A new era in cytomegalovirus vaccinology: considerations for rational design of next-generation vaccines to prevent congenital cytomegalovirus infection

Human cytomegalovirus (HCMV), a member of the beta-herpesvirus family, is the most common cause of congenital infection worldwide as well as an important cause of morbidity in transplant recipients and immunosuppressed individuals. An estimated 1 in 150 infants are infected with HCMV at birth, which can result in lifelong, debilitating neurologic sequelae including microcephaly, sensorineural hearing loss, and cognitive impairment. Natural maternal immunity to HCMV decreases the frequency of reinfection and reduces risk of congenital transmission but does not completely protect against neonatal disease. Thus, a vaccine to reduce the incidence and severity of infant infection is a public health priority. A variety of candidate HCMV vaccine approaches have been tried previously, including live-attenuated viruses, glycoprotein subunit formulations, viral vectors, and single/bivalent DNA plasmids, but all have failed to reach target endpoints in clinical trials. Nevertheless, there is a great deal to be learned from the successes and failures of the HCMV vaccine field (both congenital and transplant-associated), as well as from vaccine development efforts for other herpesvirus pathogens including herpes simplex virus 1 and 2, varicella zoster virus, and Epstein-Barr virus. Here, we review those successes and failures, evaluating recent cutting-edge discoveries that have shaped the HCMV vaccine field and identifying topics of critical importance for future investigation. These considerations will inform rational design and evaluation of next-generation vaccines to prevent HCMV-associated congenital infection and disease.