Discussion
B-cell deficiency, primary immunodeficiency, cancer, T-cell defects, SARS-CoV-2 T-cell immunity, acquired B-cell deficiency, congenital B-cell deficiency, autoimmune disease, B-cell defects
PRIMARY IMMUNODEFICIENCY, CANCER, DISEASE, COMMON VARIABLE IMMUNODEFICIENCY, AUTOIMMUNE DISEASE
Recently, evaluation of the peptide-based T-cell activator CoVac-1 in healthy adults showed promising safety and immunogenicity in terms of profound and long-lasting SARS-CoV-2-specific T-cell responses that are not affected by VOCsHere, we report on the Phase I/II clinical trial evaluating CoVac-1 in patients with congenital or acquired B-cell deficiency, which confirmed the favorable safety profile and documented potent de novo induction of T-cell responses after one single administration even in this highly immunocompromised study population. Of note, beyond B-cell deficiency, 50% of patients additionally presented with CD4CoVac-1-induced T-cell responses exceeded spike-specific T-cell responses induced by mRNA vaccinationSubgroup analysis points towards higher frequency and intensity of T-cell responses in cancer patients with acquired B-cell deficiency compared to patients with congenital B-cell deficiency, however, the small size of the primary immunodeficiency cohort limits this conclusion. This could be the consequence of additional T-cell defects in patients with congenital immune defects (e.g., Common Variable Immunodeficiency, CVID)Even after receipt of two or more doses of approved vaccines, none of the patients showed any humoral immune response to SARS-CoV-2 at study inclusion; after CoVac-1 application, induction of low-level SARS-CoV-2 anti-spike IgG antibodies was observed in single patients, despite consistently negative results in sequential SARS-CoV-2 PCRs. This finding may be due to stimulation of pre-existingT cell-mediated immunity and, in particular CD4To elucidate which frequencies and phenotypes of T cells are required to effectively combat COVID-19 and to what extend CoVac-1-induced T-cell responses are protective for severe disease, a longitudinal Phase III efficacy study with CoVac-1 is presently in preparation. Evidence that CoVac-1-induced T-cell responses may confer immunity to severe COVID-19 in this highly immunocompromised population is provided by the phenotype of CoVac-1-induced T cells, which resembles that upon natural infectionLimitations of our trial include the small sample size, low ethnic diversity and exclusion of patients with autoimmune disease receiving B-cell-depleting therapies. Safety and immunogenicity data over a longer observation period are presently being collected during the study follow-up where patients are monitored for up to 6 months.In conclusion, the safety and immunogenicity data of our trial demonstrate that CoVac-1 is a promising T-cell activator for induction of SARS-CoV-2 T-cell immunity in patients with congenital or acquired B-cell defects and warrant advancement to a pivotal Phase III safety and efficacy evaluation.