title: A vaccine based on the rhesus cytomegalovirus UL128 complex induces broadly neutralizing antibodies in rhesus macaques.
abstract: Neutralizing antibodies (NAb) are important for interfering with horizontal transmission of human cytomegalovirus (HCMV) leading to primary and congenital HCMV infection. Recent findings have shown that a pentameric virion complex formed by the glycoproteins gH/gL, UL128, UL130, and UL131A (UL128C) is required for HCMV entry into epithelial/endothelial cells (Epi/EC) and is the target of potent NAb in HCMV-seropositive individuals. Using bacterial artificial chromosome technology, we have generated a modified vaccinia Ankara virus (MVA) that stably coexpresses all 5 rhesus CMV (RhCMV) proteins homologous to HCMV UL128C, termed MVA-RhUL128C. Coimmunoprecipitation confirmed the interaction of RhgH with the other 4 RhCMV subunits of the pentameric complex. All 8 RhCMV-naïve rhesus macaques (RM) vaccinated with MVA-RhUL128C developed NAb that blocked infection of monkey kidney epithelial cells (MKE) and rhesus fibroblasts. NAb titers induced by MVA-RhUL128C measured on both cell types at 2 to 6 weeks postvaccination were comparable to levels observed in naturally infected RM. In contrast, MVA expressing a subset of RhUL128C proteins or RhgB glycoprotein only minimally stimulated NAb that inhibited infection of MKE. In addition, following subcutaneous RhCMV challenge at 8 weeks postvaccination, animals vaccinated with MVA-RhUL128C showed reduced plasma viral loads. These results indicate that MVA expressing the RhUL128C induces NAb inhibiting RhCMV entry into both Epi/EC and fibroblasts and limits RhCMV replication in RM. This novel approach is the first step in developing a prophylactic HCMV vaccine designed to interfere with virus entry into major cell types permissive for viral replication, a required property of an effective vaccine.
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Wussow
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Yue
authors.forename: Joy
authors.initials: J
authors.lastname: Martinez
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Deere
authors.forename: Jeff
authors.initials: J
authors.lastname: Longmate
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Peter A
authors.initials: PA
authors.lastname: Barry
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral / Q000097:blood*; D003586:Cytomegalovirus Infections / Q000517:prevention & control; D022482:Cytomegalovirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D004337:Drug Carriers; D004847:Epithelial Cells / Q000821:virology; D005347:Fibroblasts / Q000821:virology; D005822:Genetic Vectors; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000008:administration & dosage / Q000276:immunology*; D014766:Viremia / Q000517:prevention & control; D053586:Virus Internalization
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D022482:Cytomegalovirus Vaccines; D004279:DNA, Viral; D004337:Drug Carriers; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; D014759:Viral Envelope Proteins