SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: everybody does their best

Fernandez Salinas, A.; Piano Mortari, E.; Terreri, S.; Quintarelli, C.; Pulvirenti, F.; Di Cecca, S.; Guercio, M.; Milito, C.; Bonanni, L.; Auria, S.; Romaggioli, L.; Cusano, G.; Albano, C.; Zaffina, S.; Perno, C. F.; Spadaro, G.; Locatelli, F.; Carsetti, R.; Quinti, I.

Background. Patients with Primary Antibody Deficiencies (PAD) represent a potential at-risk group in the current COVID-19 pandemic. However, unexpectedly low cumulative incidence, low infection-fatality rate, and mild COVID-19 or asymptomatic SARS-CoV-2 infections were frequently reported in PAD. The discrepancy between clinical evidence and impaired antibody production requires in-depth studies on patients immune responses. Methods. Forty-one patients with Common Variable Immune Deficiencies (CVID), 6 patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-RBD antibody production, generation of low and high affinity Spike-specific memory B-cells, Spike-specific T-cells before and one week after the second dose of BNT162b2 vaccine. Results. HD produced antibodies, and generated memory B-cells with high affinity for Trimeric Spike. In CVID, the vaccine induced poor Spike-specific antibodies, and atypical B-cells with low affinity for Trimeric Spike, possibly by extra-follicular reactions or incomplete germinal center reactions. In HD, among Spike positive memory B-cells, we identified receptor-binding-domain-specific cells that were undetectable in CVID, indicating the incapability to generate this new specificity. Specific T-cell responses toward Spike-protein were evident in HD and defective in CVID. Due to the absence of B-cells, patients with XLA responded to immunization by specific T-cell responses only. Conclusions. We present detailed data on early non-canonical immune responses in PAD to a vaccine against an antigen never encountered before by humans. From our data, we expect that after BNT162b2 immunization, XLA patients might be protected by specific T-cells, while CVID patients might not be protected by immunization. Key words: Primary Antibody Deficiencies, Common Variable Immune Deficiencies, X-linked Agammaglobulinemia, COVID-19, SARS-CoV-2, BNT162b2 vaccine, memory cells, affinity, Trimeric Spike, receptor-binding-domain.