Cross-protection against St. Louis encephalitis virus and Usutu virus by West Nile virus convalescent plasma.

West Nile virus (WNV), Usutu virus (USUV), and Saint Louis encephalitis virus (SLEV) are emerging mosquito-borne flaviviruses within the Japanese encephalitis virus serocomplex. They share a similar transmission cycle between passerine birds and Culex spp. mosquitoes, and their spillover can cause neuroinvasive diseases among humans and animals. Individuals might be exposed to more than one of these viruses during their lifetime. Previously, we found that WNV vaccination protected mice from USUV disease, and sera collected from the WNV vaccinated mice cross-neutralized USUV in vitro. However, whether WNV convalescent (post-recovery) plasma cross-protects against heterologous SLEV or USUV infection is unknown. In this study, in vivo experiments were conducted to assess whether WNV human convalescent plasma and/or mouse convalescent serum afforded protection to mice against SLEV and USUV infection and neuroinvasion. First, we found that human and mouse WNV convalescent samples cross-neutralized USUV and SLEV in vitro. We then passively transferred human or mouse WNV convalescent samples into mice and challenged them with WNV, USUV, or SLEV. Both human and mouse WNV convalescent samples reduced WNV neuroinvasion and SLEV and USUV viremia during acute infection. Mouse WNV convalescent serum significantly reduced SLEV titers in the brain and showed a trend towards resulting in less inflammation in the brain. These findings helped to better understand the potential cross-protection among WNV, SLEV, and USUV, and identified cross-neutralizing antibodies as potential correlates of protection for individuals exposed to multiple flaviviruses, though protection was incomplete.