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

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

Author information

1
Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710.
2
Department of Surgery, Duke University Medical Center, Durham, NC 27710.
3
Department of Pediatrics, University of Alabama, Birmingham, AL 35233.
4
Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710; sallie.permar@duke.edu.

Abstract

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

PMID:
29712861
PMCID:
PMC6004431
DOI:
10.1073/pnas.1800177115
[Indexed for MEDLINE]
Free PMC Article

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