Human Cytomegalovirus Vaccine Based on the Envelope gH/gL Pentamer Complex

Felix Wussow, Flavia Chiuppesi, Joy Martinez, John Campo, Erica Johnson, Christin Flechsig, Maegan Newell, Elaine Tran, Jose Ortiz, Corinna La Rosa, Andreas Herrmann, Jeff Longmate, Rana Chakraborty, Peter A Barry, Don J. Diamond

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Human Cytomegalovirus (HCMV) utilizes two different pathways for host cell entry. HCMV entry into fibroblasts requires glycoproteins gB and gH/gL, whereas HCMV entry into epithelial and endothelial cells (EC) requires an additional complex composed of gH, gL, UL128, UL130, and UL131A, referred to as the gH/gL-pentamer complex (gH/gL-PC). While there are no established correlates of protection against HCMV, antibodies are thought to be important in controlling infection. Neutralizing antibodies (NAb) that prevent gH/gL-PC mediated entry into EC are candidates to be assessed for in vivo protective function. However, these potent NAb are predominantly directed against conformational epitopes derived from the assembled gH/gL-PC. To address these concerns, we constructed Modified Vaccinia Ankara (MVA) viruses co-expressing all five gH/gL-PC subunits (MVA-gH/gL-PC), subsets of gH/gL-PC subunits (gH/gL or UL128/UL130/UL131A), or the gB subunit from HCMV strain TB40/E. We provide evidence for cell surface expression and assembly of complexes expressing full-length gH or gB, or their secretion when the corresponding transmembrane domains are deleted. Mice or rhesus macaques (RM) were vaccinated three times with MVA recombinants and serum NAb titers that prevented 50% infection of human EC or fibroblasts by HCMV TB40/E were determined. NAb responses induced by MVA-gH/gL-PC blocked HCMV infection of EC with potencies that were two orders of magnitude greater than those induced by MVA expressing gH/gL, UL128-UL131A, or gB. In addition, MVA-gH/gL-PC induced NAb responses that were durable and efficacious to prevent HCMV infection of Hofbauer macrophages, a fetal-derived cell localized within the placenta. NAb were also detectable in saliva of vaccinated RM and reached serum peak levels comparable to NAb titers found in HCMV hyperimmune globulins. This vaccine based on a translational poxvirus platform co-delivers all five HCMV gH/gL-PC subunits to achieve robust humoral responses that neutralize HCMV infection of EC, placental macrophages and fibroblasts, properties of potential value in a prophylactic vaccine.

Original languageEnglish (US)
JournalPLoS Pathogens
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2014

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Cytomegalovirus Vaccines
Cytomegalovirus
Neutralizing Antibodies
Vaccinia
Endothelial Cells
Cytomegalovirus Infections
Fibroblasts
Macaca mulatta
Antibody Formation
Vaccines
Macrophages
Poxviridae
Vaccinia virus
Globulins
Infection

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Wussow, F., Chiuppesi, F., Martinez, J., Campo, J., Johnson, E., Flechsig, C., ... Diamond, D. J. (2014). Human Cytomegalovirus Vaccine Based on the Envelope gH/gL Pentamer Complex. PLoS Pathogens, 10(11). https://doi.org/10.1371/journal.ppat.1004524

Human Cytomegalovirus Vaccine Based on the Envelope gH/gL Pentamer Complex. / Wussow, Felix; Chiuppesi, Flavia; Martinez, Joy; Campo, John; Johnson, Erica; Flechsig, Christin; Newell, Maegan; Tran, Elaine; Ortiz, Jose; La Rosa, Corinna; Herrmann, Andreas; Longmate, Jeff; Chakraborty, Rana; Barry, Peter A; Diamond, Don J.

In: PLoS Pathogens, Vol. 10, No. 11, 01.11.2014.

Research output: Contribution to journalArticle

Wussow, F, Chiuppesi, F, Martinez, J, Campo, J, Johnson, E, Flechsig, C, Newell, M, Tran, E, Ortiz, J, La Rosa, C, Herrmann, A, Longmate, J, Chakraborty, R, Barry, PA & Diamond, DJ 2014, 'Human Cytomegalovirus Vaccine Based on the Envelope gH/gL Pentamer Complex', PLoS Pathogens, vol. 10, no. 11. https://doi.org/10.1371/journal.ppat.1004524
Wussow F, Chiuppesi F, Martinez J, Campo J, Johnson E, Flechsig C et al. Human Cytomegalovirus Vaccine Based on the Envelope gH/gL Pentamer Complex. PLoS Pathogens. 2014 Nov 1;10(11). https://doi.org/10.1371/journal.ppat.1004524
Wussow, Felix ; Chiuppesi, Flavia ; Martinez, Joy ; Campo, John ; Johnson, Erica ; Flechsig, Christin ; Newell, Maegan ; Tran, Elaine ; Ortiz, Jose ; La Rosa, Corinna ; Herrmann, Andreas ; Longmate, Jeff ; Chakraborty, Rana ; Barry, Peter A ; Diamond, Don J. / Human Cytomegalovirus Vaccine Based on the Envelope gH/gL Pentamer Complex. In: PLoS Pathogens. 2014 ; Vol. 10, No. 11.
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