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

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.

裂谷热病毒（Rift Valley fever virus, RVFV）是一类重要的虫媒传播人畜共患病原，曾在非洲及阿拉伯半岛引发多起重症疾病大规模暴发。目前尚无获批疫苗或治疗药物可用于防控这一具有致命潜力的疾病。RVFV暴发的迅猛特性，以及其意外或故意传入无RVFV流行区域后可能造成的严重后果，推动了针对家畜与人类的新型候选疫苗研发。
研究人员借助反向遗传学技术理性设计候选疫苗，构建了两种已知RVFV毒力因子——NSs与NSm基因的缺失突变株。此前已有研究证实，这些重组病毒在大鼠、小鼠及绵羊体内可诱发保护性免疫应答，且不会使受试动物出现临床病症。
本研究在此前成果的基础上，以模拟人类重症RVF发病过程的非人灵长类（non-human primate, NHP）模型——普通狨猴（Callithrix jacchus）为受试对象，评估单缺失突变株（ΔNSs rRVFV）与双缺失突变株（ΔNSs-ΔNSm rRVFV）候选疫苗的效果。
本次研究结果显示，ΔNSs与ΔNSs-ΔNSm rRVFV两种候选疫苗均具备安全性与免疫原性。受试动物仅需接种一剂疫苗即可诱发强烈的抗体应答，且未观察到疫苗相关不良反应、临床病症迹象或感染性病毒检出。所有后续接受RVFV攻毒的免疫动物，均获得了针对病毒血症与肝脏疾病的保护。
综上，本研究结果为将ΔNSs与ΔNSs-ΔNSm rRVFV开发为针对这一重大公共卫生威胁的安全、高效人用RVFV疫苗奠定了基础。