title: Preconceptual administration of an alphavirus replicon UL83 (pp65 homolog) vaccine induces humoral and cellular immunity and improves pregnancy outcome in the guinea pig model of congenital cytomegalovirus infection.
abstract: Development of a vaccine against congenital cytomegalovirus (CMV) infection is a major public health priority. We report the use of a propagation-defective, single-cycle, RNA replicon vector system, derived from an attenuated strain of the alphavirus Venezuelan equine encephalitis virus, to produce virus-like replicon particles (VRPs) expressing GP83, the guinea pig CMV (GPCMV) homolog of the human CMV pp65 phosphoprotein. Vaccination with VRP-GP83 induced antibodies and CD4(+) and CD8(+) T cell responses in GPCMV-seronegative female guinea pigs. Guinea pigs immunized with VRP-GP83 vaccine or with a VRP vaccine expressing influenza hemagglutinin (VRP-HA) were bred for pregnancy and subsequent GPCMV challenge during the early third trimester. Dams vaccinated with VRP-GP83 had improved pregnancy outcomes, compared with dams vaccinated with the VRP-HA control. For VRP-GP83-vaccinated dams, there were 28 live pups and 4 dead pups (13% mortality) among 10 evaluable litters, compared with 9 live pups and 12 dead pups (57% mortality) among 8 evaluable litters in the VRP-HA-vaccinated group (P<.001, Fisher's exact test). Improved pregnancy outcome was accompanied by reductions in maternal blood viral load, measured by real-time polymerase chain reaction. These results indicate that cell-mediated immune responses directed against a CMV matrix protein can protect against congenital CMV infection and disease.
authors.affiliation: Department of Pediatrics, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, MN, 55455, USA. schleiss@umn.edu
authors.forename: Mark R
authors.initials: MR
authors.lastname: Schleiss
authors.forename: Juan C
authors.initials: JC
authors.lastname: Lacayo
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Belkaid
authors.forename: Alistair
authors.initials: A
authors.lastname: McGregor
authors.forename: Greg
authors.initials: G
authors.lastname: Stroup
authors.forename: Jon
authors.initials: J
authors.lastname: Rayner
authors.forename: Kimberly
authors.initials: K
authors.lastname: Alterson
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Chulay
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Smith
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D003587:Cytomegalovirus / Q000276:immunology*; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007111:Immunity, Cellular; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000276:immunology*; D011247:Pregnancy; D011256:Pregnancy Outcome; D012093:Replicon / Q000276:immunology; D012469:Salivary Glands / Q000821:virology; D014763:Viral Matrix Proteins / Q000276:immunology*; D014765:Viral Vaccines / Q000627:therapeutic use*; D014779:Virus Replication
chemical_list: D017931:DNA Primers; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; D014765:Viral Vaccines; C065418:cytomegalovirus matrix protein 65kDa