IgA binds to the AD‐2 epitope of glycoprotein B and neutralizes human cytomegalovirus

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that is potentially pathogenic in immunosuppressed individuals and pregnant females during primary infection. The HCMV envelope glycoprotein B (gB) facilitates viral entry into all cell types and induces a potent immune response. AD‐2 epitope is a highly conserved linear neutralizing epitope of gB and a critical target for antibodies; however, only 50% of sero‐positive individuals make IgG antibodies to this site and IgA responses have not been fully investigated. This study aimed to compare IgG and IgA responses against gB and the AD‐2 epitope in naturally exposed individuals and those receiving a recombinant gB/MF59 adjuvant vaccine. Thus, vaccination of sero‐positive individuals improved pre‐existing gB‐specific IgA and IgG levels and induced de novo gB‐specific IgA and IgG responses in sero‐negative recipients. Pre‐existing AD‐2 IgG and IgA responses were boosted with vaccination, but de novo AD‐2 responses were not detected. Naturally exposed individuals had dominant IgG responses towards gB and AD‐2 compared with weaker and variable IgA responses, although a significant IgA binding response to AD‐2 was observed within human breastmilk samples. All antibodies binding AD‐2 contained kappa light chains, whereas balanced kappa/lambda light chain usage was found for those binding to gB. V region‐matched AD‐2‐specific recombinant IgG and IgA bound both to gB and to AD‐2 and neutralized HCMV infection in vitro. Overall, these results indicate that although human IgG responses dominate, IgA class antibodies against AD‐2 are a significant component of human milk, which may function to protect neonates from HCMV.