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A Novel Non-Replication Competent Cytomegalovirus Capsid Mutant Vaccine Strategy Is Effective in Reducing Congenital Infection.

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Choi KY, Root M, McGregor A,


Choi KY, Root M, McGregor A, (click to view)

Choi KY, Root M, McGregor A,

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Journal of virology 2016 6 22() pii

Abstract

Congenital cytomegalovirus (CMV) is a leading cause of mental retardation and deafness in newborns. The guinea pig is the only small animal model for congenital CMV. A novel CMV vaccine was investigated as an intervention strategy against congenital guinea pig cytomegalovirus (GPCMV). In this disabled infectious single cycle (DISC) vaccine strategy, a GPCMV mutant lacked the ability to express an essential capsid gene (UL85 homolog, GP85), except when grown on a complementing cell line. In vaccinated animals, the GP85 mutant virus (GP85 DISC) induced an antibody response to important glycoprotein complexes considered neutralizing target antigens (gB, gH/gL/gO and gM/gN). The vaccine also generated a T cell response to the pp65 homolog (GP83), determined via a newly established guinea pig interferon gamma ELISPOT assay. In a congenital protection study, GP85 DISC vaccinated animals and non-vaccinated control group were challenged during pregnancy with wild type GPCMV (10^5 pfu). Animals went to term and viral load in target organs of pups analyzed. Based on live pup births in the vaccinated and control groups (94.1% vs 63.6%) the vaccine was successful in reducing mortality (P=0.0002). Additionally, pups from the vaccinated group had reduced CMV transmission with 23.5% infected target organs compared to 75.9% in the control group .Overall, these preliminary studies indicate that a DISC CMV vaccine strategy has the ability to induce an immune response similar to that of natural virus infection but has the increased safety of a non-replication competent virus, which makes this approach attractive as a CMV vaccine strategy.

IMPORTANCE
Congenital CMV is a leading cause of mental retardation and deafness in newborns. An effective vaccine against CMV still remains an elusive goal despite over fifty years of CMV research. The guinea pig, with a placenta structure similar to humans, is the only small animal model for congenital CMV and recapitulates disease symptoms (eg. deafness) in newborn pups. In this report, a novel vaccine strategy against congenital guinea pig cytomegalovirus (GPCMV) was developed, characterized and tested for efficacy. This disabled infectious single cycle (DISC) vaccine strategy induced a neutralizing antibody, or T cell response to important target antigens. In a congenital protection study, animals were protected against CMV in comparison to the non-vaccinated group (52% reduction of transmission). This novel vaccine was more effective than previously tested gB based vaccines and most other strategies live virus vaccines. Overall, the DISC vaccine is a safe and promising approach against congenital CMV.

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