HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions

Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):6267-6272. doi: 10.1073/pnas.1800177115. Epub 2018 Apr 30.


Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to date, demonstrating ∼50% efficacy in preventing HCMV acquisition in multiple phase 2 trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 postpartum women gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and nonneutralizing anti-HCMV effector functions and compared with an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and domain I. Vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this nonneutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, although were poor mediators of NK cell activation. Altogether, these data suggest that nonneutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.

Keywords: cytomegalovirus; glycoprotein B; pediatrics; vaccines.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / immunology
  • Cells, Cultured
  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Vaccines / immunology*
  • Epitopes / immunology
  • Female
  • Humans
  • Immunoglobulin G / immunology
  • Polysorbates
  • Squalene / immunology
  • Vaccines, Subunit / immunology*
  • Viral Envelope Proteins / immunology*
  • Young Adult


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Cytomegalovirus Vaccines
  • Epitopes
  • Immunoglobulin G
  • MF59 oil emulsion
  • Polysorbates
  • Vaccines, Subunit
  • Viral Envelope Proteins
  • glycoprotein B, Simplexvirus
  • Squalene