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

Siddiqui, Saima, Hackl, Sarah, Ghoddusi, Hamid, McIntosh, Megan, Gomes, Ariane, Ho, Joshua, Reeves, Matthew B. and McLean, Gary R. (2020) IgA binds to the AD-2 epitope of glycoprotein B and neutralizes human cytomegalovirus. Immunology, 162 (3). pp. 314-327. ISSN 0019-2805


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 neutralising epitope of gB and a critical target for antibodies, however, only 50% of seropositive 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 seropositive individuals improved pre-existing gB specific IgA and IgG levels and induced de novo gB specific IgA and IgG responses in seronegative recipients. Pre-existing AD-2 IgG and IgA responses were boosted with vaccination but de novo synthesis wasAD-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 breast milk 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 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.

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