The Frequency of SARS-CoV-2 Specific Memory B Cells in COVID-19 Recovered Patients Remain Stable While Antibodies Decay Over Time

Abstract

The breadth of the humoral immune response following SARS-CoV-2 infection was indicated to be important for recovery from COVID-19. Recent studies have provided valuable insights regarding the dynamics of the antibody response in symptomatic COVID-19 patients. However, the information regarding the dynamics of the serological and cellular memory in COVID-19 recovered patients is scarce. It is imperative to determine the persistence of humoral memory in COVID-19 recovered patients as it will help to evaluate the susceptibility of recovered patients to re-infection. Here, we describe the dynamics of both the SARS-CoV-2 specific serological and B cell response in COVID-19 recovered patients. We found that acute phase SARS-CoV-2 patients mount a rapid, robust antibody response following infection however, the serological memory decays in COVID-19 recovered patients over the period of six months. Using an in vitro neutralization assay revealed a strong correlation between total RBD-specific (RBD+) antibodies and neutralizing antibodies suggesting that antibody levels can be used as proxy to determine neutralizing capacity. In contrast to the antibody decay observed in recovered patients, the RBD+ memory B cell (mBC) frequency was found to be stable over time. Moreover, the frequency of RBD+ B cell plasmablasts (PB) was found to be associated with the RBD+ IgG levels. B cell receptor sequencing (BCR-Seq) of RBD+ PB show unregular high frequency of the IgG4 isotype which is known to contribute to the manifestation of IgG4 related disease and other autoimmune diseases. These data, suggests that the differentiation of short-lived PB to become long-lived plasma cells may be impaired and the main contributor of antibody production in recovered COVID-19 patient are the short-lived PB that predominantly encode to IgG4 subclass. The skewed class switch towards IgG4 may contribute to the severeness of the COVID-19 morbidity. Moreover, the persistence of RBD+ mBC following recovery may contribute to a robust recall humoral response in a case of re-infection by SARS-CoV-2. Overall, our data obtained in this study reveals a discordance between serological and cellular memory in COVID-19 recovered patients which has important implications on re-infection susceptibility and vaccine design.Ethical Approval: All patients provided informed consent to the use of their data and clinical samples for the purposes of the present study and blood collection was performed under institutional review board approvals number 0001281-4 and 0000406-1. All blood samples were collected at the Hasharon Hospital, Rabin Medical Center under ethical approval number 0265-20.