A DNA vaccine candidate for Zika: The ongoing Zika epidemic in the Americas and the Caribbean urgently needs a protective vaccine. Two DNA vaccines composed of the genes that encode the structural premembrane and envelope proteins of Zika virus have been tested in monkeys. Dowd et al. show that two doses of vaccine given intramuscularly completely protected 17 of 18 animals against Zika virus challenge. A single low dose of vaccine was not protective but did reduce viral loads. Protection correlated with serum antibody neutralizing activity. Phase I clinical trials testing these vaccines are already ongoing. Science , this issue p. 237

Building a better RSV vaccine: Respiratory syncytial virus (RSV) causes severe respiratory disease, especially in infants and the elderly. However, attempts to produce effective human vaccines have largely been unsuccessful. Structure-based design has been used to generate an RSV fusion glycoprotein stabilized in its prefusion conformation (DS-Cav1). This immunogen is highly effective in mice and macaques. Crank et al. now report the results of a phase I vaccine clinical trial using the stabilized prefusion DS-Cav1 molecule. Four weeks after immunization, these vaccines elicited substantially more high-quality antibody titers than those typically generated using earlier RSV immunogens. The findings provide a proof of concept for how structural biology can contribute to precision vaccine design. Science , this issue p. 505

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.

Cytomegalovirus vectors are promising delivery vehicles for vaccine strategies that aim to elicit effector CD8+ T cells. To determine how the route of immunization affects CD8+ T-cell responses in the lungs of mice vaccinated with a murine cytomegalovirus vector expressing the respiratory syncytial virus matrix (M) protein, we infected CB6F1 mice via the intranasal or intraperitoneal route and evaluated the M-specific CD8+ T-cell response at early and late time points. We found that intranasal vaccination generated robust and durable tissue-resident effector and effector memory CD8+ T-cell populations that were undetectable after intraperitoneal vaccination. The generation of these antigen-experienced cells by intranasal vaccination resulted in earlier T-cell responses, interferon gamma secretion, and viral clearance after respiratory syncytial virus challenge. Collectively, these findings validate a novel approach to vaccination that emphasizes the route of delivery as a key determinant of immune priming at the site of vulnerability.