The increased demand for yellow fever (YF) vaccines over the last decade, along with insufficient avail-ability of specific pathogen-free embryonated eggs required for timely vaccine production, has led to glo-bal YF vaccine shortages. A new live-attenuated YF vaccine candidate (generically referred to as vYF) cloned from a YF-VAX (R) vaccine (YF-17D vaccine) substrain adapted for growth in Vero cells cultured in serum-free media is currently in development. Here, we assessed the safety and immunogenicity of vYF, and its protective activity upon virulent challenge with wild-type yellow fever virus (YFV) Asibi, compared to licensed YF-17D vaccines in the translational cynomolgus macaque model. vYF was well tol-erated with no major safety concerns. Vaccine-related safety observations were limited to minimal/minor microscopic findings at the injection sites and in the draining lymph nodes, consistent with expected stimulation of the immune system. vYF induced early differential expression of genes involved in antivi-ral innate immunity previously described in humans vaccinated with YF-17D vaccines, as well as YFV-specific IgM and IgG antibodies, high and sustained YFV neutralizing antibody titers from Day 14 up to at least Day 258 post-immunization, IgM+ and IgG+ memory B cells from Day 14 up to at least Day 221 post-vaccination, and Th1 interferon (IFN)-c and interleukin (IL)-2 secreting effector and memory T cells. Additionally, vYF provided effective resistance to virulent challenge with wild-type YFV Asibi including complete protection against YFV-induced mortality, pathology, dysregulation of blood and liver soluble biomarkers, and a significant reduction in viremia and viral load to the limit of detection. These NHP data suggest that vYF would provide protection against YFV infection in practice, at least similar to that achieved with currently marketed YF-17D vaccines.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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