Preclinical Evaluation of a Novel rLCMV Single-Cycle Vectored CMV Vaccine

DESCRIPTION (provided by applicant): Immunity to human cytomegalovirus (CMV) following infection is complex, and not fully protective against reactivation and reinfection with new strains. Because of the lifelong disabilities caused by congenital CMV infection, understanding the host defense determinants that protect the developing fetus is critical, toward the goal of developing an effective preconception vaccine. Clinical trials of an adjuvanted glycoprotein B (gB) vaccine showed protection in young women of childbearing age, but waning immunity and modest efficacy (~50%) necessitate consideration of other strategies. Recent evidence suggests that the CMV pentameric complex (PC) of proteins (gH/gL/UL128/UL130/UL131) may be a more efficacious vaccine target, since antibodies to the PC potently block virus entry into epithelial and endothelial cells. The overarching goal of these studies is to use a relevant small animal model of congenital CMV transmission, the guinea pig cytomegalovirus (GPCMV) model, to identify the optimal vaccine strategy for protection against fetal virus transmission. Toward this goal, Aim 1 will test the hypothesis that a novel recombinant lymphocytic choriomeningitis virus (rLCMV)-vectored PC vaccine will confer improved protection when compared to a combination rLCMV-vectored gB/GP83 (pp65 homolog) vaccine, and to an MPL adjuvanted recombinant gB vaccine. Both subcutaneous (Aim 1a) and transmucosal/intravaginal (Aim 1b) routes of virulent salivary gland- passaged GPCMV virus challenge will be evaluated in vaccinated and control animals to identify the optimal protective strategy. This will represent the first evaluation of an LCMV vaccine in an animal model of congenital CMV infection. Interferon-? ELISPOT and a novel high-throughput luminex bDNA cytokine assay will explore correlates of immunity that are associated with protection against placental transmission. Aim 2 will test the hypothesis that an LCMV-vectored PC vaccine also confers superior protection, compared to gB/GP83 vaccine, against virus-induced hearing loss memory/spatial neurocognitive deficits (using a Barnes maze model) following sublethal challenge during pregnancy. This study will represent the first animal model evaluation of a prenatal vaccine to prevent congenital CMV-induced hearing loss, and will increase the clinical relevance of the GPCMV model. Another area of complexity in CMV vaccines is the phenomena of re-infection. It has become increasingly clear that, in spite of previous immunity, women can become re-infected with new strains of CMV in pregnancy, and these strains can be transmitted to the fetus, leading to injury. Therefore, in Aim 3, we will utilize a newly discovered heterotypic strain of GPCMV, the CIDMTR strain, to model re-infection studies in the guinea pig. We will test whether LCMV PC vaccination can protect against re-infection and fetal transmission with improved efficacy when compared to adjuvanted gB vaccine. Since most congenital CMV infections occur in the context of non-primary maternal infections, these studies will substantially advance the field, and clarify the requirements of an effective congenital CMV vaccine for women of childbearing potential.