2024-04-15 カリフォルニア大学リバーサイド校(UCR)
<関連情報>
- https://news.ucr.edu/articles/2024/04/15/vaccine-breakthrough-means-no-more-chasing-strains
- https://www.pnas.org/doi/10.1073/pnas.2321170121
RNAi抑制に欠陥のある弱毒化ウイルス生ワクチンは、成熟B細胞およびT細胞を欠く新生児および成体マウスにおいて迅速な防御を誘導する Live-attenuated virus vaccine defective in RNAi suppression induces rapid protection in neonatal and adult mice lacking mature B and T cells
Gang Chen, Qingxia Han, Wan-Xiang Li, +1, and Shou-Wei Ding
Proceedings of the National Academy of Sciences Published:April 17, 2024
DOI:https://doi.org/10.1073/pnas.2321170121
Significance
Current antiviral vaccines take weeks to elicit protein-based protection via adaptive immunity. Here, we characterized a unique live-attenuated RNA virus vaccine, where attenuation resulted from the elimination of the viral RNAi suppressor and enhanced the production of virus-targeting small-interfering RNAs. We showed that single-dose immunization with the vaccine just 2 d in advance induced full protection in neonatal and adult mutant mice lacking adaptive immunity. Moreover, the immunized mutant mice remained protected against lethal challenge for at least 90 d postvaccination. Human enterovirus-A71, influenza A, and dengue viruses all encode a similar RNAi suppressor, suggesting potential for developing a distinct type of virus vaccine to confer rapid and effective protection in infants and other immune-compromised individuals.
Abstract
Global control of infectious diseases depends on the continuous development and deployment of diverse vaccination strategies. Currently available live-attenuated and killed virus vaccines typically take a week or longer to activate specific protection by the adaptive immunity. The mosquito-transmitted Nodamura virus (NoV) is attenuated in mice by mutations that prevent expression of the B2 viral suppressor of RNA interference (VSR) and consequently, drastically enhance in vivo production of the virus-targeting small-interfering RNAs. We reported recently that 2 d after immunization with live-attenuated VSR-disabled NoV (NoVΔB2), neonatal mice become fully protected against lethal NoV challenge and develop no detectable infection. Using Rag1-/- mice that produce no mature B and T lymphocytes as a model, here we examined the hypothesis that adaptive immunity is dispensable for the RNAi-based protective immunity activated by NoVΔB2 immunization. We show that immunization of both neonatal and adult Rag1-/- mice with live but not killed NoVΔB2 induces full protection against NoV challenge at 2 or 14 d postimmunization. Moreover, NoVΔB2-induced protective antiviral immunity is virus-specific and remains effective in adult Rag1-/- mice 42 and 90 d after a single-shot immunization. We conclude that immunization with the live-attenuated VSR-disabled RNA virus vaccine activates rapid and long-lasting protective immunity against lethal challenges by a distinct mechanism independent of the adaptive immunity mediated by B and T cells. Future studies are warranted to determine whether additional animal and human viruses attenuated by VSR inactivation induce similar protective immunity in healthy and adaptive immunity-compromised individuals.
