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Comparison of monovalent glycoprotein B with bivalent gB/pp65 (GP83) vaccine for congenital cytomegalovirus infection in a guinea pig model: Inclusion of GP83 reduces gB antibody response but both vaccine approaches provide equivalent protection against pup mortality.

ABSTRACT: Cytomegalovirus (CMV) subunit vaccine candidates include glycoprotein B (gB), and phosphoprotein ppUL83 (pp65). Using a guinea pig cytomegalovirus (GPCMV) model, this study compared immunogenicity, pregnancy outcome, and congenital viral infection following pre-pregnancy immunization with a three-dose series of modified vaccinia virus Ankara (MVA)-vectored vaccines consisting either of gB administered alone, or simultaneously with a pp65 homolog (GP83)-expressing vaccine. Vaccinated and control dams were challenged at midgestation with salivary gland-adapted GPCMV. Comparisons included ELISA and neutralizing antibody responses, maternal viral load, pup mortality, and congenital infection rates. Strikingly, ELISA and neutralization titers were significantly lower in the gB/GP83 combined vaccine group than in the gB group. However, both vaccines protected against pup mortality (63.2% in controls vs. 11.4% and 13.9% in gB and gB/GP83 combination groups, respectively; p<0.0001). Reductions in pup viral load were noted for both vaccine groups compared to control, but preconception vaccination resulted in a significant reduction in GPCMV transmission only in the monovalent gB group (26/44, 59% v. 27/34, 79% in controls; p<0.05). We conclude that, using the MVA platform, the addition of GP83 to a gB subunit vaccine interferes with antibody responses and diminishes protection against congenital GPCMV infection, but does not decrease protection against pup mortality.

SUBMITTER: Swanson EC

PROVIDER: S-EPMC4772145 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Comparison of monovalent glycoprotein B with bivalent gB/pp65 (GP83) vaccine for congenital cytomegalovirus infection in a guinea pig model: Inclusion of GP83 reduces gB antibody response but both vaccine approaches provide equivalent protection against pup mortality.

Swanson Elizabeth C EC Gillis Pete P Hernandez-Alvarado Nelmary N Fernández-Alarcón Claudia C Schmit Megan M Zabeli Jason C JC Wussow Felix F Diamond Don J DJ Schleiss Mark R MR

Vaccine 20150613 32

Cytomegalovirus (CMV) subunit vaccine candidates include glycoprotein B (gB), and phosphoprotein ppUL83 (pp65). Using a guinea pig cytomegalovirus (GPCMV) model, this study compared immunogenicity, pregnancy outcome, and congenital viral infection following pre-pregnancy immunization with a three-dose series of modified vaccinia virus Ankara (MVA)-vectored vaccines consisting either of gB administered alone, or simultaneously with a pp65 homolog (GP83)-expressing vaccine. Vaccinated and control ...[more]

PMID: 26079615

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Project description:AimsCongenital 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 methodsOutbred Hartley guinea pigs were vaccinated prior to pregnancy with a two-dose series of 5×104 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 (1×106 pfu) in the second trimester, and pregnancy outcomes were compared to controls.ResultsCompared 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.ConclusionsIn 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.

Project description:The guinea pig is the only small animal model for congenital CMV but requires species-specific guinea pig cytomegalovirus (GPCMV). Tegument protein GP83 is the presumed homolog of HCMV pp65 but gene duplication in the UL82-UL84 homolog locus in various animal CMV made it unclear if GP83 was a functional homolog. A GP83 null deletion mutant GPCMV (GP83dPC+) generated in the backdrop of glycoprotein pentamer complex (PC) positive virus, required for non-fibroblast infection, had normal growth kinetics on fibroblasts but was highly impaired on epithelial and trophoblast cells. GP83dPC+ virus was highly sensitive to IFN-I suggesting GP83 had an innate immune evasion function. GP83 interacted with cellular DNA sensors guinea pig IFI16 and cGAS indicating a role in the cGAS/STING pathway. Ectopically expressed GP83 in trophoblast cells restored GP83dPC+ virus growth. Additionally, mutant virus growth was restored in epithelial cells by expression of bovine viral diarrhea virus (BVDV) NPRO protein targeting IRF3 as part of the cGAS/STING pathway or alternatively by expression of fibroblast cell receptor PDGFRA. HCMV pp65 is a T cell target antigen and a recombinant adenovirus encoding GP83 was evaluated as a vaccine. In GPCMV challenge studies, vaccinated animals had varying levels of protection against wild type virus with a protective response against 22122 prototype strain but little protection against a novel clinical strain of GPCMV (TAMYC), despite 100% identity in GP83 protein sequences. Overall, GP83 is a functional pp65 homolog with novel importance for epithelial cell infection but a GP83 T cell response provides limited vaccine efficacy.ImportanceCongenital CMV (cCMV) is a leading cause of cognitive impairment and deafness in newborns and a vaccine is a high priority. The guinea pig is the only small animal model for cCMV but requires guinea pig cytomegalovirus (GPCMV). The translational impact of GPCMV research is potentially reduced if the virus does not encode functional HCMV homolog proteins. This study demonstrates that tegument protein GP83 (pp65 homolog) is involved in innate immune evasion and highly important for infection of non-fibroblast cells via the viral glycoprotein pentamer complex (PC)-dependent endocytic entry pathway. The PC pathway is highly significant for virus dissemination and disease in the host, including cCMV. A GP83 candidate Ad-vaccine strategy in animals induced a cell-mediated response but failed to provide cross strain protection against a novel clinical strain of GPCMV. Results suggest that the pp65 antigen provides very limited efficacy as a stand-alone vaccine, especially in cross strain protection.

Dataset Information

Comparison of monovalent glycoprotein B with bivalent gB/pp65 (GP83) vaccine for congenital cytomegalovirus infection in a guinea pig model: Inclusion of GP83 reduces gB antibody response but both vaccine approaches provide equivalent protection against pup mortality.

Publications

Comparison of monovalent glycoprotein B with bivalent gB/pp65 (GP83) vaccine for congenital cytomegalovirus infection in a guinea pig model: Inclusion of GP83 reduces gB antibody response but both vaccine approaches provide equivalent protection against pup mortality.

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