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. 2021 Apr 24;9(5):428.
doi: 10.3390/vaccines9050428.

Designing a SARS-CoV-2 T-Cell-Inducing Vaccine for High-Risk Patient Groups

Hans-Georg Rammensee  1   2   3   4 , Cécile Gouttefangeas  1   2   3 , Sonja Heidu  1 , Reinhild Klein  5 , Beate Preuß  5 , Juliane Sarah Walz  1   3   6   7 , Annika Nelde  1   3   6 , Sebastian P Haen  1   2   8 , Michael Reth  9 , Jianying Yang  9 , Ghazaleh Tabatabai  2   10   11 , Hans Bösmüller  12 , Helen Hoffmann  1 , Michael Schindler  13 , Oliver Planz  1 , Karl-Heinz Wiesmüller  14 , Markus W Löffler  1   2   3   15   16
Affiliations

Designing a SARS-CoV-2 T-Cell-Inducing Vaccine for High-Risk Patient Groups

Hans-Georg Rammensee et al. Vaccines (Basel). .

Abstract

We describe the results of two vaccinations of a self-experimenting healthy volunteer with SARS-CoV-2-derived peptides performed in March and April 2020, respectively. The first set of peptides contained eight peptides predicted to bind to the individual's HLA molecules. The second set consisted of ten peptides predicted to bind promiscuously to several HLA-DR allotypes. The vaccine formulation contained the new TLR 1/2 agonist XS15 and was administered as an emulsion in Montanide as a single subcutaneous injection. Peripheral blood mononuclear cells isolated from blood drawn before and after vaccinations were assessed using Interferon-γ ELISpot assays and intracellular cytokine staining. We detected vaccine-induced CD4 T cell responses against six out of 11 peptides predicted to bind to HLA-DR after 19 days, following vaccination, for one peptide already at day 12. We used these results to support the design of a T-cell-inducing vaccine for application in high-risk patients, with weakened lymphocyte performance. Meanwhile, an according vaccine, incorporating T cell epitopes predominant in convalescents, is undergoing clinical trial testing.

Keywords: COVID-19; SARS-CoV-2; adjuvant; high-risk patient; lipopeptide; peptide vaccine.

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Conflict of interest statement

H.G. Rammensee has ownership interest in Immatics Biotechnologies GmbH, CureVac AG, Bamomab GmbH, and Synimmune GmbH. H.G. Rammensee and K.H. Wiesmüller share the patent for XS15. K.H. Wiesmüller further holds ownership interest in EMC microcollections GmbH. O. Planz has ownership interest in Atriva Therapeutics GmbH and is a consultant for Atriva Therapeutics GmbH. H. Hoffmann is an employee of Atriva Therapeutics GmbH. H.G. Rammensee, A. Nelde, J.S. Walz, S.P. Haen, and M.W. Löffler are the inventors of patents for vaccine peptides owned by Immatics. H.G. Rammensee, A. Nelde, and J.S. Walz hold patents on peptides described in this manuscript secured under the numbers 20_169_047.6 and 20_190_070.1. M.W. Löffler acts as a paid consultant in cancer immunology for Boehringer Ingelheim Pharma GmbH & Co. KG. G. Tabatabai reports personal fees (advisory board, speaker’s fees) from AbbVie, Bayer, Bristol-Myers-Squibb, Medac, Novocure, travel grants from Bristol-Myers-Squibb, educational and travel grants from Novocure, research grants from Roche Diagnostics, and research and travel grants from Medac. All other authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1
Illustration of the potential interactions between SARS-CoV-2 and B and T cells. (A) If a virus-specific B cell takes up the entire virus particle via B cell receptor (BCR)-mediated phagocytosis, all structural viral proteins should be processed in the HLA class II processing vesicle. The resulting peptides should be loaded onto the HLA class II molecules. For a review, see Avalos et al. (2014) [14]. Only a selection of the resulting peptides fit to the respective HLA molecules present, based on their peptide specificity. The B cell will then present these peptides on the cell surface, with one peptide per HLA molecule. If a T cell is specific for exactly this peptide–HLA combination and if the B cell is activated via its BCR–antigen contact, then the CD4 T helper cell would deliver help to this B cell, both through cellular interaction and cytokines. Since all viral proteins are presented on the B cell’s HLA in this scenario, a nucleocapsid-specific T cell also activates a spike-specific B cell. (B) If the virus-specific B cell takes up separate viral proteins via BCR-mediated phagocytosis, e.g., after previous destruction of viral particles by follicular dendritic cells, only peptides from these proteins are presented on the B cell’s HLA molecules. This is shown here for the spike glycoprotein. Thus, a nucleocapsid-specific T cell does not activate a spike-specific B cell in this constellation. (C) If the same B cells as described in (B) are activated by a spike-specific CD4 T helper cell, the B cell is now activated. Abbreviations: BCR—B cell receptor, HLA—human leucocyte antigen, SARS-CoV-2—severe acute respiratory syndrome coronavirus 2, TCR—T cell receptor. Figure was designed with BioRender.
Figure 2
Figure 2
Results of the ex vivo Interferon-γ ELISpot after the first vaccination. (A) ELISpot wells showing spot counts obtained from pre- and post-vaccination PBMC samples tested against each of the specified vaccine peptides (n = 10, in triplicate). The negative control (ctrl.—DMSO and water) was tested in six replicate wells and the positive control (+ ctrl.—phytohemagglutinin) in duplicate wells. The images representing the ELISpot wells were rearranged for this illustration. (B) Graph of spot numbers for the three SARS-CoV-2-derived HLA-DR peptides. The mean and SD are shown from three technical replicates. Abbreviations: CMV—cytomegalovirus, ctrl.—control, DMSO—dimethyl sulfoxide, env—envelope protein, nuc—nucleoprotein, pre-vac—36 days before vaccination, post-vac—19 days after vaccination, and SARS-CoV-2—severe acute respiratory syndrome coronavirus 2.
Figure 3
Figure 3
Results of the Interferon-γ ELISpot after the second vaccination. (A) PBMCs were assayed by ex vivo interferon-γ ELISpot. Wells showing spot counts from post-vaccination PBMC samples obtained from blood drawn 19 days after the second vaccination. The specified peptide pools, consisting of several of the vaccinated peptides, were either vaccinated before (boost; second vac) or vaccinated for the first time (after first vaccination); tests were performed in triplicates. The negative control (- ctrl.—DMSO and water) was tested in six replicate wells and the positive control (+ ctrl.—phytohemagglutinin) in duplicate wells. The images representing the ELISpot wells were rearranged for this illustration. (B) PBMCs were assayed by interferon-γ ELISpot (100.000 cells/well), after 12 days of in vitro expansion in the presence of the relevant peptides (in vitro stimulation; IVS). PBMCs were isolated from blood drawn 5 days (left side) or 12 days (right side) after the second vaccination; peptides were either vaccinated before (boost; second vaccination) or newly vaccinated for the first time (after first vac), as indicated by the column number. Figure was designed with BioRender.
Figure 4
Figure 4
In silico prediction of the localization of a CD4 candidate epitope within the SARS-CoV-2 spike protein. Ribbon representation of the top view (left) and side view (right) of the SARS-CoV-2 spike ectodomain in its closed state (PDB:6VXX) with the peptide VADYSVLYNSASFST highlighted in the Red Corey-Pauling-Koltun (CPK) model. Image was produced using the Molsoft ICM-Browser.
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