title: Pentameric complex of viral glycoprotein H is the primary target for potent neutralization by a human cytomegalovirus vaccine.
abstract: Human cytomegalovirus (HCMV) can cause serious morbidity/mortality in transplant patients, and congenital HCMV infection can lead to birth defects. Developing an effective HCMV vaccine is a high medical priority. One of the challenges to the efforts has been our limited understanding of the viral antigens important for protective antibodies. Receptor-mediated viral entry to endothelial/epithelial cells requires a glycoprotein H (gH) complex comprising five viral proteins (gH, gL, UL128, UL130, and UL131). This gH complex is notably missing from HCMV laboratory strains as well as HCMV vaccines previously evaluated in the clinic. To support a unique vaccine concept based on the pentameric gH complex, we established a panel of 45 monoclonal antibodies (mAbs) from a rabbit immunized with an experimental vaccine virus in which the expression of the pentameric gH complex was restored. Over one-half (25 of 45) of the mAbs have neutralizing activity. Interestingly, affinity for an antibody to bind virions was not correlated with its ability to neutralize the virus. Genetic analysis of the 45 mAbs based on their heavy- and light-chain sequences identified at least 26 B-cell linage groups characterized by distinct binding or neutralizing properties. Moreover, neutralizing antibodies possessed longer complementarity-determining region 3 for both heavy and light chains than those with no neutralizing activity. Importantly, potent neutralizing mAbs reacted to the pentameric gH complex but not to gB. Thus, the pentameric gH complex is the primary target for antiviral antibodies by vaccination.
authors.affiliation: Department of Vaccines Research, Merck Research Laboratories, West Point, PA 19486.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Freed
authors.forename: Qi
authors.initials: Q
authors.lastname: Tang
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: Zhao
authors.initials: Z
authors.lastname: Huang
authors.forename: Weixu
authors.initials: W
authors.lastname: Meng
authors.forename: Lin
authors.initials: L
authors.lastname: Xia
authors.forename: Adam C
authors.initials: AC
authors.lastname: Finnefrock
authors.forename: Eberhard
authors.initials: E
authors.lastname: Durr
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
authors.forename: Ningyan
authors.initials: N
authors.lastname: Zhang
authors.forename: John W
authors.initials: JW
authors.lastname: Shiver
authors.forename: Dai
authors.initials: D
authors.lastname: Wang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
authors.forename: Tong-Ming
authors.initials: TM
authors.lastname: Fu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology*; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000235:genetics / 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; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology*; D011817:Rabbits; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D022801:Complementarity Determining Regions; D022482:Cytomegalovirus Vaccines; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; C532797:UL128 protein, human cytomegalovirus; C502890:UL130 protein, human cytomegalovirus; D014759:Viral Envelope Proteins; C071440:glycoprotein H, Cytomegalovirus
keywords: antiviral antibody; monoclonal antibody