Cold-adapted influenza vaccine carrying three repeats of a respiratory syncytial virus (RSV) fusion glycoprotein epitope site protects BALB/c mice and cotton rats against RSV infection

• Published in: Antiviral research Vol. 229; p. 105960
• Main Authors: Xu, Yongru, Sun, Fang, Chuai, Zhengran, Wang, Junyun, Bai, Zhifang, Bian, Chengrong, Wang, Xiliang, Zhao, Zhongpeng, Liu, Yongzhuang, Yang, Penghui
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2024
• Subjects: Animals; Antibodies, Neutralizing - blood; Antibodies, Neutralizing - immunology; Antibodies, Viral - blood; Antibodies, Viral - immunology; Cold Temperature; Epitopes - genetics; Epitopes - immunology; Female; Fusion glycoprotein; Humans; Influenza Vaccines - administration & dosage; Influenza Vaccines - genetics; Influenza Vaccines - immunology; Intranasal immunization; Live attenuated influenza virus; Lung - immunology; Lung - pathology; Lung - virology; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - prevention & control; Respiratory syncytial virus; Respiratory Syncytial Virus Infections - immunology; Respiratory Syncytial Virus Infections - prevention & control; Respiratory Syncytial Virus Vaccines - administration & dosage; Respiratory Syncytial Virus Vaccines - immunology; Respiratory Syncytial Virus, Human - genetics; Respiratory Syncytial Virus, Human - immunology; Respiratory Syncytial Viruses - genetics; Respiratory Syncytial Viruses - immunology; RSV vaccine; Sigmodontinae; Viral Fusion Proteins - genetics; Viral Fusion Proteins - immunology; Fusion glycoprotein; RSV vaccine; Intranasal immunization; Respiratory syncytial virus; Live attenuated influenza virus
• ISSN: 0166-3542; 1872-9096; 1872-9096
• DOI: 10.1016/j.antiviral.2024.105960

Respiratory syncytial virus is the major cause of respiratory viral infections, particularly in infants, immunocompromised populations, and the elderly (over 65 years old), the prevention of RSV infection has become a priority. In this study, we generated a chimeric influenza virus, termed LAIV/RSV/HA-3F, using reverse genetics technology which contained three repeats of the RSV fusion protein neutralizing epitope site II to the N terminal in the background of the hemagglutinin (HA) gene of cold adapted influenza vaccine A/California/7/2009 ca. LAIV/RSV/HA-3F exhibited cold-adapted (ca) and attenuated (att) phenotype. BALB/c mice immunized intranasally with LAIV/RSV/HA-3F showed robust immunogenicity, inducing viral-specific antibody responses against both influenza and RSV, eliciting RSV-specific humoral, cellular and mucosal immune responses. LAIV/RSV/HA-3F also conferred protection as indicated by reduced viral titers and improved lung histopathological alterations against live RSV virus challenge. Mechanismly, single-cell RNA sequencing (scRNA-seq) and single-cell T cell antigen receptor (TCR) sequencing were employed to characterize the immune responses triggered by chimeric RSV vaccine, displaying that LAIV/RSV/HA-3F provided protection mainly via interferon-γ (IFN-γ). Moreover, we found that LAIV/RSV/HA-3F significantly inhibited viral replication in the challenged lung and protected against subsequent RSV challenge in cotton rats without causing lung disease. Taken together, our findings demonstrated that LAIV/RSV/HA-3F has potential as a promising bivalent vaccine with dual purpose candidate for the prevention of influenza and RSV, and preclinical and clinical studies warrant further investigations. •We generated a chimeric influenza virus LAIV/RSV/HA-3F carrying three repeats of RSV F neutralizing epitope site II.•LAIV/RSV/HA-3F elicited vigorous humoral, cellular and mucosal immune responses.•LAIV/RSV/HA-3F protected BALB/c mice and cotton rats from RSV infection without causing ERD.•LAIV/RSV/HA-3F provided protection mainly depended on IFN-γ signaling pathway.