title: Restoration of viral epithelial tropism improves immunogenicity in rabbits and rhesus macaques for a whole virion vaccine of human cytomegalovirus.
abstract: Maternal immunity to human cytomegalovirus (HCMV) prior to conception is ~70% protective against congenital transmission and in utero infection of HCMV. Both functional antibodies capable of neutralizing virus and effective T-cells are believed to be important for the protection. Previous HCMV vaccines have rarely been shown able to induce neutralizing antibody titers comparable to those seen in naturally infected HCMV seropositive subjects. Recent studies link a glycoprotein H (gH) complex to receptor-mediated viral entry of endothelial/epithelial cells and leukocytes. This pentameric gH complex, composed of five proteins (gH, gL, UL128, UL130 and UL131 proteins), is notably missing in all HCMV vaccine previously evaluated in clinic. Here we showed that a HCMV virus, with restored expression of the pentameric gH complex, can induce 10-fold higher neutralizing antibody titers than an attenuated AD169 virus or a recombinant glycoprotein B vaccine in multiple animal species in which viral replication is not expected. Encouragingly, the peak neutralizing titers post vaccination in rabbits and monkeys were within 2-4-fold of the levels determined in HCMV seropositive subjects. Functional antibodies by vaccination could further be improved when formulated with a novel adjuvant, and the titers of the antiviral antibodies were sustained in rabbits for over a year after vaccination. These results indicate that the pentameric gH complex is associated with greatly improved functional antibodies following vaccination, and support a vaccine concept based on a nonreplicating whole HCMV with the pentameric gH-associated epithelial tropism restored.
authors.affiliation: Department of Vaccines Research, Merck Research Laboratories, West Point, PA, United States. tong-ming_fu@merck.com
authors.forename: Tong-Ming
authors.initials: TM
authors.lastname: Fu
authors.forename: Dai
authors.initials: D
authors.lastname: Wang
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Freed
authors.forename: Aimin
authors.initials: A
authors.lastname: Tang
authors.forename: Fengsheng
authors.initials: F
authors.lastname: Li
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.forename: Suzanne
authors.initials: S
authors.lastname: Cole
authors.forename: Sheri
authors.initials: S
authors.lastname: Dubey
authors.forename: Adam C
authors.initials: AC
authors.lastname: Finnefrock
authors.forename: Jan
authors.initials: J
authors.lastname: ter Meulen
authors.forename: John W
authors.initials: JW
authors.lastname: Shiver
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D003587:Cytomegalovirus / Q000276:immunology* / Q000502:physiology*; D022482:Cytomegalovirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D004847:Epithelial Cells / Q000821:virology*; D005260:Female; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D011817:Rabbits; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D056189:Viral Tropism
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D022482:Cytomegalovirus Vaccines; D014764:Viral Proteins