Single-chain A35R-M1R-B6R trivalent mRNA vaccines protect mice against both mpox virus and vaccinia virus.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-11-01 Epub Date: 2024-10-18 DOI:10.1016/j.ebiom.2024.105392

Tianxiang Kong, Pei Du, Renyi Ma, Han Wang, Xuehui Ma, Jian Lu, Zhengrong Gao, Hai Qi, Ruiqi Li, Hao Zhang, Fei Xia, Yuanlang Liu, Ruyu Wang, Kai Duan, Zejun Wang, Qihui Wang, George F Gao

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Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Funding: National Natural Science Foundation of China and Youth Innovation Promotion Association of the CAS.

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单链 A35R-M1R-B6R 三价 mRNA 疫苗可保护小鼠免受 mpox 病毒和疫苗病毒的侵害。

背景：麻腮风已蔓延到世界许多国家。虽然现有的麻痘减毒活疫苗很有效，但 21 世纪技术的进步使我们能够开发出抗原更特异、机制更清晰、副作用更可控的疫苗：我们系统地评估了 mpox 病毒 (MPXV) 的 A35R、M1R 和 B6R 抗原的免疫原性和保护效力。根据这些研究结果，我们设计了三种单链三价 mRNA 疫苗（AMAB-wt、AMAB-C140S 和 AMB-C140S），方法是根据这些抗原的蛋白质结构将其可溶性区域整合到单个 mRNA 编码的多肽中。然后，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：结果：三种单链疫苗都能激发中和抗体，有效中和 VACV 和 MPXV。单链疫苗或含有编码可溶性抗原的 mRNA 的鸡尾酒疫苗（sA35R + sM1R + sB6R）对致命剂量的 VACV 挑战具有 100% 或 80% 的保护作用，而全长抗原鸡尾酒疫苗（A35 + M1 + B6）和 VACV 天坛减毒活疫苗（VACV-VTT）则完全不能保护小鼠。此外，单链疫苗显著降低了MPXV感染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越的免疫原性和保护效力。重要的是，单链疫苗的简易性增强了麻痘疫苗的可控性和可及性。我们相信这些单链疫苗可作为下一代麻痘疫苗：国家自然科学基金和中国科学院青年创新促进会。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.