Research ArticleVaccines

A replication-defective human cytomegalovirus vaccine for prevention of congenital infection

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Science Translational Medicine  26 Oct 2016:
Vol. 8, Issue 362, pp. 362ra145
DOI: 10.1126/scitranslmed.aaf9387

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Progress toward a human cytomegalovirus vaccine

Most adults carry latent human cytomegalovirus, with no apparent symptoms. But if a pregnant woman becomes newly infected or an active infection is triggered, the fetus can be harmed and show severe neurodevelopmental deficits. Wang and colleagues report a key step toward an effective vaccine against this dangerous herpesvirus. They engineered a genetic off switch into the whole virus to render it harmless and show that it can elicit desirable immune responses such as neutralizing antibodies cell-mediated immune responses in several animal species, including nonhuman primates.

Abstract

Congenital human cytomegalovirus (HCMV) infection occurs in ~0.64% of infants born each year in the United States and is the leading nongenetic cause of childhood neurodevelopmental disabilities. No licensed HCMV vaccine is currently available. Natural immunity to HCMV in women before pregnancy is associated with a reduced risk of fetal infection, suggesting that a vaccine is feasible if it can reproduce immune responses elicited by natural infection. On the basis of this premise, we developed a whole-virus vaccine candidate from the live attenuated AD169 strain, with genetic modifications to improve its immunogenicity and attenuation. We first restored the expression of the pentameric gH/gL/pUL128-131 protein complex, a major target for neutralizing antibodies in natural immunity. We then incorporated a chemically controlled protein stabilization switch in the virus, enabling us to regulate viral replication with a synthetic compound named Shield-1. The virus replicated as efficiently as its parental virus in the presence of Shield-1 but failed to produce progeny upon removal of the compound. The vaccine was immunogenic in multiple animal species and induced durable neutralizing antibodies, as well as CD4+ and CD8+ T cells, to multiple viral antigens in nonhuman primates.

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