Tissue-resident memory CD8 T-cell responses elicited by a single injection of a multi-target COVID-19 vaccine
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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.
Statement of Significance
Humoral and cellular adaptive immunity are different and complementary immune defenses engaged by the body to clear viral infection. While neutralizing antibodies have the capacity to block virus binding to its entry receptor expressed on human cells, memory T lymphocytes have the capacity to eliminate infected cells and are required for viral clearance. However, viruses evolve quickly, and their antigens are prone to mutations to avoid recognition by the antibodies (phenomenon named ‘antigenic drift’). This limitation of the antibody-mediated immunity could be addressed by the T-cell mediated immunity, which is able to recognize conserved viral peptides from any viral proteins presented by virus-infected cells. Thus, by targeting several proteins and conserved regions on the genome of a virus, T-cell epitope-based vaccines are less subjected to mutations and may work effectively on different strains of the virus. We designed a multi-target T cell-based vaccine containing epitope regions optimized for CD8+ T cell stimulation that would drive long-lasting cellular immunity with high specificity, avoiding undesired effects such as antibody-dependent enhancement (ADE) and antibody-induced macrophages hyperinflammation that could be observed in subjects with severe COVID-19. Our in-vivo results showed that a single injection of selected CD8 T cell epitopes induces memory viral-specific T-cell responses with a phenotype of tissue-resident memory T cells (Trm). Trm has attracted a growing interest for developing vaccination strategies since they act as immune sentinels in barrier tissue such as the respiratory tract and the lung. Because of their localization in tissues, they are able to immediately recognize infected cells and, because of their memory phenotypes, they rapidly respond to viral infection by orchestrating local protective immune responses to eliminate pathogens. Lastly, such multiepitope-based vaccination platform uses robust and well-validated synthetic peptide production technologies that can be rapidly manufactured in a distributed manner.
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SciScore for 10.1101/2020.08.14.240093: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Study Approval: Animal housing and procedures have been conducted according to the guidelines of the French Agriculture Ministry and were approved by the regional ethical committee (APAFIS 25256.
IRB: Human studies were performed under the clinical protocol COVEPIT-1 approved by French Central Ethic Committee (CPP) and registered by the French Regulatory Authority (ANSM) under the ID-RCB n° 2020-A01654-35.
Consent: Written informed consent has been obtained from each of the participating subject.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Immunization was measured 15 days after injection. 3 males and … SciScore for 10.1101/2020.08.14.240093: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Study Approval: Animal housing and procedures have been conducted according to the guidelines of the French Agriculture Ministry and were approved by the regional ethical committee (APAFIS 25256.
IRB: Human studies were performed under the clinical protocol COVEPIT-1 approved by French Central Ethic Committee (CPP) and registered by the French Regulatory Authority (ANSM) under the ID-RCB n° 2020-A01654-35.
Consent: Written informed consent has been obtained from each of the participating subject.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Immunization was measured 15 days after injection. 3 males and 3 females have been evaluated per group. Table 2: Resources
Antibodies Sentences Resources HLA-peptide complexes stability was detected by ELISA with β2-microglobulin coated antibodies and incubation of 3 ng/ml of complexes for 1h at room temperature under shaking condition. β2-microglobulinsuggested: NoneExperimental Models: Organisms/Strains Sentences Resources T-cell epitopes immunization: B6.Cg-Immp2lTg(HLA-A/H2-D)2Enge/J (HLA-A2.1) transgenic mice (JAX # 004191, The Jackson Laboratory, Bar Harbor, USA) received a single subcutaneous injection of 6 SARS-CoV-2 peptides (50μg each, WT and mutated peptide of a same epitope have not been evaluated in same mice) plus the universal PADRE helper T-cell epitope30 emulsified in Montanide ISA-51 adjuvant. B6.Cg-Immp2lTg(HLA-A/H2-D)2Enge/J (HLA-A2.1)suggested: RRID:IMSR_JAX:004191)Software and Algorithms Sentences Resources All statistical analyses were performed on GraphPad Software (GraphPad Software, San Diego, CA). GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 32. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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