title: Neutralization of Diverse Human Cytomegalovirus Strains Conferred by Antibodies Targeting Viral gH/gL/pUL128-131 Pentameric Complex.
abstract: Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection, and developing a prophylactic vaccine is of high priority to public health. We recently reported a replication-defective human cytomegalovirus with restored pentameric complex glycoprotein H (gH)/gL/pUL128-131 for prevention of congenital HCMV infection. While the quantity of vaccine-induced antibody responses can be measured in a viral neutralization assay, assessing the quality of such responses, including the ability of vaccine-induced antibodies to cross-neutralize the field strains of HCMV, remains a challenge. In this study, with a panel of neutralizing antibodies from three healthy human donors with natural HCMV infection or a vaccinated animal, we mapped eight sites on the dominant virus-neutralizing antigen-the pentameric complex of glycoprotein H (gH), gL, and pUL128, pUL130, and pUL131. By evaluating the site-specific antibodies in vaccine immune sera, we demonstrated that vaccination elicited functional antiviral antibodies to multiple neutralizing sites in rhesus macaques, with quality attributes comparable to those of CMV hyperimmune globulin. Furthermore, these immune sera showed antiviral activities against a panel of genetically distinct HCMV clinical isolates. These results highlighted the importance of understanding the quality of vaccine-induced antibody responses, which includes not only the neutralizing potency in key cell types but also the ability to protect against the genetically diverse field strains.IMPORTANCEHCMV is the leading cause of congenital viral infection, and development of a preventive vaccine is a high public health priority. To understand the strain coverage of vaccine-induced immune responses in comparison with natural immunity, we used a panel of broadly neutralizing antibodies to identify the immunogenic sites of a dominant viral antigen-the pentameric complex. We further demonstrated that following vaccination of a replication-defective virus with the restored pentameric complex, rhesus macaques can develop broadly neutralizing antibodies targeting multiple immunogenic sites of the pentameric complex. Such analyses of site-specific antibody responses are imperative to our assessment of the quality of vaccine-induced immunity in clinical studies.
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Ha
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Fengsheng
authors.initials: F
authors.lastname: Li
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Troutman
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Freed
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Aimin
authors.initials: A
authors.lastname: Tang
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Loughney
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Dai
authors.identifier: http://orcid.org/0000-0001-5666-8622
authors.initials: D
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Vlasak
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Nickle
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Rustandi
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hamm
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Pete A
authors.initials: PA
authors.lastname: DePhillips
authors.affiliation: Texas Therapeutics Institute, the Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Ningyan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: McLellan
authors.affiliation: Rutgers-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: CMV Research Foundation, Richmond, Virginia, USA.
authors.forename: Stuart P
authors.initials: SP
authors.lastname: Adler
authors.affiliation: Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McVoy
authors.affiliation: Texas Therapeutics Institute, the Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
authors.affiliation: Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey, USA tong-ming_fu@merck.com.
authors.forename: Tong-Ming
authors.identifier: http://orcid.org/0000-0003-1420-2271
authors.initials: TM
authors.lastname: Fu
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000737:chemistry* / Q000276:immunology; D000914:Antibodies, Viral / Q000097:blood / Q000737:chemistry* / Q000276:immunology; D000918:Antibody Specificity; D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D018604:Epitope Mapping; D006801:Humans; D008253:Macaca mulatta; D011485:Protein Binding; D011817:Rabbits; D014611:Vaccination; D014759:Viral Envelope Proteins / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage; D053586:Virus Internalization
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014759:Viral Envelope Proteins; D014765:Viral Vaccines; C071440:glycoprotein H, Cytomegalovirus
keywords: antibodies; epitope mapping; human cytomegalovirus; neutralization; pentameric complex; strain coverage; vaccines