Designing a therapeutic SARS-CoV-2 T-cell-inducing vaccine for high-risk patient groups

Rammensee, Hans‐Georg; Stevanović, Stefan; Gouttefangeas, Cécile; Heidu, Sonja; Klein, Reinhild; Preuß, B.; Walz, Juliane S.; Nelde, Annika; Haen, Sebastian P.; Reth, Michael; Yang, Jianying; Tabatabai, Ghazaleh; Bösmüller, Hans; Hoffmann, Helen; Schindler, Michael; Planz, Oliver; Wiesmüller, Karl‐Heinz; Löffler, Markus

doi:10.21203/rs.3.rs-27316/v1

Cited by 6 publications

(14 citation statements)

References 25 publications

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“…In line with other recent reports, we also observed in one unexposed donor very low frequencies of CD4 + and CD8 + T cells against spike and nucleocapsid proteins, respectively, probably due to cross-reactive cells primed against other SARS viruses [12][13][14]. We also used m24 Ab staining to con rm the induction of anti-vaccine CD4 + T cells after experimental immunization of a healthy volunteer with synthetic peptides from the spike and nucleocapsid proteins [9]. Importantly, the results matched those of a previous IFN-γ ELISpot, and our method allowed to reliably detect the weakest anti-peptide response (0.012% m24 + CD154 + CD4 + T cells vs 29 spots/ 300,000 PBMCs against CoV-2/FYV peptide).…”

Section: Discussionsupporting

confidence: 90%

“…6C-E). These results are coherent with those obtained by IFN-γ ELISpot approximately 3 weeks after immunization [9]. m24 Ab stainings of antigen-speci c CD4 + and CD8 + T cells in frozen/thawed PBMCs…”

Section: Monitoring Of Sars-cov-2 Speci C T Cell Immunitysupporting

confidence: 86%

“…We next tested CD4 + T cell reactivity in the blood of a healthy volunteer who had been immunized approximately 6 weeks before with a cocktail of synthetic peptides containing HLA-class II SARS-CoV-2 sequences derived from the nucleocapsid (N) protein (IGYYRRATRRIRGGD, IGY and ASAFFGMSRIGMEVT, ASA) and from the envelope (Env) protein (FYVYSRVKNLNSSRV, FYV), as well as one recall CMV pp65 peptide (YQEFFWDANDIYRIF, YQE) [9]. Virtually no m24 + cells producing CD154 or cytokines were detected when cells were left unstimulated for 6 h (0-0.001%, Fig.…”

Section: Monitoring Of Sars-cov-2 Speci C T Cell Immunitymentioning

confidence: 99%

“…4 and 5 did not show any IgG reaction (data not shown). All studies were approved by the Ethics Committee of the University of Tübingen (approvals 156/2012B01, 713/2018BO2, and 256/2020BO2), and participants gave written informed consent.The self-experimenting healthy volunteer vaccinated with SARS-CoV-2 derived peptides has been presented in details elsewhere[9]. Brie y, the donor received CMV-and CoV-2-derived synthetic peptides together with the adjuvant XS15.…”

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confidence: 99%

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Integrin activation enables simultaneous and sensitive detection of functional virus-specific CD4+ and CD8+ T cells

Schöllhorn

Schuhmacher

Besedovsky

et al. 2020

Preprint

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We have previously shown that beta2-integrin conformational change is a very early activation marker that can be detected with fluorescent multimers of its ligand ICAM-1 for a rapid assessment of antigen-specific CD8+ T cells. Here, we describe a modified protocol of this assay for sensitive detection of functional antigen-specific CD4+ T cells using a monoclonal antibody (clone m24) specific for the open, high affinity conformation of the beta2-integrin. Kinetics of beta2-integrin activation were different on CD4+ and CD8+ T cells (several hours vs. few minutes, respectively), however, m24 antibody readily stained both cell types 4-6 hours after antigen stimulation. With this protocol, we were able to monitor CD4+ and CD8+ virus-specific T cells specific for CMV, EBV, HBV, and SARS-CoV-2 in whole blood or cryopreserved PBMCs of infected or vaccinated individuals. By costaining with m24 and CD154 antibodies, we assessed extremely low frequencies of polyfunctional CD4+ T cell responses to SARS-CoV-2 derived peptides. Our novel assay thus allows very sensitive and simultaneous screening of both CD4+ and CD8+ T cell reactivities with versatile applicability in clinical and vaccination studies, and for epitope discovery.

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Section: Discussionsupporting

confidence: 90%

Section: Monitoring Of Sars-cov-2 Speci C T Cell Immunitysupporting

confidence: 86%

Section: Monitoring Of Sars-cov-2 Speci C T Cell Immunitymentioning

confidence: 99%

mentioning

confidence: 99%

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Integrin activation enables simultaneous and sensitive detection of functional virus-specific CD4+ and CD8+ T cells

Schöllhorn

Schuhmacher

Besedovsky

et al. 2020

Preprint

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“…100nM) leads to a less defined separation (Figure 10). Finally, we report low scores for all the five class I pHLAs which were experimentally confirmed to be non-immunogenic by Rammensee et al 2020. None of these peptides was recommended by ArdImmune Rank as a candidate to be included in a vaccine formulation against SARS-CoV-2.…”

Section: Comparison With Other Methodsmentioning

confidence: 91%

AI aided design of epitope-based vaccine for the induction of cellular immune responses against SARS-CoV-2

Mazzocco¹,

Niemiec²,

Myronov

et al. 2020

Preprint

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The heavy burden imposed by the COVID-19 pandemic on our society triggered the race towards the development of therapies or preventive strategies. Among these, antibodies and vaccines are particularly attractive because of their high specificity, low probability of drug-drug interaction, and potentially long-standing protective effects. While the threat at hand justifies the pace of research, the implementation of therapeutic strategies cannot be exempted from safety considerations. There are several potential adverse events reported after the vaccination or antibody therapy, but two are of utmost importance: antibody-dependent enhancement (ADE) and cytokine storm syndrome (CSS). On the other hand, the depletion or exhaustion of T-cells has been reported to be associated with worse prognosis in COVID-19 patients. This observation suggests a potential role of vaccines eliciting cellular immunity, which might simultaneously limit the risk of ADE and CSS. Such risk was proposed to be associated with FcR-induced activation of proinflammatory macrophages (M1) by Fu et al. 2020 and Iwasaki et al. 2020. All aspects of the newly developed vaccine (including the route of administration, delivery system, and adjuvant selection) may affect its effectiveness and safety. In this work we use a novel in silico approach (based on AI and bioinformatics methods) developed to support the design of epitope-based vaccines. We evaluated the capabilities of our method for predicting the immunogenicity of epitopes. Next, the results of our approach were compared with other vaccine-design strategies reported in the literature. The risk of immuno-toxicity was also assessed. The analysis of epitope conservation among other Coronaviridae was carried out in order to facilitate the selection of peptides shared across different SARS-CoV-2 strains and which might be conserved in emerging zootic coronavirus strains. Finally, the potential applicability of the selected epitopes for the development of a vaccine eliciting cellular immunity for COVID-19 was discussed, highlighting the benefits and challenges of such an approach.

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Long-term efficacy of the peptide-based COVID-19 T cell activator CoVac-1 in healthy adults

Tandler

Michael

Marconato

et al. 2023

Preprint

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Background: T cell immunity is key for the control of viral infections including SARS-CoV-2, in particular with regard to immune memory and protection against arising genetic variants. Method: We recently evaluated a peptide-based SARS-CoV-2 T cell activator termed CoVac-1 in a first-in-human clinical trial and observed a favorable safety profile and induction of poly-specific T cell responses until month 3. Here, we report on long-term safety and efficacy data of CoVac-1 in healthy adults until month 12. Findings: CoVac-1 is well tolerated without long-term immune-related side effects and induces long-lasting anti-viral T cell responses in 100% of study participants. Potent expandability of CD4+ and CD8+ T cells targeting multiple different CoVac-1 T cell epitopes was observed 6 and 12 months after one single dose of CoVac-1. T cell responses were associated with the severity and the number of local adverse events at injection site. Beyond induction of T cell immunity, 89% of study participants developed CoVac-1-specific IgG antibody titers which associated with the intensity of the T cell response, indicating that CoVac-1-specific CD4+ T cells support the induction of B cell responses. Vaccination with approved COVID-19 vaccines boosted CoVac-1-specific T cell responses. Overall, a low SARS-CoV-2 infection rate was observed in the study population (8.3% of participants until month 12). Interpretation: Together, a single application of CoVac-1 elicits long-lived and broad SARS-CoV-2-specific T cell immunity, which further supports the current evaluation of our T cell activator in patients with congenital or acquired B cell defects (NCT04954469). Funding: This trial is funded by the Ministry of Science, Research and the Arts Baden-Wuerttemberg., Germany

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Designing a therapeutic SARS-CoV-2 T-cell-inducing vaccine for high-risk patient groups

Cited by 6 publications

References 25 publications

Integrin activation enables simultaneous and sensitive detection of functional virus-specific CD4+ and CD8+ T cells

Integrin activation enables simultaneous and sensitive detection of functional virus-specific CD4+ and CD8+ T cells

AI aided design of epitope-based vaccine for the induction of cellular immune responses against SARS-CoV-2

Long-term efficacy of the peptide-based COVID-19 T cell activator CoVac-1 in healthy adults

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