CD4+ T cell-mediated immunity protects from VSV-SUD lethal challenge in a mouse model of Sudan virus infection

Recurring outbreaks of filoviruses, including Ebola virus and Sudan virus, threaten to cause large epidemics. No treatment or vaccine is available for Sudan virus and how protective immunity is achieved remains unknown. To unravel mechanisms contributing to protection, we used a surrogate mouse model of Sudan virus infection amenable to deep functional analysis. Mice vaccinated with a live viral vector based on live-attenuated YF17D expressing Sudan virus glycoprotein were protected against lethal challenge with a surrogate virus, a chimeric recombinant vesicular stomatitis virus expressing Sudan virus glycoprotein, despite lacking virus-neutralizing antibodies. Glycoprotein-specific humoral responses associated with antibody-mediated neutrophil phagocytosis and natural killer cell activation suggested Fcγ receptor (FcγR) effector involvement. However, protection was not compromised in FcγR-deficient mice. By contrast, targeted depletion and reconstitution experiments identified antigen-experienced interferon-γ (IFNγ)-secreting CD4+ T cells, particularly short-lived effector cells and regulatory T cells as key players for survival. Multiple complementary vaccination-induced effector mechanisms may contribute to Sudan virus immunity; however, only proliferative antigen-specific CD4+ T cells and sustained IFNγ production, orchestrating an acute antiviral response, appear required for protection. In a mouse model that mimics Sudan virus infection, a deadly relative of Ebola virus, vaccine protection depends on virus-specific CD4 T cells that coordinate antiviral defenses, even in the absence of neutralizing antibodies.