Highly scalable prefusion-stabilized RSV F vaccine with enhanced immunogenicity and robust protection

Qingrui Huang (), Qingyun Lang, Yao Li, Fengjie Wang, Xiaonan Han, Ling Luo, Xiaomin Duan, Xuerong Cao, Yue Wang, Yu Bai, Yaxin Song, Yanpeng Xu, Lianlian Bian, Chenyan Gao, Linqing Zhao () and Jinghua Yan ()
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Qingrui Huang: Changping Laboratory
Qingyun Lang: Changping Laboratory
Yao Li: Changping Laboratory
Fengjie Wang: Capital Institute of Pediatrics
Xiaonan Han: Chinese Academy of Sciences
Ling Luo: Changping Laboratory
Xiaomin Duan: Changping Laboratory
Xuerong Cao: Changping Laboratory
Yue Wang: Chinese Academy of Sciences
Yu Bai: Changping Laboratory
Yaxin Song: Changping Laboratory
Yanpeng Xu: Capital Institute of Pediatrics
Lianlian Bian: Changping Laboratory
Chenyan Gao: Changping Laboratory
Linqing Zhao: Capital Institute of Pediatrics
Jinghua Yan: Changping Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Stabilizing the RSV F protein in its prefusion conformation is crucial for effective vaccine development but has remained a significant challenge. Traditional stabilization methods, such as disulfide bonds and cavity-filling mutations, have been labor-intensive and have often resulted in suboptimal expression levels. Here, we report the design of an RSV prefusion F (preF) antigen using a proline-scanning strategy, incorporating seven proline substitutions to achieve stabilization. The resulting variant, preF7P, is structurally and biochemically validated to maintain the correct prefusion state. PreF7P demonstrates superior immunogenicity with a 1.8-fold increase in neutralizing antibody titers when compared to DS-cav2, and provides protection from clinical disease against both RSV A and B strains in female murine and female cotton rat models. In clinical development, preF7P exhibits high expression levels (~10 g/L) in clinical-grade CHO cells. The clinical-grade vaccine elicits robust immunogenic responses across female mice, female SD rats, and both male and female cynomolgus macaques, significantly boosting RSV pre-infection neutralizing antibody titers, and providing sustained protection for at least six months in female mice. This proline-scanning strategy offers a streamlined approach for stabilizing class I fusion proteins, potentially accelerating the development of vaccines for other pathogens.

Date: 2025
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DOI: 10.1038/s41467-025-63084-z

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