Priorities for CMV vaccine development

Abstract

A multidisciplinary meeting addressed priorities related to development of vaccines against cytomegalovirus (CMV), the cause of congenital CMV (cCMV) disease and of serious disease in the immunocompromised. Participants discussed optimal uses of a CMV vaccine, aspects of clinical study design, and the value of additional research. A universal childhood CMV vaccine could potentially rapidly reduce cCMV disease, as infected children are sources of viral transmission to seronegative and seropositive mothers. A vaccine administered to adolescents or adult women could also reduce cCMV disease by making them immune prior to pregnancy. Clinical trials of CMV vaccines in women should evaluate protection against cCMV infection, an essential precursor of cCMV disease, which is a more practical and acceptable endpoint for assessing vaccine effects on maternal-fetal transmission. Clinical trials of vaccines to evaluate prevention of CMV disease in stem cell transplant recipients could use CMV viremia at a level triggering preemptive antiviral therapy as an endpoint, because widespread use of preemptive and prophylactic antivirals has rendered CMV-induced disease too rare to be a practical endpoint for clinical trials. In solid organ transplant patients, CMV-associated disease is sufficiently common for use as a primary endpoint. Additional research to advance CMV vaccine development should include identifying factors that predict fetal loss due to CMV, determining age-specific incidence and transmission rates, defining the mechanism and relative contributions of maternal reactivation and re-infection to cCMV disease, developing assays that can distinguish between reactivation and re-infection in seropositive vaccinees, further defining predictors of sequelae from cCMV infection, and identifying clinically relevant immune response parameters to CMV (including developing validated assays that could assess CMV antibody avidity) that could lead to the establishment of immune correlates of protection.

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

“…82,[88][89][90] Consequently, non-primary infections caused by either re-infection of, or reactivation in, HCMV seropositive mothers are also likely to be a cause of congenital infection, despite preformed HCMV-specific maternal antibodies. Although the relative contribution of virus reactivation or reinfection to congenital infections is not clear, 91 prevention of infection in either scenario would be beneficial. While this could be achieved through education of pregnant mothers (e.g., in hygiene measures), any potential therapy to reduce the latent viral reservoir during pregnancy could also reduce the risk of congenital infection from virus reactivation.…”

Congenital Human Cytomegalovirus Infection and the Enigma of Maternal Immunity

“…Development of an efficacious vaccine remains a high priority for federal agencies, and several pharmaceutical companies are actively pursuing vaccine development. Candidate vaccines, including attenuated live-virus vaccines and adjuvanted viral proteins, have provided insight into the development of an effective vaccine but not definitive evidence of efficacy (12)(13)(14). Efforts to develop vaccines to limit disease associated with congenital HCMV infections have identified several hurdles that continue to challenge vaccine development.…”

Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection

“…Besides its leading role in permanent birth defects, HCMV is also a major cause of morbidity and mortality in hematopoietic stem cell and solid organ transplant recipients (11)(12)(13). Based on the societal and financial health burden and in the absence of effective treatment options, HCMV has been assigned as one of the highest priority vaccine targets (14,15). However, incompletely defined correlates of protection, lack of animal models susceptible to HCMV infection, insufficiently powered vaccine trials, and general unawareness, are a number of obstacles that have hampered the development of an effective and safe HCMV vaccine (16).…”