Advancing Our Understanding of Protective Maternal Immunity as a Guide for Development of Vaccines To Reduce Congenital Cytomegalovirus Infections

Abstract

Human cytomegalovirus (HCMV) is the most common congenitally transmitted pathogen worldwide, impacting an estimated 1 million newborns annually. Congenital HCMV (cCMV) infection is a major global contributor to long-term neurologic deficits, including deafness, microcephaly, and neurodevelopmental delay, as well as to fetal loss and occasional infant mortality. Accordingly, design of a maternal vaccine to prevent cCMV continues to be a top public health priority. Nevertheless, we remain without a licensed vaccine. Maternal immunity provides partial protection, as the risk of vertical HCMV transmission from chronically infected mothers is reduced compared to settings in which the mother is newly infected during pregnancy. Therefore, an understanding of the maternal immune correlates of protection against cCMV is critical to informing design of an efficacious maternal vaccine. Although vaccine development is being assiduously pursued by a large number of pharmaceutical manufacturers, biotechnology organizations, and academic researchers, some pessimism has been expressed regarding the issue of whether a vaccine to protect against cCMV is possible. This pessimism is based on observations that natural immunity is not completely protective against maternal reinfection and congenital transmission. However, we assert that optimism regarding vaccine development is indeed justified, on the basis of accruing evidence of immune correlates of protection-readily achievable by vaccination-that are associated with reduced transmission of HCMV to the fetus in seronegative women. In light of the substantial burden on society conferred by cCMV infection, even a modest reduction in the occurrence of this fetal disease is an important public health goal and justifies aggressive clinical evaluation of vaccines currently in the pipeline.

Keywords: congenital infections; cytomegalovirus; vaccines.

FIG 1

Congenital HCMV transmission rates in CMV-seronegative and -seropositive women. (A) Primary HCMV infection occurs infrequently (rate, 1% to 3%) in HCMV-seronegative pregnant women, but rates of cCMV transmission (30% to 40%) and infant disease (25%) are known to be high following primary maternal infection (1, 97). (B) The rate of systemic maternal HCMV reactivation in chronically infected women is not known; nor is the rate of cCMV infection in the setting of maternal reactivation known. (C) HCMV reinfection rates, identified by detection of a serologic response against a new strain of HCMV, have suggested that nearly 1 of 3 CMV seropositive women become reinfected during pregnancy (24, 39), and yet the cCMV transmission rate is up to 10-fold lower than that in primary maternal infection (3.4%) (23) and the disease rates have been reported as 10% or less (24, 29, 33, 34). Thus, similar numbers of cCMV-infected and -impaired infants occur in HCMV-seronegative and -seropositive pregnant women populations (1). *, data points where more studies are needed to further advance our understanding of the partial protective nature of preexisting HCMV immunity.