title: Additive Protection against Congenital Cytomegalovirus Conferred by Combined Glycoprotein B/pp65 Vaccination Using a Lymphocytic Choriomeningitis Virus Vector.
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.
authors: Center for Infectious Diseases and Microbiology Translational Research and Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA schleiss@umn.edu.
authors: Mark R
authors: MR
authors: Schleiss
authors: Hookipa Biotech AG, Vienna, Austria.
authors: Ursula
authors: U
authors: Berka
authors: Hookipa Biotech AG, Vienna, Austria.
authors: Elizabeth
authors: E
authors: Watson
authors: Hookipa Biotech AG, Vienna, Austria.
authors: Mario
authors: M
authors: Aistleithner
authors: Hookipa Biotech AG, Vienna, Austria.
authors: Bettina
authors: B
authors: Kiefmann
authors: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors: Bastien
authors: B
authors: Mangeat
authors: Center for Infectious Diseases and Microbiology Translational Research and Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors: Elizabeth C
authors: EC
authors: Swanson
authors: Center for Infectious Diseases and Microbiology Translational Research and Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors: Peter A
authors: PA
authors: Gillis
authors: Center for Infectious Diseases and Microbiology Translational Research and Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors: Nelmary
authors: N
authors: Hernandez-Alvarado
authors: Center for Infectious Diseases and Microbiology Translational Research and Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors: Claudia
authors: C
authors: Fernández-Alarcón
authors: Center for Infectious Diseases and Microbiology Translational Research and Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors: Jason C
authors: JC
authors: Zabeli
authors: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors: Daniel D
authors: DD
authors: Pinschewer
authors: Hookipa Biotech AG, Vienna, Austria.
authors: Anders E
authors: AE
authors: Lilja
authors: Hookipa Biotech AG, Vienna, Austria.
authors: Michael
authors: M
authors: Schwendinger
authors: Hookipa Biotech AG, Vienna, Austria.
authors: Farshad
authors: F
authors: Guirakhoo
authors: Hookipa Biotech AG, Vienna, Austria.
authors: Thomas P
authors: TP
authors: Monath
authors: Hookipa Biotech AG, Vienna, Austria.
authors: Klaus K
authors: KK
authors: Orlinger
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000151:congenital / Q000517:prevention & control*; D022482:Cytomegalovirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D004195:Disease Models, Animal; D004337:Drug Carriers; D005260:Female; D006168:Guinea Pigs; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics*; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D017778:Vaccines, Combined / Q000008:administration & dosage / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D022482:Cytomegalovirus Vaccines; D004337:Drug Carriers; D010750:Phosphoproteins; D017778:Vaccines, Combined; D014614:Vaccines, Synthetic; D014759:Viral Envelope Proteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; C040495:glycoprotein B, Simplexvirus
keywords: congenital cytomegalovirus; cytomegalovirus; fetal infection; live vector vaccines; lymphocytic choriomeningitis virus; placental immunology