Zika virus (ZIKV) infection of pregnant patients could cause a wide range of congenital abnormalities (including microcephaly) now collectively known as congenital ZIKV syndrome1. A vaccine to prevent or significantly attenuate viremia in pregnant women and travelers to epidemic/endemic regions is needed to avert congenital ZIKV syndrome, and could also be useful to suppress epidemic transmission. Here we report a live-attenuated vaccine candidate that contains a 10-nucleotide deletion in the 3’ untranslated region of ZIKV genome (10-del ZIKV). The 10-del ZIKV is highly attenuated, immunogenic, and protective in the A129 mouse model. Critically, a single dose of 10-del ZIKV induced sterilizing immunity with a high level of neutralizing antibodies and completely prevented viremia after challenge. The immunized mice also developed a robust T cell response. Intracranial inoculation of one-day-old CD1 mice with 1×104 IFU of 10-del ZIKV caused no detectable disease, whereas infections with 10 IFU of wild-type ZIKV were lethal. Mechanistically, the 10-del ZIKV attenuated its virulence through decreased viral RNA synthesis and increased sensitivity to type-I interferon inhibition. The attenuated 10-del ZIKV was incompetent in infecting mosquitoes after oral feeding of spiked blood meals, representing an additional safety feature for use in non-endemic regions. Collectively, the safety and efficacy results warrant further development of this promising live-attenuated ZIKV vaccine candidate.

Zika virus infection during pregnancy can cause congenital abnormities or fetal demise. The persistence of Zika virus in the male reproductive system poses a risk of sexual transmission. Here we demonstrate that live-attenuated Zika virus vaccine candidates containing deletions in the 3′ untranslated region of the Zika virus genome (ZIKV-3′UTR-LAV) prevent viral transmission during pregnancy and testis damage in mice, as well as infection of nonhuman primates. After a single-dose vaccination, pregnant mice challenged with Zika virus at embryonic day 6 and evaluated at embryonic day 13 show markedly diminished levels of viral RNA in maternal, placental, and fetal tissues. Vaccinated male mice challenged with Zika virus were protected against testis infection, injury, and oligospermia. A single immunization of rhesus macaques elicited a rapid and robust antibody response, conferring complete protection upon challenge. Furthermore, the ZIKV-3′UTR-LAV vaccine candidates have a desirable safety profile. These results suggest that further development of ZIKV-3′UTR-LAV is warranted for humans.

Yellow fever is a viral hemorrhagic fever, which affects people living in Africa and South America and is caused by the yellow fever virus, the prototype species in the Flavivirus genus (Flaviviridae family). Yellow fever virus infection can produce a wide spectrum of symptoms, ranging from asymptomatic infection or oligosymptomatic illness to severe disease with a high fatality rate. In this review, we focus in the mechanisms associated with the physiopathology of yellow fever in humans and animal models. It has been demonstrated that several factors play a role in the pathological outcome of the severe form of the disease including direct viral cytopathic effect, necrosis and apoptosis of hepatocyte cells in the midzone, and a minimal inflammatory response as well as low-flow hypoxia and cytokine overproduction. New information has filled several gaps in the understanding of yellow fever pathogenesis and helped comprehend the course of illness. Finally, we discuss prospects for an immune therapy in the light of new immunologic, viral, and pathologic tools.