Progress on pursuit of human cytomegalovirus vaccines for prevention of congenital infection and disease

Congenital infection of human cytomegalovirus (HCMV) is the leading cause of childhood hearing loss and mental retardation. Unfortunately, a preventive vaccine remains elusive. Two strategies have been employed to develop HCMV vaccines, including (1) attenuating HCMV to generate modified virus vaccines and (2) isolating subunit viral antigen(s) to create individual antigen vaccines. The most studied candidate in each category is live attenuated Towne virus and recombinant gB/MF59 vaccine, respectively. Although both were moderately efficacious, neither could induce the durable, robust humoral and cellular immunity commonly seen in HCMV seropositive subjects. In addition, both vaccines failed to induce neutralizing antibodies against viral infection of endothelial cells, epithelial cells and leukocytes. This review summarizes the recent understanding of host natural immunity to HCMV, including the importance of antibodies targeting HCMV epithelial tropism, and discusses its implications for vaccine design. We also highlight some recent key discoveries that may lead to the development of an effective HCMV vaccine.