VP1 codon deoptimization and high-fidelity substitutions in 3D polymerase as potential vaccine strategies for eliciting immune responses against enterovirus A71

• Published in: Journal of virology 2024-01, Vol.98 (1), p.e0155823
• Main Authors: Hsieh, Wen-Sheng, Chao, Chiao-Hsuan, Shen, Chun-Yu, Cheng, Dayna, Huang, Sheng-Wen, Wang, Ya-Fang, Chen, Chien-Chin, Chen, Shun-Hua, Hsu, Li-Jin, Wang, Jen-Ren
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Capsid Proteins - genetics; Codon; Enterovirus A, Human - genetics; Enterovirus Infections - immunology; Immunity, Cellular; Immunity, Humoral; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; RNA-Dependent RNA Polymerase - genetics; Vaccines; Vaccines and Antiviral Agents; Vaccines, Attenuated; Viral Vaccines
• ISSN: 0022-538X; 1098-5514; 1098-5514
• DOI: 10.1128/jvi.01558-23

Enterovirus A71 (EV-A71) can induce severe neurological complications and even fatal encephalitis in children, and it has caused several large outbreaks in Taiwan since 1998. We previously generated VP1 codon-deoptimized (VP1-CD) reverse genetics (rg) EV-A71 viruses (rgEV-A71s) that harbor a high-fidelity (HF) 3D polymerase. These VP1-CD-HF rgEV-A71s showed lower replication kinetics and decreased virulence in an Institute of Cancer Research (ICR) mouse model of EV-A71 infection, while still retaining their antigenicity in comparison to the wild-type virus. In this study, we aimed to further investigate the humoral and cellular immune responses elicited by VP1-CD-HF rgEV-A71s to assess the potential efficacy of these EV-A71 vaccine candidates. Following intraperitoneal (i.p.) injection of VP1-CD-HF rgEV-A71s in mice, we observed a robust induction of EV-A71-specific neutralizing IgG antibodies in the antisera after 21 days. Splenocytes isolated from VP1-CD-HF rgEV-A71s-immunized mice exhibited enhanced proliferative activities and cytokine production (IL-2, IFN-γ, IL-4, IL-6, and TNF-α) upon re-stimulation with VP1-CD-HF rgEV-A71, as compared to control mice treated with adjuvant only. Importantly, administration of antisera from VP1-CD-HF rgEV-A71s-immunized mice protected against lethal EV-A71 challenge in neonatal mice. These findings highlight that our generated VP1-CD-HF rgEV-A71 viruses are capable of inducing both cellular and humoral immune responses, supporting their potential as next-generation EV-A71 vaccines for combating EV-A71 infection.IMPORTANCEEV-A71 can cause severe neurological diseases and cause death in young children. Here, we report the development of synthetic rgEV-A71s with the combination of codon deoptimization and high-fidelity (HF) substitutions that generate genetically stable reverse genetics (rg) viruses as potential attenuated vaccine candidates. Our work provides insight into the development of low-virulence candidate vaccines through a series of viral genetic editing for maintaining antigenicity and genome stability and suggests a strategy for the development of an innovative next-generation vaccine against EV-A71.