School of Medicine, Tsinghua University, Beijing, 100190, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
EBioMedicine. 2024 Nov;109:105392. doi: 10.1016/j.ebiom.2024.105392. Epub 2024 Oct 18.
Mpox has spread to many countries around the world. While the existing live attenuated mpox vaccines are effective, advances in 21st century technologies now enable the development of vaccines with more specific antigens, clearer mechanisms, and more controllable side effects.
We systematically evaluated the immunogenicity and protective efficacy of the A35R, M1R and B6R antigens of the mpox virus (MPXV). With these findings, we designed three single-chain trivalent mRNA vaccines (AMAB-wt, AMAB-C140S and AMB-C140S) by integrating the soluble regions of these antigens into single mRNA-encoded polypeptides based on their protein structures. Then, the immunogenicity and protective efficacy of these single-chain mRNA vaccines were evaluated in mice models against both VACV and MPXV.
The three single-chain vaccines elicited neutralising antibodies that effectively neutralised both VACV and MPXV. The single-chain vaccines or cocktail vaccine containing mRNAs encoding soluble antigen (sA35R + sM1R + sB6R) exhibited 100% or 80% protection against a lethal dose of VACV challenge, while the cocktail of full-length antigens (A35 + M1 + B6) and the live attenuated vaccine, VACV Tian Tan (VACV-VTT), completely failed to protect mice. Moreover, the single-chain vaccines significantly reduced viral load in the lungs and ovaries of MPXV-challenged mice.
Compared with the cocktail vaccines, our single-chain designs demonstrated similar or superior immunogenicity and protective efficacy. Importantly, the simplicity of the single-chain vaccines enhances both the controllability and accessibility of mpox vaccines. We believe these single-chain vaccines qualify as the next-generation mpox vaccines.
National Natural Science Foundation of China and Youth Innovation Promotion Association of the CAS.
猴痘已在全球许多国家传播。虽然现有的减毒活猴痘疫苗有效，但 21 世纪技术的进步现在使具有更特异抗原、更清晰机制和更可控副作用的疫苗的开发成为可能。
我们系统地评估了猴痘病毒（MPXV）的 A35R、M1R 和 B6R 抗原的免疫原性和保护效力。根据这些发现，我们基于这些抗原的蛋白质结构，将这些抗原的可溶性区域整合到单个 mRNA 编码的多肽中，设计了三种单链三价 mRNA 疫苗（AMAB-wt、AMAB-C140S 和 AMB-C140S）。然后，我们在小鼠模型中评估了这些单链 mRNA 疫苗对 VACV 和 MPXV 的免疫原性和保护效力。
这三种单链疫苗均能诱导产生中和抗体，能有效中和 VACV 和 MPXV。单链疫苗或含有编码可溶性抗原（sA35R+sM1R+sB6R）的 mRNA 的鸡尾酒疫苗对 VACV 致死剂量的攻击具有 100%或 80%的保护作用，而全长抗原（A35+M1+B6）的鸡尾酒疫苗和减毒活疫苗 VACV Tian Tan（VACV-VTT）完全未能保护小鼠。此外，单链疫苗显著降低了 MPXV 攻击小鼠肺部和卵巢中的病毒载量。
与鸡尾酒疫苗相比，我们的单链设计显示出相似或更优的免疫原性和保护效力。重要的是，单链疫苗的简单性增强了猴痘疫苗的可控性和可及性。我们认为这些单链疫苗是下一代猴痘疫苗。
国家自然科学基金委员会和中国科学院青年创新促进会。
