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Vaccine. 2018 Sep 5;36(37):5580-5590. doi: 10.1016/j.vaccine.2018.07.056. Epub 2018 Aug 3.

Novel trimeric human cytomegalovirus glycoprotein B elicits a high-titer neutralizing antibody response.

Author information

1
Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States. Electronic address: xinle.cui@usuhs.edu.
2
Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States.
3
Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States.
4
Department of Pediatrics, Virginia Commonwealth University, Richmond, VA 23298, United States.
5
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, United States.
6
CMV Research Foundation, Richmond VA 23229, United States.

Abstract

Human cytomegalovirus (HCMV) is a major cause of disability in congenitally infected infants and in the immunosuppressed. There is currently no licensed prophylactic HCMV vaccine. The HCMV envelope glycoprotein B (gB) is considered a major vaccine target antigen based on its critical role in mediating viral-host cell fusion and thus viral entry. The natural conformation of HCMV gB within the viral envelope is a trimer, but there has been no reported success in producing a recombinant trimeric gB suitable for vaccine use. Phase II clinical trials of a monomeric recombinant gB protein demonstrated 50% efficacy in preventing HCMV infection in seronegative women of reproductive age, and in reducing viremia in solid organ transplantation recipients. We now report the production of a uniformly trimeric recombinant HCMV gB protein in Chinese ovary cells, as demonstrated by Western blot analysis under modified non-reducing conditions and size exclusion chromatography with multi-angle scattering. Immunization of mice with trimeric HCMV gB induced up to 11-fold higher serum titers of total gB-specific IgG relative to monomeric HCMV gB using Alum + CpG as adjuvants. Further, trimeric HCMV gB elicited 50-fold higher complement-independent and 20-fold higher complement-dependent HCMV neutralizing titers compared to monomeric HCMV gB using the fibroblast cell line, MRC-5, and up to 6-fold higher complement-independent and -dependent HCMV neutralizing titers using the epithelial cell line, ARPE-19. The markedly enhanced HCMV neutralizing activity in response to trimeric HCMV gB was also observed using an additional four distinct clinical HCMV isolates. These data support a role for trimeric HCMV gB as an important component for clinical testing of a prophylactic HCMV vaccine.

KEYWORDS:

Antibody; Glycoprotein B; Human cytomegalovirus; Neutralization; Recombinant protein; Vaccine

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