A regression analysis was performed to assess a feasible correlation between viral load and the magnitude of gB-binding or HCMV-neutralizing antibodies elicited by vaccination

A regression analysis was performed to assess a feasible correlation between viral load and the magnitude of gB-binding or HCMV-neutralizing antibodies elicited by vaccination. we used viral DNA isolated from patients enrolled in a gB vaccine trial who acquired HCMV and identified several impacts that this vaccine had on the size, distribution, and composition of the viral population. These results have increased our understanding of why the gB/MF59 vaccine was partially efficacious, and such investigations will inform future rational design of a vaccine to prevent congenital HCMV. KEYWORDS: DNA sequencing, glycoprotein B, Olanzapine (LY170053) human cytomegalovirus, vaccine ABSTRACT Human cytomegalovirus (HCMV) is the most common congenital infection worldwide and a frequent cause of hearing loss and debilitating neurologic disease in newborn infants. Thus, a vaccine to prevent HCMV-associated congenital disease is a public health priority. One potential strategy is vaccination of women of child bearing age to prevent maternal HCMV acquisition during pregnancy. The glycoprotein B (gB) plus MF59 adjuvant subunit vaccine is the most efficacious tested clinically to date, demonstrating 50% protection against primary HCMV infection in a phase 2 clinical trial. Yet, the impact of gB/MF59-elicited immune responses on the population of viruses acquired by trial participants has not been assessed. In this analysis, we employed quantitative PCR as well as multiple sequencing methodologies to interrogate the magnitude and genetic composition of HCMV populations infecting gB/MF59 vaccinees and placebo recipients. We identified several differences between the viral dynamics in acutely infected vaccinees and placebo recipients. First, viral load was reduced in the saliva of gB vaccinees, though not in whole blood, vaginal fluid, or urine. Additionally, we observed possible anatomic compartmentalization of gB variants in the majority of vaccinees compared to only a single placebo recipient. Finally, we observed reduced acquisition of genetically related gB1, gB2, and gB4 genotype supergroup HCMV variants among vaccine recipients, suggesting that the gB1 Olanzapine (LY170053) genotype vaccine construct may have elicited partial protection against HCMV Olanzapine (LY170053) viruses with antigenically similar gB sequences. These findings suggest that gB immunization had a measurable impact on viral intrahost population dynamics and support future analysis of a larger cohort. IMPORTANCE Though not a household name like Zika virus, human cytomegalovirus (HCMV) causes permanent neurologic disability in one newborn child every hour in the United States, which is more than that for Down syndrome, fetal alcohol syndrome, and neural tube defects combined. There are currently no established effective measures to prevent viral transmission to the infant following HCMV infection of a pregnant mother. However, the glycoprotein B (gB)/MF59 vaccine, which aims to prevent pregnant women from acquiring HCMV, is the most successful HCMV vaccine tested clinically to date. Here, we used viral DNA isolated from patients enrolled in a gB IL9 antibody vaccine trial who acquired HCMV and identified several impacts that this vaccine had on the size, distribution, and composition of the viral population. These results have increased our understanding of why the gB/MF59 vaccine was partially efficacious, and such investigations will inform future rational design of a vaccine to prevent congenital HCMV. KEYWORDS: DNA sequencing, glycoprotein B, human cytomegalovirus, vaccine INTRODUCTION Human cytomegalovirus (HCMV) congenital infection affects 1 in 150 pregnancies (1) and is the most frequent nongenetic cause of sensorineural hearing loss and neurodevelopmental delay in infants worldwide (2). Additionally, HCMV is the most common infectious agent among allograft recipients, often causing end-organ disease such as hepatitis, pneumonitis, or gastroenteritis and predisposing the individual to graft rejection (3). It has been estimated that an efficacious HCMV vaccine would save the United States 4 billion dollars and 70,000 quality-adjusted life years annually; thus, HCMV vaccine development has remained a tier 1 priority of the National Academy of Medicine for the past 17?years (4). The glycoprotein B (gB) plus MF59 Olanzapine (LY170053) adjuvant vaccine is the most efficacious HCMV vaccine platform trialed to date, demonstrating partial vaccine protection in multiple patient populations. In a cohort of HCMV-seronegative postpartum women, gB vaccination achieved a promising 50% vaccine efficacy (5). When subsequently repeated in a cohort of seronegative adolescent women, a similar level of vaccine Olanzapine (LY170053) protection was identified, though the protection was not statistically significant (6). Furthermore, in allograft recipients, the same gB vaccine reduced the duration of HCMV viremia and antiviral therapy (7). There are many hypothesized reasons why this vaccine did not achieve a higher level of protection, including rapidly waning antibody titers, poor inhibition of epithelial cell entry, or a postfusion gB conformation. We and others have observed that the gB/MF59 vaccine platform was particularly poor at eliciting heterologous neutralizing antibodies in diverse populations and hypothesize that nonneutralizing antibody responses may have played a role in vaccine protection (8,C10). Previously, we reported population-level virus sequencing of HCMV hypervariable genes in this cohort,.