV-2 genome. We observed that a single subcutaneous injection of a serie of epitopes induces a robust immunogenicity in-vivo as measured by IFNγ ELIspot. Upon tetramer characterization we found that this serie of epitopes induces a strong proportion of virus-specific CD8 T cells expressing CD103, CD44, CXCR3 and CD49a, the specific phenotype of tissue-resident memory T lymphocytes (Trm). Finally, we observed broad cellular responses, as characterized by IFNγ production, upon restimulation with structural and non-structural protein-derived epitopes using blood T cells isolated from convalescent asymptomatic, moderate and severe COVID-19 patients. These data provide insights for further development of a second generation of COVID-19 vaccine focused on inducing lasting Th1-biased memory CD8 T cell sentinels protection using immunodominant epitopes naturally observed after SARS-CoV-2 infection resolution.

Immunogenic SARS-CoV2 Epitopes Defined by Mass Spectrometry

“…What has not been demonstrated however, is whether any of these 1,500 predicted peptides are in fact processed and presented by SARS-CoV2+ cells and represent naturally-occurring epitopes recognized by T cells. A preliminary screen of predicted SARS-CoV2 epitopes considered "immunodominant" among widely cited reports appears to support this premise: previously we found that 7 of these 8 predicted peptides were unable to elicit a T cell response that would lead to recognition of SARS-CoV2+ targets suggesting that responses to these peptides may be artifactual, or at best cross-reactive (4,7,(15)(16)(17)(18)(19)(20)(21)(22) . To date, there has been no empiric validation of SARS-CoV2 epitopes for immunogenicity.…”

A Combination Adjuvant for the Induction of Potent Antiviral Immune Responses for a Recombinant SARS-CoV-2 Protein Vaccine

“…While the role of the TH17 response in SARS-CoV-2 immunity remains to be determined, a robust TH17 response is important for promoting effective immunity to several respiratory viruses, including influenza virus, in which it is associated with enhanced viral clearance and survival 68,69 . In addition, TH17 lineage CD4 + T cells play a critical role in effective mucosal immunity and the development of TRM's in the lung, which increasing evidence supports, are critical elements of immunity to SARS-CoV-2 70 . Indeed, both NE and NE/IVT DI adjuvants induced S1-specific IgA in the bronchial alveolar lavage fluid (BAL) (Figure S2).…”

“…Indeed, NE and NE/IVT induced significant antigen-specific IgA in the bronchial alveolar lavage (BAL) of immunized animals (Figure S2). T H 17 CD4 + T cells are also critical for development of T RM ’s residing in the lung mucosa, which are critical elements of local immunity to SARS-CoV-2, functioning early before circulating effector and central memory cells are recruited 68, 69 . While IL-17A has been associated with lung pathology in certain situations, this is primarily observed in the context of high T H 2 cytokines, whereas pathological inflammatory effects of IL-17A are prevented by IL10 70 .…”

Vaccines for COVID-19

“…Several groups are exploring the use of multi-epitope peptide vaccines against SARS-CoV-2; following bioinformatic and immune-informatic-based predictions of immunogenic epitopes [138][139][140][141], the studies are focusing upon T rather than B cell epitopes. OSE Immunotherapeutics have used a multiepitope peptide approach to induce T cell responses in mice [142]. Covaxx and the University of Nebraska Medical center have recently registered a Phase I clinical trial for a multi-epitope peptide vaccine (NCT04545749) as has the Vector Institute (NCT04527575) currently in clinical trial.…”