Additive protection against congenital cytomegalovirus conferred by combined glycoprotein B/pp65 vaccination using a lymphocytic choriomeningitis virus vector

Mark R. Schleiss, Ursula Berka, Elizabeth Watson, Mario Aistleithner, Bettina Kiefmann, Bastien Mangeat, Elizabeth C. Swanson, Peter A. Gillis, Nelmary Hernandez-Alvarado, Claudia Fernández-Alarcón, Jason C. Zabeli, Daniel D. Pinschewer, Anders E. Lilj, Michael Schwendinger, Farshad Guirakhoo, Thomas P. Monath, Klaus K. Orlinger

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Abstract

Subunit vaccines for prevention of congenital cytomegalovirus (CMV) infection based on glycoprotein B (gB) and pp65 are in clinical trials, but it is unclear whether simultaneous vaccination with both antigens enhances protection. We undertook evaluation of a novel bivalent vaccine based on nonreplicating lymphocytic choriomeningitis virus (rLCMV) vectors expressing a cytoplasmic tail-deleted gB [gB(dCt)] and full-length pp65 from human CMV in mice. Immunization with the gB(dCt) vector alone elicited a comparable gB-binding antibody response and a superior neutralizing response to that elicited by adjuvanted subunit gB. Immunization with the pp65 vector alone elicited robust T cell responses. Comparable immunogenicity of the combined gB(dCt) and pp65 vectors with the individual monovalent formulations was demonstrated. To demonstrate proof of principle for a bivalent rLCMV-based HCMV vaccine, the congenital Guinea pig cytomegalovirus (GPCMV) infection model was used to compare rLCMV vectors encoding homologs of pp65 (GP83) and gB(dCt), alone and in combination versus Freund's adjuvanted recombinant gB. Both vectors elicited significant immune responses, and no loss of gB immunogenicity was noted with the bivalent formulation. Combined vaccination with rLCMV-vectored GPCMV gB(dCt) and pp65 (GP83) conferred better protection against maternal viremia than subunit or either monovalent rLCMV vaccine. The bivalent vaccine also was significantly more effective in reducing pup mortality than the monovalent vaccines. In summary, bivalent vaccines with rLCMV vectors expressing gB and pp65 elicited potent humoral and cellular responses and conferred protection in the GPCMV model. Further clinical trials of LCMV-vectored HCMV vaccines are warranted.

Original languageEnglish (US)
Article numbere00300
JournalClinical and Vaccine Immunology
Volume24
Issue number1
DOIs
StatePublished - Jan 2017

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Keywords

  • Congenital cytomegalovirus
  • Cytomegalovirus
  • Fetal infection
  • Live vector vaccines
  • Lymphocytic choriomeningitis virus
  • Placental immunology

Cite this

Schleiss, M. R., Berka, U., Watson, E., Aistleithner, M., Kiefmann, B., Mangeat, B., Swanson, E. C., Gillis, P. A., Hernandez-Alvarado, N., Fernández-Alarcón, C., Zabeli, J. C., Pinschewer, D. D., Lilj, A. E., Schwendinger, M., Guirakhoo, F., Monath, T. P., & Orlinger, K. K. (2017). Additive protection against congenital cytomegalovirus conferred by combined glycoprotein B/pp65 vaccination using a lymphocytic choriomeningitis virus vector. Clinical and Vaccine Immunology, 24(1), [e00300]. https://doi.org/10.1128/CVI.0030016