Attenuation and efficacy of live-attenuated Rift Valley fever virus vaccine candidates in non-human primates

Abstract

Rift Valley fever virus (RVFV) is an important mosquito-borne veterinary and human pathogen that has caused large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Currently, no licensed vaccine or therapeutics exists to treat this potentially deadly disease. The explosive nature of RVFV outbreaks and the severe consequences of its accidental or intentional introduction into RVFV-free areas provide the impetus for the development of novel vaccine candidates for use in both livestock and humans. Rationally designed vaccine candidates using reverse genetics have been used to develop deletion mutants of two known RVFV virulence factors, the NSs and NSm genes. These recombinant viruses were demonstrated to be protective and immunogenic in rats, mice, and sheep, without producing clinical illness in these animals. Here, we expand upon those findings and evaluate the single deletion mutant (ΔNSs rRVFV) and double deletion mutant (ΔNSs-ΔNSm rRVFV) vaccine candidates in the common marmoset (Callithrix jacchus), a non-human primate (NHP) model resembling severe human RVF disease. We demonstrate that both the ΔNSs and ΔNSs-ΔNSm rRVFV vaccine candidates were found to be safe and immunogenic in the current study. The vaccinated animals received a single dose of vaccine that led to the development of a robust antibody response. No vaccine-induced adverse reactions, signs of clinical illness or infectious virus were detected in the vaccinated marmosets. All vaccinated animals that were subsequently challenged with RVFV were protected against viremia and liver disease. In summary, our results provide the basis for further development of the ΔNSs and ΔNSs-ΔNSm rRVFV as safe and effective human RVFV vaccines for this significant public health threat.

A Look into Bunyavirales Genomes: Functions of Non-Structural (NS) Proteins

“…In respect to safety, these mutants are able to replicate efficiently but are unable to shut off host protein synthesis in vitro [ 100 ]. Additionally, live attenuated vaccines, distinct from MP-12, achieved protective efficacy with NSs deletions [ 101 , 102 , 103 , 104 ] as did antiviral treatments such as bortezomib [ 105 ] and curcumin [ 106 ] which target NSs or interfere with NSs-host protein interactions. Overall, targeting of NSs in successful vaccines and antivirals indicate the importance of this NS protein in disease virulence and the need to account for it in intervention development.…”

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

“…Considering that the NSs protein, which is only present in the parent viruses, is known to efficiently counteract early innate immune responses 8 , we hypothesize that NSs delays the induction of an innate immune response in marmosets inoculated with wild-type RVFV. It is plausible that also other liveattenuated RVFV candidate vaccines lacking NSs induce a short-lived pyrexia, however, such responses may not have been noted in earlier studies as body temperatures were not measured continuously 28 , as was done in the present study. Overall, the dose-dependent pyrexia could be considered a mild side effect of the vaccines but also suggests that the vaccines induce potent innate immune responses, likely supporting subsequent adaptive responses.…”

p38γ Activation and BGP (Biliary Glycoprotein) Induction in Primates at Risk for Inflammatory Bowel Disease and Colorectal Cancer—A Comparative Study with Humans

“…Our future aim is to better define the role of p38 and BGP, a family member of CEA, in colon-induced liver metastasis. Both the CTT and more recently the CM have been used as models for vaccination research, superior to the older macaque model [ 57 , 58 ]. By focusing on elements of the MAPK and an innate-immune system effector cell product we believe that we have provided a novel perspective that combines these elements that could be integrated into the newly advocated holistic approach to vaccine development [ 59 ].…”