Vaccine-derived neutralizing antibodies to the human cytomegalovirus gH/gL pentamer potently block primary cytotrophoblast infection

Flavia Chiuppesi, Felix Wussow, Erica Johnson, Chao Bian, Meng Zhuo, Augustine Rajakumar, Peter A Barry, William J. Britt, Rana Chakraborty, Don J. Diamond

Research output: Contribution to journalArticle

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Abstract

Human cytomegalovirus (HCMV) elicits neutralizing antibodies (NAb) of various potencies and cell type specificities to prevent HCMVentry 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, HCMVentry into EpC/EnC is additionally blocked by extremely potent NAb to conformational epitopes of the gH/gL/UL128/130/131A pentamer complex (PC).Werecently 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 preventHCMVspread in EpC and infection of human placental cytotrophoblasts, cell types thought to be of critical importance forHCMVtransmission to the fetus. These findings further validate MVA-PC as a clinical vaccine candidate to elicit NAb that resembles those induced duringHCMVinfection and provide valuable insights into the potency of PC-specific NAb to interfere with HCMVcell-associated spread and infection of key placental cells.

Original languageEnglish (US)
Pages (from-to)11884-11898
Number of pages15
JournalJournal of Virology
Volume89
Issue number23
DOIs
StatePublished - 2015

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Human herpesvirus 5
Trophoblasts
Neutralizing Antibodies
Cytomegalovirus
neutralizing antibodies
Vaccines
vaccines
Vaccinia virus
Infection
infection
fibroblasts
Fibroblasts
neutralization
epitopes
Epitopes
cells
Macaca mulatta
endothelial cells
fetus
glycoproteins

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Chiuppesi, F., Wussow, F., Johnson, E., Bian, C., Zhuo, M., Rajakumar, A., ... Diamond, D. J. (2015). Vaccine-derived neutralizing antibodies to the human cytomegalovirus gH/gL pentamer potently block primary cytotrophoblast infection. Journal of Virology, 89(23), 11884-11898. https://doi.org/10.1128/JVI.01701-15

Vaccine-derived neutralizing antibodies to the human cytomegalovirus gH/gL pentamer potently block primary cytotrophoblast infection. / Chiuppesi, Flavia; Wussow, Felix; Johnson, Erica; Bian, Chao; Zhuo, Meng; Rajakumar, Augustine; Barry, Peter A; Britt, William J.; Chakraborty, Rana; Diamond, Don J.

In: Journal of Virology, Vol. 89, No. 23, 2015, p. 11884-11898.

Research output: Contribution to journalArticle

Chiuppesi, F, Wussow, F, Johnson, E, Bian, C, Zhuo, M, Rajakumar, A, Barry, PA, Britt, WJ, Chakraborty, R & Diamond, DJ 2015, 'Vaccine-derived neutralizing antibodies to the human cytomegalovirus gH/gL pentamer potently block primary cytotrophoblast infection', Journal of Virology, vol. 89, no. 23, pp. 11884-11898. https://doi.org/10.1128/JVI.01701-15
Chiuppesi, Flavia ; Wussow, Felix ; Johnson, Erica ; Bian, Chao ; Zhuo, Meng ; Rajakumar, Augustine ; Barry, Peter A ; Britt, William J. ; Chakraborty, Rana ; Diamond, Don J. / Vaccine-derived neutralizing antibodies to the human cytomegalovirus gH/gL pentamer potently block primary cytotrophoblast infection. In: Journal of Virology. 2015 ; Vol. 89, No. 23. pp. 11884-11898.
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