An Attenuated CMV Vaccine with a Deletion in Tegument Protein GP83 (pp65 Homolog) Protects against Placental Infection and Improves Pregnancy Outcome in a Guinea Pig Challenge Model.
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AIMS: Congenital human cytomegalovirus (HCMV) infection can lead to long-term neurodevelopmental sequelae, including mental retardation and sensorineural hearing loss. Preconception vaccine strategies relevant to prevention of HCMV-mediated injury to the newborn can be studied in the guinea pig cytomegalovirus (GPCMV) model. The objectives of this study were: 1) to assess in guinea pigs the protective efficacy against congenital infection and disease of a recombinant live, attenuated vaccine with a targeted deletion of the GPCMV homolog of the HCMV pUL83 tegument protein, GP83; and, 2) to compare the extent of placental infection in vaccine and control groups, using an in situ hybridization (ISH) assay. MATERIALS AND METHODS: Outbred Hartley guinea pigs were vaccinated prior to pregnancy with a two-dose series of 5104 pfu of vAM409, a GP83 deletion virus. Deletion of the GP83 gene resulted in an attenuated virus, and vAM409 vaccinated animals did not demonstrate evidence of DNAemia following vaccination, although ELISA antibody responses were comparable to those observed in natural infection. After mating, pregnant animals were challenged with salivary gland-adapted (SG) GPCMV (1106 pfu) in the second trimester, and pregnancy outcomes were compared to controls. RESULTS: Compared to placebo-immunized controls, vaccination resulted in significantly reduced maternal DNAemia following SG challenge, and there was significantly decreased pup mortality in litters born to vaccinated dams (3/29; 10%), compared to control (35/50; 70%; p<0.001). By in situ hybridization study, recovered placentas in the vAM409 vaccine group demonstrated reduced infection and fewer infectious foci compared to the control group. CONCLUSIONS: In summary, preconception immunization with a GP83 deletion vaccine reduced maternal DNAemia and results in protection against congenital GPCMV-associated pup mortality compared to unvaccinated controls. Vaccination resulted in reduced placental infection, probably related to the reduction in maternal DNAemia. Although the pp65 homolog in GPCMV, GP83, is a known target of protective T cell immune responses, it is nevertheless dispensable for effective vaccination against maternal and fetal CMV disease in this model.
