Reply to Gantt et al., “Higher Expectations for a Vaccine To Prevent Congenital Cytomegalovirus Infection”

REPLY

Gantt et al. (1) make useful and valid points about the importance of developing a cytomegalovirus (CMV) vaccine that targets reduction in congenital infections in seropositive women, in addition to preventing infection (with subsequent transmission) in seronegative patients. We agree that congenital transmission in seropositive women is the largest contributor to the global burden of congenital CMV disease. However, their suggestions for vaccine development may be premature. Although transmission to fetuses from seropositive mothers (who either reactivate latent infection or are reinfected with novel strains) is the most common circumstance by which congenital CMV infection occurs, we suggest that the available data demonstrate that the risk of transmission and injury to the fetus is greatest when a primary maternal infection occurs in a seronegative woman. Since knowledge and awareness of the importance of congenital CMV is increasing, vaccine developers now perceive that the incidence of congenital disease is sufficient to yield a return on investment in developing and marketing a CMV vaccine for girls and young women of childbearing age. Our current state of knowledge regarding the partial but significant protection conferred by preconception immunity justifies a CMV vaccine program that would target this group as a positive first step in vaccine policy. Newborns would benefit, and disabilities would be prevented. We also agree that, inevitably, protection against congenital transmission in seropositive mothers is a critical future goal. This goal will depend on identifying the maternal immune responses that must be augmented or newly elicited to protect the mother and/or fetus in the setting of reinfections superimposed on patients with preexisting CMV immunity. As we emphasized in our review, the maternal immune correlates of protection against congenital transmission in the setting of natural immunity are currently unknown and should be the focus of research that can take advantage of large international mother-infant population studies, such as those that were initiated in the wake of the Zika virus epidemic. We also agree with Gantt et al., and as previously suggested by others in the field, that reduction of CMV excretion in infants by a vaccine would reduce the risk of maternal infection, but we do not yet know whether that is achievable by a vaccine. In the case of the rubella vaccine, its first application was to protect women intending pregnancy, but after vaccine efficacy was established, it was applied to infants to achieve the secondary goal of reducing the exposure of pregnant women. We foresee that ultimate strategy for a CMV vaccine, but only after demonstration of efficacy in seronegative women and clarification of the issues which will arise with respect to vaccination of males. In summary, we have the knowledge and ability to improve the health and developmental outcomes of at least some infants with congenital CMV at our fingertips, and we should not let the need for more knowledge about correlates of protection prevent us from taking action now to help improve pregnancy outcomes in seronegative women.