ABSTRACT
Individuals with impaired ability to mount a humoral immune response, either during natural infection or upon prophylactic vaccination, are at high risk for a severe course of COVID-19. Besides humoral immunity mediated by B cells, T cell immunity is key for the control of viral infections. We developed the peptide-based vaccine candidate CoVac-1, which primarily aims for the induction of SARS-CoV-2-specific T cells. CoVac-1 comprises six promiscuous HLA-DR-binding SARS-CoV-2-derived T cell epitopes from various viral proteins proven (i) to be frequently and HLAindependently recognized by T cells in COVID-19 convalescents, (ii) to be of pathophysiological relevance for T cell immunity to combat COVID-19, and (iii) to mediate long-term immunity after infection (Nelde et al. Nat Immunol 2021, Bilich et al. Sci Transl Med 2021). CoVac-1 vaccine peptides are adjuvanted with the novel toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG. In a first-in-human clinical trial in healthy adults (NCT04546841), CoVac-1 showed a favorable safety profile and induced profound and long-lasting T cell immunity after single dose administration in 100% of the study subjects, mediated by multifunctional T-helper 1 CD4+ and CD8+ T cells. CoVac-1-induced T cell responses surpassed those after SARS-CoV-2 infection as well as those after vaccination with approved vaccines and were unaffected by current SARS-CoV-2 variants of concern (Heitmann et al. Nature 2021). Here we present the interim safety and immunogenicity results of our Phase I/II trial evaluating CoVac-1 in patients with congenital or acquired B cell deficiency, mainly comprising leukemia and lymphoma patients (NCT04954469). 64% of study subjects had previously been vaccinated with approved vaccines without developing any humoral immune response. Alike in the healthy adults, CoVac-1 showed a good safety and tolerability profile without relevant systemic adverse events. CoVac-1-specific T cell responses could be documented in 93% of study subjects on day 28 after CoVac-1 application, with earliest responses evidenced at day 14 (71%). Vaccine-induced T cell responses were mediated by multifunctional T-helper 1 CD4+ T cells. Of note, CoVac-1 induced T cell responses in this highly immune compromised study population were similar to those occurring in healthy volunteers after natural infection or induced by approved vaccines. These results identify CoVac-1 as promising vaccine candidate for cancer and other immunocompromised patients with immunoglobulin deficiency. Recruitment of the Phase II part of the trial is ongoing with results expected for March 2022.
ABSTRACT
SARS-CoV-2 causing COVID-19 has evolved to a pandemic with dramatic socioeconomic consequences. Meanwhile, available vaccines can in most cases prevent dismal disease outcome. So far largely neglected are patients unable to mount humoral i.e. antibody-mediated SARS-CoV-2 immune responses This comprises individuals with congenital B cell deficiency, but also cancer patients, particularly those receiving B cell depleting therapy as routinely applied in leukemia and lymphoma. These patients are at high risk for a severe course of COVID-19 and may not receive the available vaccines and/or will mount insufficient immune responses when vaccinated with compounds mainly aiming for protective antibody induction. Besides humoral immunity mediated by B cells, T cell immunity is key to control viral infections. We have developed a peptide-based vaccine (CoVac-1), which primarily aims for induction of SARS-CoV-2-specific T cells. CoVac-1 comprises six promiscuous HLA-DR-binding SARSCoV- 2-derived Tcell epitopes from various viral proteins, which enables the induction of broad anti-SARS-CoV-2 T cell immunity independent of newly arising mutations.The pathophysiological relevance of CoVac-1 T cell epitopes in the natural course of COVID-19 and also for long term T cell immunity after infection was documented (Nelde et al. Nat Immunol 2021, Bilich et al. Science Transl Med 2021). Besides the CoVac-1 peptides, the vaccine contains the novel TLR1/2 ligand XS15 and Montanide ISA 51 VG as adjuvants. At present, CoVac-1 is evaluated in a first-in-human clinical trial in healthy adults (NCT04546841), which showed a good safety and tolerability profile without relevant systemic adverse events. In 100% of the study subjects, potent induction of T cell immunity was documented on day 28 after application of the single dose of CoVac-1. Earliest T cell responses were evidenced at day 14 in 92% of cases. In all cases, immune responses were directed against multiple of the vaccine peptides (median 5/subject, range 4-6). CD8+ T cell responses against HLA class I-presented T cell epitopes, embedded in the HLA-DR-restricted CoVac-1 vaccine peptides, were detected in 75% of the study subjects. This favourable safety and efficacy profile indicates CoVac-1 as a promising vaccine candidate for the induction of broad T cell immunity in patients with antibody deficiency and will be evaluated in an upcoming study in this highrisk population (B-pVAC-SARS-CoV-2, EudraCT-Nr. 2021-001070-38).