This work explores immunity induced by the yellow fever vaccine, 17D, efficacy. First, we provide a comprehensive review of breakthrough yellow fever infection. Next, we use a unique panel of antigenically diverse wild-type YFVs and a cohort of non-endemic vaccinees with diverse orthoflavivirus immune profiles >11 years post-vaccination to reveal new insights into the potency of breadth of YFV vaccine (17D)-mediated neutralizing antibodies. The findings described here have implications for future vaccine strategies against a disease of public health concern.