title: Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex.
abstract: Human Cytomegalovirus (HCMV) utilizes two different pathways for host cell entry. HCMV entry into fibroblasts requires glycoproteins gB and gH/gL, whereas HCMV entry into epithelial and endothelial cells (EC) requires an additional complex composed of gH, gL, UL128, UL130, and UL131A, referred to as the gH/gL-pentamer complex (gH/gL-PC). While there are no established correlates of protection against HCMV, antibodies are thought to be important in controlling infection. Neutralizing antibodies (NAb) that prevent gH/gL-PC mediated entry into EC are candidates to be assessed for in vivo protective function. However, these potent NAb are predominantly directed against conformational epitopes derived from the assembled gH/gL-PC. To address these concerns, we constructed Modified Vaccinia Ankara (MVA) viruses co-expressing all five gH/gL-PC subunits (MVA-gH/gL-PC), subsets of gH/gL-PC subunits (gH/gL or UL128/UL130/UL131A), or the gB subunit from HCMV strain TB40/E. We provide evidence for cell surface expression and assembly of complexes expressing full-length gH or gB, or their secretion when the corresponding transmembrane domains are deleted. Mice or rhesus macaques (RM) were vaccinated three times with MVA recombinants and serum NAb titers that prevented 50% infection of human EC or fibroblasts by HCMV TB40/E were determined. NAb responses induced by MVA-gH/gL-PC blocked HCMV infection of EC with potencies that were two orders of magnitude greater than those induced by MVA expressing gH/gL, UL128-UL131A, or gB. In addition, MVA-gH/gL-PC induced NAb responses that were durable and efficacious to prevent HCMV infection of Hofbauer macrophages, a fetal-derived cell localized within the placenta. NAb were also detectable in saliva of vaccinated RM and reached serum peak levels comparable to NAb titers found in HCMV hyperimmune globulins. This vaccine based on a translational poxvirus platform co-delivers all five HCMV gH/gL-PC subunits to achieve robust humoral responses that neutralize HCMV infection of EC, placental macrophages and fibroblasts, properties of potential value in a prophylactic vaccine.
authors.affiliation: Department of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Felix
authors.initials: F
authors.lastname: Wussow
authors.affiliation: Department of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Flavia
authors.initials: F
authors.lastname: Chiuppesi
authors.affiliation: Department of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Joy
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Department of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Campo
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Erica
authors.initials: E
authors.lastname: Johnson
authors.affiliation: Department of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Christin
authors.initials: C
authors.lastname: Flechsig
authors.affiliation: Department of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Maegan
authors.initials: M
authors.lastname: Newell
authors.affiliation: Department of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tran
authors.affiliation: Department of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Jose
authors.initials: J
authors.lastname: Ortiz
authors.affiliation: Department of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Corinna
authors.initials: C
authors.lastname: La Rosa
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.affiliation: Department of Information Sciences, City of Hope, Duarte, California, United States of America.
authors.forename: Jeff
authors.initials: J
authors.lastname: Longmate
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Rana
authors.initials: R
authors.lastname: Chakraborty
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Davis, Davis, California, United States of America.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Barry
authors.affiliation: Department of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D022482:Cytomegalovirus Vaccines / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D022482:Cytomegalovirus Vaccines; D046912:Multiprotein Complexes; D014759:Viral Envelope Proteins