Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB/MF59 vaccination

Congenital infection with cytomegalovirus (CMV) is an important cause of hearing, cognitive, and motor impairments in newborns. In this phase 2, placebo-controlled, randomized, double-blind trial, we evaluated a vaccine consisting of recombinant CMV envelope glycoprotein B with MF59 adjuvant, as compared with placebo. Three doses of the CMV vaccine or placebo were given at 0, 1, and 6 months to CMV-seronegative women within 1 year after they had given birth. We tested for CMV infection in the women in quarterly tests during a 42-month period, using an assay for IgG antibodies against CMV proteins other than glycoprotein B. Infection was confirmed by virus culture or immunoblotting. The primary end point was the time until the detection of CMV infection. We randomly assigned 234 subjects to receive the CMV vaccine and 230 subjects to receive placebo. A scheduled interim analysis led to a stopping recommendation because of vaccine efficacy. After a minimum of 1 year of follow-up, there were 49 confirmed infections, 18 in the vaccine group and 31 in the placebo group. Kaplan-Meier analysis showed that the vaccine group was more likely to remain uninfected during a 42-month period than the placebo group (P=0.02). Vaccine efficacy was 50% (95% confidence interval, 7 to 73) on the basis of infection rates per 100 person-years. One congenital infection among infants of the subjects occurred in the vaccine group, and three infections occurred in the placebo group. There were more local reactions (pain, erythema, induration, and warmth) and systemic reactions (chills, arthralgias, and myalgias) in the vaccine group than in the placebo group. CMV glycoprotein B vaccine has the potential to decrease incident cases of maternal and congenital CMV infection. (ClinicalTrials.gov number, NCT00125502.) 2009 Massachusetts Medical Society

Human cytomegalovirus (HCMV) is a widely circulating pathogen that causes severe disease in immunocompromised patients and infected fetuses. By immortalizing memory B cells from HCMV-immune donors, we isolated a panel of human monoclonal antibodies that neutralized at extremely low concentrations (90% inhibitory concentration [IC(90)] values ranging from 5 to 200 pM) HCMV infection of endothelial, epithelial, and myeloid cells. With the single exception of an antibody that bound to a conserved epitope in the UL128 gene product, all other antibodies bound to conformational epitopes that required expression of two or more proteins of the gH/gL/UL128-131A complex. Antibodies against gB, gH, or gM/gN were also isolated and, albeit less potent, were able to neutralize infection of both endothelial-epithelial cells and fibroblasts. This study describes unusually potent neutralizing antibodies against HCMV that might be used for passive immunotherapy and identifies, through the use of such antibodies, novel antigenic targets in HCMV for the design of immunogens capable of eliciting previously unknown neutralizing antibody responses.

Cytomegalovirus (CMV) infection is the most common intrauterine infection in the United States, and it exacts a heavy toll when it infects children and immunocompromised individuals. A CMV vaccine was assigned the highest priority by the Institute of Medicine in its 1999 assessment of targets for vaccine development. The priority was based on the cost and human suffering that would be alleviated by reducing the disease burden of congenital CMV infection. The National Vaccine Advisory Committee and invited experts examined the prospects for a CMV vaccine and the actions needed to bring about successful vaccine development at a National Vaccine Program Office workshop in October 2000. This article summarizes information about the changing epidemiology of CMV and immune responses to infection and immunity, and it reviews the current status of several vaccine candidates. Support of government agencies for CMV vaccine research and development is critical to address this need.