Safety and Immunogenicity Trial of Multi-peptide Vaccination to Prevent COVID-19 Infection in Adults

Overview

Part I: 12 subjects will receive an open-label 500 µl subcutaneous injection via needle and syringe of the study IMP (CoVac-1). No more than one subject per day will be enrolled. 28 days following vaccination of the 12th volunteer, there will be an interim analysis of safety and a safety review by the data safety monitoring board (DSMB) as well as an amendment to the regulatory authorities (Paul-Ehrlich Institute and Ethics Committee) before proceeding to Part II. Part II: 12 subjects will receive an open-label 500 µl subcutaneous injection via needle and syringe of the study investigational medicinal product (IMP) (CoVac-1). 28 days following vaccination of the 12th volunteer, there will be an interim analysis of safety and a safety review by the DSMB whether to proceed to next Part III. Part III: 12 subjects will receive an open-label 500 µl subcutaneous injection via needle and syringe of the study IMP (CoVac-1). The aim of the clinical is to evaluate the safety and immunogenicity of a single use of a SARS-CoV-2-derived multi-peptide vaccine in combination with the toll like receptor (TLR)1/2 ligand XS15 in adults

SARS-CoV-2 peptide vaccine The aim of this study is to investigate the safety and immunogenicity of a peptide vaccine consisting of SARS-CoV-2 specific HLA class II peptides in volunteers without prior or current SARS-CoV-2 infection. The identification and characterization of T cell epitopes is a long-standing and unparalleled expertise of the Department of Immunology. This unique approach is based on i) the prediction of HLA binding sequences for HLA class I and class II alleles using the world's first prediction tool (www.syfpeithi.de) and newer, more refined methods, all based on SYFPEITHI (database for MHC ligands), ii) the identification of naturally presented HLA class I and class II ligands, iii) the synthesis of synthetic peptides, and iv) the characterization of T-cell epitopes and peptide-specific cluster of differentiation (CD)4+ and CD8+ T cell responses. This strategy has been successfully applied in recent years to define and characterize T-cell epitopes derived from various viruses such as cytomegalovirus (CMV),Epstein-Barr virus (EBV), adenovirus (ADV) and influenza as well as tumor-associated antigens of various solid and hematological malignancies. Based on this work, the results were translated into therapeutic vaccination and T cell transfer studies in cancer patients (e.g. NCT02802943) and viral infections. This direct translation is made possible by the Wirkstoffpeptidlabor (Prof. Dr. rer. nat. Stefan Stevanović) of the Department of Immunology and the good manufacturing practice (GMP) facility for individualized drugs at the University Hospital Tuebingen as well as our immune monitoring platform equipped with state-of-the-art, validated T-cell assays and methods. The existing experience and logistics can be directly used for the treatment and prevention of COVID-19 disease. In preliminary work for this study, CD4+ T cell epitopes have already been characterized in a large cohort of SARS-CoV-2 infected donors validating their high relevance in the natural course of COVID-19. The vaccination cocktail in the study will consist of eight promiscuous HLA class II peptides from the different proteins of the SARS-CoV-2 virus, predicted to bind to several HLA class II allotypes. Furthermore, especially those peptides were selected that contain embedded HLA class I sequences in order to induce CD4+ T cell responses and CD8+ T cell responses simultaneously. Furthermore, especially for peptides derived from virus surface proteins, only sequences were selected that do not represent antibody epitopes. This should prevent the formation of antibodies against the vaccinated peptides, which could possibly have a deteriorative effect on COVID-19. Immunogenicity was proven for all HLA class II peptides included in the peptide cocktail in a large cohort of SARS-CoV-2 convalescent donors as well as for single peptides in a first vaccination of a healthy volunteer. A further prerequisite for successful peptide vaccination, besides selection of optimal antigen targets, is the use of a suitable adjuvant, which is able to induce potent and long-lasting immune responses. Among the most effective approaches tested in humans is the subcutaneous injection of peptides emulsified in Montanide ISA 51 VG, a water-in-oil-emulsion, combined with the TLR9 ligand CpG.However, CpG is not available for clinical trials, and a peptide/antigen vaccine emulsified in Montanide without any additional adjuvant induces no or only weak immune responses. In the P-pVac-SARS-CoV-2 trial, the novel TLR1/2 ligand XS15 emulsified in Montanide ISA 51 VG will be employed as adjuvant, applied subcutaneously together with the peptide vaccine. XS15 is a water-soluble derivative of the TLR1/2 ligand Pam3Cys and induced a strong CD8+ and Th1CD4+ T-cell response against free short peptides in Montanide ISA 51 VG after a single s.c. injection in a healthy volunteer as well as in cancer patients.Immune responses could be induced against viral peptides (including SARS-CoV-2 derived peptides), neo-epitopes derived from cancer-specific mutations as well as tumor-associated self-peptides. XS15 results in granuloma formation on the vaccination site, where the vaccinated peptides persist for at least 7 weeks. Peptide-specific T cells were detected at the granuloma site, however, with a lower frequency than in peripheral blood, which rules out the risk of T cell sequestration, dysfunction or deletion at the vaccination site due to the use of XS15 in Montanide ISA 51 VG. Strikingly, the induced immune responses were found to persist for more than 1.5 years. With regard to the planned study we could also show that this vaccination method is able to induce potent SARS-CoV-2 specific T-cell responses in a human volunteer.