Higher Expectations for a Vaccine To Prevent Congenital Cytomegalovirus Infection

We strongly agree with our colleagues Permar, Schleiss, and Plotkin (1) that optimism about a vaccine to prevent congenital cytomegalovirus infection (cCMV) is warranted. We also agree that natural CMV infection appears to provide some level of protection against reinfection, congenital transmission, and (potentially) disease severity in children with nonprimary cCMV. As such, understanding the mechanistic basis of naturally acquired protection is critical for CMV vaccine development. Nevertheless, worldwide, the vast majority of cCMV infections and disease occur in children born to CMV-seropositive women (2–8). Indeed, the rates of cCMV are highest in lowto middle-income countries, where nearly everyone is infected in early childhood (5, 9). A vaccine that conferred only the equivalent of natural immunity to women of childbearing age would prevent at most around half of disease due to cCMV in high-income countries and almost none in the rest of the world (9). We suggest that the explicit goal of a vaccine to prevent cCMV should be to protect infants not only of CMV-seronegative but also of seropositive women. This might be achieved by preventing reinfection, preventing transplacental transmission, and/or reducing viral shedding and horizontal transmission. Inducing protection against incident infection in seropositive individuals is daunting given the frequency of CMV reinfections in humans and nonhuman-primate models (10–12). Although a better understanding of the determinants of in utero transmission by women with nonprimary infection is badly needed, it is apparent that maternal reinfection during pregnancy represents a major risk factor (11, 13). Thus, reducing CMV exposures in seropositive women represents a promising strategy to greatly reduce the total burden of cCMV. Given the ubiquity of CMV infection, horizontal transmission is remarkably inefficient (14, 15) and appears to require frequent, high-viral-load exposures (16). The most common routes of transmission are from mother to child as a result of nearly universal viral shedding in breast milk (17) and from children to other children and adults (including pregnant women) due to prolonged shedding with high viral loads in saliva and urine (16, 18–20). Importantly, the risk of CMV transmission appears to be strongly correlated with the viral load of the exposure (16, 21, 22). Therefore, a CMV vaccine that confers even a modest reduction in viral shedding in breast milk and by children might have a profound effect on horizontal transmission, thereby reducing the overall prevalence of CMV infection as well as disease from cCMV (23). Indeed, estimates from mathematical models suggest that even a vaccine with only modest efficacy to interrupt transmission might eradicate CMV from the population (14), which is indeed reason for optimism. Achieving the goal of protecting all children from cCMV will require more studies of immune control of CMV shedding and horizontal transmission Citation Gantt S, Marchant A, Boppana SB. 2018. Higher expectations for a vaccine to prevent congenital cytomegalovirus infection. J Virol 92:e00764-18. https://doi.org/10.1128/ JVI.00764-18. Editor Rozanne M. Sandri-Goldin, University of California, Irvine Copyright © 2018 American Society for Microbiology. All Rights Reserved. Address correspondence to Soren Gantt, sgantt@bcchr.ubc. ca. For the author reply, see https://doi.org/10 . 1128/JVI.00771-18. LETTER TO THE EDITOR