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

Abstract

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.

HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

“…Yet over the past decade, following discovery that the most potent HCMV-neutralizing antibodies in human sera target the gH/gL/UL128-131A pentameric complex [22, 23], the focus has expanded from gB vaccine development. Nevertheless, it is important to recognize that the gB/MF59 protein subunit vaccine achieved partial moderate vaccine efficacy in preventing primary HCMV infection and seroconversion [12, 13] – a feat unparalleled in the HCMV vaccine field [24]. Furthermore, the gB/MF59 vaccine reduced viremia and demonstrated a protective benefit in transplant recipients [14].…”

“…In this investigation, we specifically focused on the implications of the gB/MF59-elicited immune-dominant response directed against gB AD-3 [25]. We hypothesized the absence of neutralizing antibodies in gB/MF59 vaccinees may be attributable to the dominant responses against the AD-3 ‘decoy epitope’, which diverted antibody targeting away from ‘more functional’ epitopes [24]. We directly tested this hypothesis with our gB ecto group by excluding AD-3 from the immunogen.…”

“…Protein subunit vaccines (gB FL, gB ecto) were given I.M. at a dose of 20μg, mimicking the protocol for gB/MF59 immunized humans in the partially-efficacious clinical trials [12, 13, 24]. In contrast, 50μg of the gB nucleoside-modified mRNA-LNP was administered I.D, which was selected because this delivery method enhances protein expression in vivo [49].…”

Evaluation of glycoprotein E subunit and live attenuated varicella‐zoster virus vaccines formulated with a single‐strand RNA‐based adjuvant

“…In contrast, its preventive efficacy against herpes zoster is only~60%. 15 LAV promotes relatively lower VZV-specific cellular immune responses against herpes zoster in older patients as immunosenescence accompanies the aging process. Immunosenescence is characterized by decreased T-cell numbers and impaired T-cell function.…”

“…Its reported efficacy against herpes zoster was 97%. 15 Therefore, the subunit vaccine may have greater efficacy against herpes zoster than LAV. A recombinant subunit vaccine is a potential alternative to live attenuated herpes zoster vaccine.…”