A safe and effective mucosal RSV vaccine in mice consisting of RSV phosphoprotein and flagellin variant

• Published in: Cell reports (Cambridge) Vol. 36; no. 3; p. 109401
• Main Authors: Zhao, Bali, Yang, Jingyi, He, Bing, Li, Xian, Yan, Hu, Liu, Shuning, Yang, Yi, Zhou, Dihan, Liu, Bowen, Fan, Xuxu, Zhong, Maohua, Zhang, Ejuan, Zhang, Fan, Zhang, Yue, Chen, Yao-Qing, Jiang, Shibo, Yan, Huimin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-07-2021
• Subjects: Animals; Antibodies, Viral - immunology; CD4+ T cells; CD4-Positive T-Lymphocytes - immunology; Cell Line; Clone Cells; Cytotoxicity, Immunologic - genetics; Female; Flagellin - genetics; Humans; Immunity; Immunity, Mucosal - immunology; Immunization; Interferon-gamma - metabolism; Interleukin-17 - metabolism; Lung Diseases - pathology; Lung Diseases - virology; Lymphocyte Activation - immunology; Mice; Mice, Inbred BALB C; Mutation - genetics; P-KFD1; Phosphoproteins - metabolism; Phosphorylation; Recombinant Proteins - immunology; Respiratory Syncytial Virus Vaccines - adverse effects; Respiratory Syncytial Virus Vaccines - immunology; Respiratory Syncytial Virus, Human - immunology; RSV vaccine; scRNA-seq; Single-Cell Analysis; Th1 Cells - immunology; Th17; Th17 Cells - immunology; VED; RSV vaccine; scRNA-seq; VED; P-KFD1; Th17; CD4+ T cells; CD4(+) T cells
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109401

Respiratory syncytial virus (RSV) is a major cause of serious acute lower respiratory tract infection in infants and the elderly. The lack of a licensed RSV vaccine calls for the development of vaccines with other targets and vaccination strategies. Here, we construct a recombinant protein, designated P-KFD1, comprising RSV phosphoprotein (P) and the E.-coli-K12-strain-derived flagellin variant KFD1. Intranasal immunization with P-KFD1 inhibits RSV replication in the upper and lower respiratory tract and protects mice against lung disease without vaccine-enhanced disease (VED). The P-specific CD4+ T cells provoked by P-KFD1 intranasal (i.n.) immunization either reside in or migrate to the respiratory tract and mediate protection against RSV infection. Single-cell RNA sequencing (scRNA-seq) and carboxyfluorescein succinimidyl ester (CFSE)-labeled cell transfer further characterize the Th1 and Th17 responses induced by P-KFD1. Finally, we find that anti-viral protection depends on either interferon-γ (IFN-γ) or interleukin-17A (IL-17A). Collectively, P-KFD1 is a promising safe and effective mucosal vaccine candidate for the prevention of RSV infection.
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•An immunogen, P-KFD1, is generated by fusion of RSV P protein and a flagellin variant•Intranasal immunization of P-KFD1 protects mice from RSV infection and averts VED•Protective CD4+ T cells are identified by scRNA-seq and cell transfer•Local and peripheral CD4+ T cells provide protection via either IFN-γ or IL-17A
Zhao et al. develop a vaccine immunogen, P-KFD1, generated by fusion of RSV phosphoprotein and a truncated flagellin. Intranasal immunization with P-KFD1 avoids vaccine-enhanced disease and protects mice against RSV infection by local and peripheral Th1/Th17 responses. P-KFD1 is a promising mucosal vaccine candidate for the prevention of RSV infection.