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

Abstract

Congenital cytomegalovirus (CMV) infection is a leading cause of mental retardation and deafness in newborns. The guinea pig is the only small animal model for congenital CMV infection. A novel CMV vaccine was investigated as an intervention strategy against congenital guinea pig cytomegalovirus (GPCMV) infection. In this disabled infectious single-cycle (DISC) vaccine strategy, a GPCMV mutant virus was used that lacked the ability to express an essential capsid gene (the 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 gamma interferon enzyme-linked immunosorbent spot assay. In a congenital infection protection study, GP85 DISC-vaccinated animals and a nonvaccinated control group were challenged during pregnancy with wild-type GPCMV (10 5 PFU). The pregnant animals carried the pups to term, and viral loads in target organs of pups were analyzed. Based on live pup births in the vaccinated and control groups (94.1% versus 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 versus 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. IMPORTANCECongenital CMV infection is a leading cause of mental retardation and deafness in newborns. An effective vaccine against CMV remains an elusive goal despite over 50 years of CMV research. The guinea pig, with a placenta structure similar to that in humans, is the only small animal model for congenital CMV infection and recapitulates disease symptoms (e.g., deafness) in newborn pups. In this report, a novel vaccine strategy against congenital guinea pig cytomegalovirus (GPCMV) infection was developed, characterized, and tested for efficacy. This disabled infectious single-cycle (DISC) vaccine strategy induced a neutralizing antibody or a T cell response to important target antigens. In a congenital infection protection study, animals were protected against CMV in comparison to the nonvaccinated group (52% reduction of transmission). This novel vaccine was more effective than previously tested gB-based vaccines and most other strategies involving live virus vaccines. Overall, the DISC vaccine is a safe and promising approach against congenital CMV infection. H uman cytomegalovirus (HCMV), a betaherpesvirus, has evolved very closely with its human host. Virus infection in a healthy host is normally asymptomatic but leads to a lifelong infection. In contrast,...

Activation of Innate and Adaptive Immunity by a Recombinant Human Cytomegalovirus Strain Expressing an NKG2D Ligand

“…Another option to increase safety is the application of replication- and spread-deficient vaccine strains. Studies in the mouse model revealed that such strains preserve the ability to stimulate CMV-specific T cell immunity [82, 83], and in a guinea pig model of congenital CMV infection partial protection of pups was observed following immunization with a non-infectious guinea pig CMV BAC DNA vaccine [84] or with a non-replication-competent virus [85]. We have recently pioneered the development of conditional-replicating CMV strains [86], and this technique has already successfully been used to generate a conditionally replicating HCMV vaccine candidate, which is currently in phase 1 testing (ClinicalTrials.gov number, NCT01986010).…”

MVA-Vectored Pentameric Complex (PC) and gB Vaccines Improve Pregnancy Outcome after Guinea Pig CMV Challenge, but Only gB Vaccine Reduces Vertical Transmission

“…Furthermore, clear evidence that would suggest the production of potent neutralizing antibodies against the GPCMV PC (similar to the previously isolated human antibodies that predominantly target conformational epitopes of the UL128/130/131A subunits of the HCMV PC) was absent. Even more importantly, the protective studies were compared to historical controls that were based on responses engendered against a PC-negative "first generation" DISC vaccine [62] using a different dose regimen. The authors noted that, although both two-and three-dose regimens were examined for immunogenicity with the DISC vaccine, protection studies for the first-generation vaccine were completed using only those dams immunized with the suboptimal, two-dose vaccine regimen [62].…”

Impact of preexisting virus-specific maternal antibodies on cytomegalovirus population genetics in a monkey model of congenital transmission

“…These findings indicate that, although potently-neutralizing CMV-specific antibodies can effectively reduce viral population size and prevent congenital transmission [9], preexisting HIG had limited impact on the genetic makeup of the maternal RhCMV populations or transmitted variants. These findings are interesting given the growing evidence that preexisting HCMV-specific antibodies can reduce the incidence and severity of congenital HCMV [9,38–40], perhaps suggesting a model wherein congenital virus transmission is dependent upon the overall quantity of maternal systemically-circulating virus rather than antibody selection of specific variants at the maternal-fetal interface. Further studies, ideally starting with an inoculum containing higher levels of viral diversity, may be required to provide a deeper understanding of the extent of antibody-mediated immune-pressure on CMV populations, as well as the effect of antibodies on viral transmission dynamics across the placenta.…”