To test which effector function enhanced the activity of E16, we performed studies with 8-week-old C1qa, C4, or Fcgr1 and Fcgr3-deficient C57BL/6 mice (Fig. 5) . These mice all show increased susceptibility to lethal WNV infection compared to wild-type controls. In C1qa or C4-deficient mice, which cannot activate complement by the antibody-dependent classical pathway, E16 had a similar potency compared to wild-type mice. In contrast, in Fcgr1-and Fcgr3-deficient mice, although high doses afforded complete protection, lower doses resulted in higher mortality rates. A dose of 20 µg at day 2, which strongly protected wild-type, C1qa or C4-deficient mice, did not improve the survival rate of Fcgr1-and Fcgr3-deficient mice (P = 0.4). Thus, the Fc region enhances the potency of E16 in mice, by virtue of its ability to bind to Fc γ receptors.