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A Fully Protective Congenital CMV Vaccine Requires Neutralizing Antibodies to Viral Pentamer and gB Glycoprotein Complexes but a pp65 T-Cell Response Is Not Necessary.

ABSTRACT: A vaccine against congenital cytomegalovirus infection is a high priority. Guinea pig cytomegalovirus (GPCMV) is the only congenital CMV small animal model. GPCMV encodes essential glycoprotein complexes for virus entry (gB, gH/gL/gO, gM/gN) including a pentamer complex (gH/gL/GP129/GP131/GP133 or PC) for endocytic cell entry. The cohorts for protection against congenital CMV are poorly defined. Neutralizing antibodies to the viral glycoprotein complexes are potentially more important than an immunodominant T-cell response to the pp65 protein. In GPCMV, GP83 (pp65 homolog) is an evasion factor, and the GP83 mutant GPCMV has increased sensitivity to type I interferon. Although GP83 induces a cell-mediated response, a GP83-only-based vaccine strategy has limited efficacy. GPCMV attenuation via GP83 null deletion mutant in glycoprotein PC positive or negative virus was evaluated as live-attenuated vaccine strains (GP83dPC+/PC-). Vaccinated animals induced antibodies to viral glycoprotein complexes, and PC+ vaccinated animals had sterilizing immunity against wtGPCMV challenge. In a pre-conception vaccine (GP83dPC+) study, dams challenged mid-2nd trimester with wtGPCMV had complete protection against congenital CMV infection without detectable virus in pups. An unvaccinated control group had 80% pup transmission rate. Overall, gB and PC antibodies are key for protection against congenital CMV infection, but a response to pp65 is not strictly necessary.

SUBMITTER: Choi KY

PROVIDER: S-EPMC8402731 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cytomegalovirus is a leading cause of congenital disease and a vaccine is a high priority. The viral gB glycoprotein is essential for infection on all cell types. The guinea pig is the only small animal model for congenital CMV (cCMV), but requires guinea pig cytomegalovirus (GPCMV). Various GPCMV gB vaccine strategies have been investigated but not with a full length protein. Previous GPCMV gB vaccines have failed to fully protect against cCMV, with approximately 50% efficacy. In an effort to define the basis of GPCMV gB based vaccine failure, we evaluated recombinant defective Ad vectors encoding GPCMV gB full length (gBwt), or truncated protein lacking transmembrane domain (gBTMD). Both candidate vaccines evoked high anti-gB titers and neutralized virus infection on fibroblast cells but had varying weaker results on non-fibroblasts (renal epithelial and placental trophoblasts). Non-fibroblast cells are dependent upon the viral pentamer complex (PC) for endocytic pathway cell entry. In contrast, fibroblasts cells that express the viral receptor platelet derived growth factor receptor alpha (PDGFRA) to enable entry by direct cell fusion independent of the PC. Anti-gBwt sera was approximately 2-fold (renal epithelial) to 3-fold (fibroblasts) more effective at neutralizing virus compared to anti-gBTMD sera. Both gB vaccines were weakest against virus neutralization on trophoblasts. Knockout of PDGFRA cell receptor on fibroblast cells (GPKO) rendered virus dependent upon the PC pathway for cell entry and anti-gB GPCMV NA50 was more similar to epithelial cells. In a gBwt vaccine protection study, vaccination of animals significantly reduced, but did not prevent dissemination of wild type GPCMV challenge virus to target organs. Depletion of complement in vivo had limited impact on vaccine efficacy. Overall, a full length gB antigen has the potential to improve neutralizing antibody titer but fails to fully prevent virus dissemination and likely congenital infection.

Project description:The transmission of cytomegalovirus (CMV) from mother to fetus can give rise to severe neurodevelopment defects in newborns. One strategy to prevent these congenital defects is prophylactic vaccination in young women. A candidate vaccine antigen is glycoprotein B (gB). This antigen is abundant on the virion surface and is a major target of neutralization responses in human infections. Here, we have evaluated in a challenge model of congenital guinea pig CMV (GPCMV) infection, GPCMV-gB vaccines formulated with the clinically relevant Adjuvant Systems AS01B and AS02V, or with Freund's adjuvant (FA). Fifty-two GPCMV-seronegative female guinea pigs were administered three vaccine doses before being mated. GPCMV-challenge was performed at Day 45 of pregnancy (of an estimated 65 day gestation). Pup mortality rates in the gB/AS01B, gB/AS02V, and gB/FA groups were 24% (8/34), 10% (4/39) and 36% (12/33), respectively, and in the unvaccinated control group was 65% (37/57). Hence, efficacies against pup mortality were estimated at 64%, 84% and 44% for gB/AS01B (p<0.001), gB/AS02V (p<0.001) and gB/FA (p=0.014), respectively. Efficacies against GPCMV viremia (i.e. DNAemia, detected by PCR) were estimated at 88%, 68% and 25% for the same vaccines, respectively, but were only significant for gB/AS01B (p<0.001), and gB/AS02V (p=0.002). In dams with viremia, viral load was approximately 6-fold lower with vaccination than without. All vaccines were highly immunogenic after two and three doses. In light of these results and of other results of AS01-adjuvanted vaccines in clinical development, vaccine immunogenicity was further explored using human CMV-derived gB antigen adjuvanted with either AS01B or the related formulation AS01E. Both adjuvanted vaccines were highly immunogenic after two doses, in contrast to the lower immunogenicity of the unadjuvanted vaccine. In conclusion, the protective efficacy and immunogenicity of adjuvanted vaccines in this guinea pig model are supportive of investigating gB/AS01 and gB/AS02 in the clinic.

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A Fully Protective Congenital CMV Vaccine Requires Neutralizing Antibodies to Viral Pentamer and gB Glycoprotein Complexes but a pp65 T-Cell Response Is Not Necessary.

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