Safety and Immunogenicity of Four-Segmented Rift Valley Fever Virus in the Common Marmoset

Abstract

Rift Valley fever virus (RVFV) is an emerging mosquito-borne bunyavirus that is highly pathogenic to wild- and domesticated ruminants, camelids and humans. While animals are exclusively infected via mosquito bites, humans can also be infected via contact with tissues or blood released during the slaughtering of RVFV-infected animals. No human vaccine is available and currently commercialized veterinary vaccines do not optimally combine efficacy with safety. We previously reported the development of two novel live-attenuated RVF vaccines, created by splitting the M genome segment and deleting the major virulence determinant NSs. The vaccine candidates, referred to as the veterinary vaccine vRVFV-4s and the human vaccine hRVFV-4s, were shown to induce protective immunity in multiple species after a single vaccination. Anticipating on accidental exposure of humans to the veterinary vaccine, and to evaluate the safety of the hRVFV-4s candidate vaccine for humans, the safety of each vaccine was evaluated in the most susceptible nonhuman primate model, the common marmoset (Callithrix jacchus). Marmosets were inoculated with high doses of each vaccine and were monitored for clinical signs as well as for vaccine virus dissemination, shedding and spreading to the environment. To accurately assess the attenuation of both vaccine viruses, separate groups of marmosets were inoculated with the parent wild-type RVFV strains. Both wild-type strains induced high viremia and disseminated to primary target organs, associated with mild- to severe morbidity, while both vaccines were well tolerated with absence of dissemination and shedding, while inducing potent neutralizing antibody responses. The results of the studies support the unprecedented safety profile of both vaccines for animals and humans.

Rift Valley Fever Virus—Infection, Pathogenesis and Host Immune Responses

“…More recently, live attenuated RVFV vaccines were developed with a genome consisting of four gene segments (RVFV-4s) by splitting the Gn and Gc segments and deleting the NSs gene [138]. Two versions of the vaccine candidate were designed: a vaccine for veterinary use with RVFV strain-35/74 as backbone, and a vaccine for humans with Clone 13 as the backbone [139]. Vaccination with RVFV-4s induced VN antibodies primarily against the Gn proteins and afforded young lambs protection against challenge infection with the wild type virus [140].…”

“…A single vaccine dose was sufficient to protect lambs, goat kids and calves from virus infection [142]. Both the human and veterinary RVFV-4s vaccine candidates were tested in common marmosets and induced VN-antibody responses [139]. The RVFV-4s vaccine is highly efficacious and safe in all tested species and is a promising candidate for a veterinary and human RVF vaccine.…”