Dynamics of B-cell response in MERS-CoV patients and survivors with hybrid immunity

Middle East respiratory syndrome coronavirus (MERS-CoV) causes a highly lethal respiratory infection for which no vaccines or antiviral therapeutics are currently available. Understanding the immune response is critical for designing effective therapeutics. Here, we comprehensively characterized the dynamics of B-cell responses in severely infected MERS-CoV patients and survivors with SARS-CoV-2 exposure history. Infected patients developed robust neutralizing antibody responses within 1 month of illness, with moderate-to-high cross-neutralization activity against SARS-CoV-2. The enhanced neutralization activity coincided with an increased abundance of specific mutated, class-switched IgG clones. Notably, one such clone was detected at moderate prevalence in both patients, and its expansion was accompanied by high neutralization activity against both viruses. Conversely, MERS-CoV survivors demonstrated higher neutralization activity against MERS-CoV after vaccination, despite minimal changes in antibody titers and limited alterations in B-cell repertoire properties. This suggests that the enhanced neutralization activity may be mediated by the reactivation and expansion of cross-reactive memory B cells targeting conserved epitopes, originally generated in response to the virus that triggered the primary immune response. These findings provide valuable insights into the B-cell repertoire landscape during natural MERS-CoV infection and highlight the potential for identifying broadly neutralizing antibodies in individuals with hybrid immunity.IMPORTANCEThis study examines the immune responses of MERS-CoV patients and survivors who have had confirmed exposure to SARS-CoV-2. It offers a unique opportunity to characterize cross-reactive B-cell responses in individuals possessing hybrid immunity to both pathogenic coronaviruses. To our knowledge, no previous studies have examined longitudinal changes in the B-cell repertoire in MERS-CoV patients or survivors before and after SARS-CoV-2 vaccination. Our findings reveal enhanced neutralization activity against both MERS-CoV and SARS-CoV-2 following infection or vaccination, which appears to be associated with distinct patterns of B-cell repertoire dynamics. Notably, the data strongly suggest the presence of potent cross-neutralizing antibody responses, particularly in MERS-CoV patients, driven by dominant B-cell clones. These results underscore the potential for identifying broadly neutralizing antibodies in individuals with hybrid immunity.