Prospects of a vaccine for the prevention of congenital cytomegalovirus disease

Congenital human cytomegalovirus (HCMV) infection is one leading cause of childhood disabilities. Prevention of congenital HCMV disease by vaccination has consequently been identified as a priority public healthcare goal. Several vaccine candidates have been introduced in the past that aimed at the prevention of primary HCMV infection in pregnancy. None of these has provided complete protection, and no licensed vaccine is thus far available. An additional level of complexity has been reached by recent studies indicating that the burden of HCMV transmission and disease following non-primary infections in pregnancy may be higher than previously anticipated. Substantial progress in our understanding of the immunobiology of HCMV infection in pregnancy has fostered studies to test revised or novel vaccine strategies. Preventing HCMV transmission has been identified a surrogate endpoint, rendering the conduction of vaccine studies feasible with reasonable effort. Identification of the glycoprotein complex gH/gL/UL128-131 as a mediator of HCMV host cell tropism and evaluation of that complex as a major target of the neutralizing antibody response made manufacturers consider vaccine candidates that include these proteins. Detailed structural analyses of the neutralizing determinants on HCMV glycoprotein B (gB) have revived interest in using this protein in its pre-fusion conformation for vaccine purposes. Studies in pregnant women and in animal models have provided evidence that addressing the T lymphocyte response by vaccination may be crucial to prevent HCMV transmission to the offspring. CD4 T lymphocytes may be of particular importance in this respect. A simultaneous targeting of both the humoral and cellular immune response against HCMV by vaccination thus appears warranted in order to prevent congenital HCMV infection. There is, however, still need for further research to be able to define an immunological correlate of protection against HCMV transmission during pregnancy. This brief review will highlight recent developments in our understanding of the natural history and immunobiology of HCMV infection in pregnancy and their possible impact on the strategies for the development of an HCMV vaccine.