Antibody binding to native cytomegalovirus glycoprotein B predicts efficacy of the gB/MF59 vaccine in humans.

Human cytomegalovirus (CMV) is the most common infectious cause of infant brain damage and posttransplant complications worldwide. Despite the high global burden of disease, vaccine development to prevent infection remains hampered by challenges in generating protective immunity. The most efficacious CMV vaccine candidate tested to date is a soluble glycoprotein B (gB) subunit vaccine with MF59 adjuvant (gB/MF59), which achieved 50% protection in multiple historical phase 2 clinical trials. The vaccine-elicited immune responses that conferred this protection have remained unclear. We investigated the humoral immune correlates of protection from CMV acquisition in populations of CMV-seronegative adolescent and postpartum women who received the gB/MF59 vaccine. We found that gB/MF59 immunization elicited distinct CMV-specific immunoglobulin G (IgG)-binding profiles and IgG-mediated functional responses in adolescent and postpartum vaccinees, with heterologous CMV strain neutralization observed primarily in adolescent vaccinees. Using penalized multiple logistic regression analysis, we determined that protection against primary CMV infection in both cohorts was associated with serum IgG binding to gB present on a cell surface but not binding to the soluble vaccine antigen, suggesting that IgG binding to cell-associated gB is an immune correlate of vaccine efficacy. Supporting this, we identified gB-specific monoclonal antibodies that differentially recognized soluble or cell-associated gB, revealing that there are structural differences in cell-associated and soluble gB are relevant to the generation of protective immunity. Our results highlight the importance of the native, cell-associated gB conformation in future CMV vaccine design.

Multigenerational and Transgenerational Effects of Environmentally Relevant Concentrations of Endocrine Disruptors in an Estuarine Fish Model.

Many pollutants cause endocrine disruption in aquatic organisms. While studies of the direct effects of toxicants on exposed organisms are commonplace, little is known about the potential for toxicant exposures in a parental (F0) generation to affect unexposed F1 or F2 generations (multigenerational and transgenerational effects, respectively), particularly in estuarine fishes. To investigate this possibility, we exposed inland silversides (Menidia beryllina) to environmentally relevant (low ng/L) concentrations of ethinylestradiol, bifenthrin, trenbolone, and levonorgestrel from 8 hpf to 21 dph. We then measured development, immune response, reproduction, gene expression, and DNA methylation for two subsequent generations following the exposure. Larval exposure (F0) to each compound resulted in negative effects in the F0 and F1 generations, and for ethinylestradiol and levonorgestrel, the F2 also. The specific endpoints that were responsive to exposure in each generation varied, but included increased incidence of larval deformities, reduced larval growth and survival, impaired immune function, skewed sex ratios, ovarian atresia, reduced egg production, and altered gene expression. Additionally, exposed fish exhibited differences in DNA methylation in selected genes, across all three generations, indicating epigenetic transfer of effects. These findings suggest that assessments across multiple generations are key to determining the full magnitude of adverse effects from contaminant exposure in early life.

Animal Models of Congenital Cytomegalovirus Transmission: Implications for Vaccine Development.

Although cytomegaloviruses (CMVs) are species-specific, the study of nonhuman CMVs in animal models can help to inform and direct research aimed at developing a human CMV (HCMV) vaccine. Because the driving force behind the development of HCMV vaccines is to prevent congenital infection, the animal model in question must be one in which vertical transmission of virus occurs to the fetus. Fortunately, two such animal models-the rhesus macaque CMV and guinea pig CMV-are characterized by congenital infection. Hence, each model can be evaluated in "proof-of-concept" studies of preconception vaccination aimed at blocking transplacental transmission. This review focuses on similarities and differences in the respective model systems, and it discusses key insights from each model germane to the study of HCMV vaccines.

Efficient transplacental IgG transfer in women infected with Zika virus during pregnancy.

Zika virus (ZIKV) is a newly-identified infectious cause of congenital disease. Transplacental transfer of maternal IgG to the fetus plays an important role in preventing many neonatal infections. However, antibody transfer may also have negative consequences, such as mediating enhancement of flavivirus infections in early life, or trafficking of virus immune complexes to the fetal compartment. ZIKV infection produces placental pathology which could lead to impaired IgG transfer efficiency as occurs in other maternal infections, such as HIV-1 and malaria. In this study, we asked whether ZIKV infection during pregnancy impairs transplacental transfer of IgG. We enrolled pregnant women with fever or rash in a prospective cohort in Vitoria, Brazil during the recent ZIKV epidemic. ZIKV and dengue virus (DENV)-specific IgG, ZIKV and DENV neutralizing antibodies, and routine vaccine antigen-specific IgG were measured in maternal samples collected around delivery and 20 paired cord blood samples. We concluded that 8 of these mothers were infected with ZIKV during pregnancy and 12 were ZIKV-uninfected. The magnitude of flavivirus-specific IgG, neutralizing antibody, and vaccine-elicited IgG were highly correlated between maternal plasma and infant cord blood in both ZIKV-infected and -uninfected mother-infant pairs. Moreover, there was no difference in the magnitude of plasma flavivirus-specific IgG levels between mothers and infants regardless of ZIKV infection status. Our data suggests that maternal ZIKV infection during pregnancy does not impair the efficiency of placental transfer of flavivirus-specific, functional, and vaccine-elicited IgG. These findings have implications for the neonatal outomes of maternal ZIKV infection and optimal administration of antibody-based ZIKV vaccines and therapeutics.