title: Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection.
abstract: Human cytomegalovirus (HCMV) elicits neutralizing antibodies (NAb) of various potencies and cell type specificities to prevent HCMV entry into fibroblasts (FB) and epithelial/endothelial cells (EpC/EnC). NAb targeting the major essential envelope glycoprotein complexes gB and gH/gL inhibit both FB and EpC/EnC entry. In contrast to FB infection, HCMV entry into EpC/EnC is additionally blocked by extremely potent NAb to conformational epitopes of the gH/gL/UL128/130/131A pentamer complex (PC). We recently developed a vaccine concept based on coexpression of all five PC subunits by a single modified vaccinia virus Ankara (MVA) vector, termed MVA-PC. Vaccination of mice and rhesus macaques with MVA-PC resulted in a high titer and sustained NAb that blocked EpC/EnC infection and lower-titer NAb that inhibited FB entry. However, antibody function responsible for the neutralizing activity induced by the MVA-PC vaccine is uncharacterized. Here, we demonstrate that MVA-PC elicits NAb with cell type-specific neutralization potency and antigen recognition pattern similar to human NAb targeting conformational and linear epitopes of the UL128/130/131A subunits or gH. In addition, we show that the vaccine-derived PC-specific NAb are significantly more potent than the anti-gH NAb to prevent HCMV spread in EpC and infection of human placental cytotrophoblasts, cell types thought to be of critical importance for HCMV transmission to the fetus. These findings further validate MVA-PC as a clinical vaccine candidate to elicit NAb that resembles those induced during HCMV infection and provide valuable insights into the potency of PC-specific NAb to interfere with HCMV cell-associated spread and infection of key placental cells.
  
  
  OBJECTIVE
  As a consequence of the leading role of human cytomegalovirus (HCMV) in causing permanent birth defects, developing a vaccine against HCMV has been assigned a major public health priority. We have recently introduced a vaccine strategy based on a widely used, safe, and well-characterized poxvirus vector platform to elicit potent and durable neutralizing antibody (NAb) responses targeting the HCMV envelope pentamer complex (PC), which has been suggested as a critical component for a vaccine to prevent congenital HCMV infection. With this work, we confirm that the NAb elicited by the vaccine vector have properties that are similar to those of human NAb isolated from individuals chronically infected with HCMV. In addition, we show that PC-specific NAb have potent ability to prevent infection of key placental cells that HCMV utilizes to cross the fetal-maternal interface, suggesting that NAb targeting the PC may be essential to prevent HCMV vertical transmission.
authors.affiliation: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California.
authors.forename: Flavia
authors.initials: F
authors.lastname: Chiuppesi
authors.affiliation: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California.
authors.forename: Felix
authors.initials: F
authors.lastname: Wussow
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Erica
authors.initials: E
authors.lastname: Johnson
authors.affiliation: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California.
authors.forename: Chao
authors.initials: C
authors.lastname: Bian
authors.affiliation: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhuo
authors.affiliation: Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Augustine
authors.initials: A
authors.lastname: Rajakumar
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Davis, Davis, California.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Barry
authors.affiliation: Departments of Pediatrics, Microbiology, and Neurobiology, Children's Hospital of Alabama, University of Alabama School of Medicine, Birmingham, Alabama.
authors.forename: William J
authors.initials: WJ
authors.lastname: Britt
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Rana
authors.initials: R
authors.lastname: Chakraborty
authors.affiliation: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California ddiamond@coh.org.
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000517:prevention & control*; D015151:Immunoblotting; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D046912:Multiprotein Complexes / Q000276:immunology*; D009500:Neutralization Tests; D014327:Trophoblasts / Q000821:virology*; D014759:Viral Envelope Proteins / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*; D053586:Virus Internalization
chemical_list: D057134:Antibodies, Neutralizing; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; C532797:UL128 protein, human cytomegalovirus; C502890:UL130 protein, human cytomegalovirus; D014759:Viral Envelope Proteins; D014765:Viral Vaccines; C071440:glycoprotein H, Cytomegalovirus