New platforms are needed for the design of novel prophylactic
vaccines and advanced immune
therapies. Live-attenuated
yellow fever vaccine YF17D serves as a vector for several licensed
vaccines and platform for novel candidates. On the basis of YF17D, we developed an exceptionally potent
COVID-19 vaccine candidate called YF-S0. However, use of such live RNA viruses raises safety concerns, such as adverse events linked to original YF17D (
yellow fever vaccine-associated neurotropic disease [YEL-AND] and
yellow fever vaccine-associated viscerotropic disease [YEL-AVD]). In this study, we investigated the biodistribution and shedding of YF-S0 in hamsters. Likewise, we introduced hamsters deficient in
signal transducer and activator of transcription 2 (STAT2) signaling as a new preclinical model of YEL-AND/AVD. Compared with YF17D, YF-S0 showed improved safety with limited dissemination to brain and visceral tissues, absent or low
viremia, and no shedding of infectious virus. Considering that yellow fever virus is transmitted by Aedes mosquitoes, any inadvertent exposure to the live recombinant vector via mosquito
bites is to be excluded. The transmission risk of YF-S0 was hence compared with readily transmitting YF-Asibi strain and non-transmitting YF17D
vaccine, with no evidence for productive
infection of mosquitoes. The overall favorable safety profile of YF-S0 is expected to translate to other
vaccines based on the same YF17D platform.