Waning of Serum Antibodies, But Increase of Protective B-Cell Memory Nine Months After BNT162b2 Vaccination

Abstract

Background: Breakthrough infections in fully vaccinated HCWs are considered a marker of waning immunity. Serum antibodies represent the most visible and measurable outcome of vaccine-induced B-cell memory. When antibodies decline, memory B cells are expected to persist and perform their function, thus preventing clinical disease. We investigated whether BNT162b2 mRNA vaccine induces durable and in vivo functional B-cell memory against SARS-CoV-2 3, 6 and 9 months after the second dose.Methods: We assessed the duration of SARS-CoV-2 vaccine-induced immunity by measuring specific antibodies and memory B cells 3, 6 and 9 months after vaccination. In fully vaccinated HCWs with breakthrough SARS-CoV-2 infections, we evaluated the humoral and mucosal response of vaccine-induced memory B cells.Findings: Whereas specific serum antibodies decline, anti-Spike memory B cells continue to increase until 9 months after the last vaccine dose. HCWs with breakthrough infections had no signs of waning immunity on the day of the first positive swab. In 3-4 days, memory B cells responded to SARS-CoV-2 infection by producing high levels of specific antibodies in the serum. In the saliva, anti-Spike IgA also rapidly increased in response to the infection. Antibodies to the viral nucleoprotein were produced with the slow kinetics typical of the response to a novel antigen.Interpretation: SARS-CoV-2 specific antibodies physiologically decline months after vaccination. By contrast, memory B cells persist and increase over time. Parenteral administered vaccines do not generate mucosal immunity and serum antibodies reach mucosal sites in small amounts by transudation. In HCWs with SARS-CoV-2 breakthrough infections, memory B cells react by rapidly differentiating into antibody-producing cells and generating IgA for protection of mucosal sites.Funding Information: Italian Ministry of Health COVID-2020-12371817 grant and Ricerca Corrente 2021 “5 per mille”.Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: Ethics Committee of Bambino Gesù Children Hospital, Rome, Italy, Ethical approved the study. The study was performed in accordance with the Good Clinical Practice guidelines, the International Conference on Harmonization guidelines, and the most recent version of the Declaration of Helsinki.