Abstract
West Nile virus (WNV) and Usutu virus (USUV) are mosquito-borne flaviviruses that can cause neuroinvasive disease in humans. WNV and USUV circulate in both Africa and Europe and are closely related. Due to antigenic similarity, WNV-specific antibodies and USUV-specific antibodies have the potential to bind heterologous viruses; however, it is unclear whether this interaction may offer protection against infection. To investigate how prior WNV exposure would influence USUV infection, we used an attenuated WNV vaccine that contains the surface proteins of WNV in the backbone of a dengue virus 2 vaccine strain and protects against WNV disease. We hypothesized that vaccination with this attenuated WNV vaccine would protect against USUV infection. Neutralizing responses against WNV and USUV were measured in vitro using sera following vaccination. Sera from vaccinated CD-1 and Ifnar1−/− mice cross-neutralized with WNV and USUV. All mice were then subsequently challenged with an African or European USUV strain. In CD-1 mice, there was no difference in USUV titers between vaccinated and mock-vaccinated mice. However, in the Ifnar1−/− model, vaccinated mice had significantly higher survival rates and significantly lower USUV viremia compared to mock-vaccinated mice. Our results indicate that exposure to an attenuated form of WNV protects against severe USUV disease in mice and elicits a neutralizing response to both WNV and USUV. Future studies will investigate the immune mechanisms responsible for the protection against USUV infection induced by WNV vaccination, providing critical insight that will be essential for USUV and WNV vaccine development.
Highlights
West Nile virus (WNV) and Usutu virus (USUV) are emerging zoonotic arboviruses in the Japanese encephalitis virus (JEV) serocomplex of the Flaviviridae family
We found that WNV vaccination induced a cross-reactive neutralizing response against USUV in mice (Tables 1 and 2); these results were seen in two mouse strains, CD-1 mice and Ifnar1−/− mice, and two recent USUV strains from Spain and Uganda
The WNV vaccine did not reduce viremia in CD-1 mice, though USUV viremia in this mouse model was much lower than viremia in the Ifnar1−/− model (Figure 2)
Summary
West Nile virus (WNV) and Usutu virus (USUV) are emerging zoonotic arboviruses in the Japanese encephalitis virus (JEV) serocomplex of the Flaviviridae family. Clinical manifestations of WNV and USUV in humans include febrile illness and neuroinvasive disease, which in severe cases can be fatal. WNV was first isolated in 1937 from a febrile patient in Uganda [2] and circulated throughout Africa [3,4,5], Asia [6,7,8], Australia [9,10], the Americas [11,12,13], and Europe [14,15,16]. After the introduction of WNV into North America in 1999, the first major epizootic event of USUV occurred in Europe in 2001, where approximately 50,000 Eurasian blackbirds (Turdus merula) died [19,20]
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