A vaccine inducing solely cytotoxic T lymphocytes fully prevents Zika virus infection and fetal damage

• Published in: Cell reports (Cambridge) Vol. 35; no. 6; p. 109107
• Main Authors: Gambino, Frank, Tai, Wanbo, Voronin, Denis, Zhang, Yi, Zhang, Xiujuan, Shi, Juan, Wang, Xinyi, Wang, Ning, Du, Lanying, Qiao, Liang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.05.2021
• Subjects: Animals; antibody-dependent enhancement; cytotoxic T lymphocytes; DNA vaccine; Female; fetal damage; Fetus - virology; Mice; T-Lymphocytes, Cytotoxic - virology; Transfection; Viral Vaccines - pharmacology; Viral Vaccines - therapeutic use; Zika virus; Zika Virus Infection - virology; DNA vaccine; Zika virus; fetal damage; cytotoxic T lymphocytes; antibody-dependent enhancement
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109107

As vaccine-induced non-neutralizing antibodies may cause antibody-dependent enhancement of Zika virus (ZIKV) infection, we test a vaccine that induces only specific cytotoxic T lymphocytes (CTLs) without specific antibodies. We construct a DNA vaccine expressing a ubiquitinated and rearranged ZIKV non-structural protein 3 (NS3). The protein is immediately degraded and processed in the proteasome for presentation via major histocompatibility complex (MHC) class I for CTL generation. We immunize Ifnar1−/− adult mice with the ubiquitin/NS3 vaccine, impregnate them, and challenge them with ZIKV. Our data show that the vaccine greatly reduces viral titers in reproductive organs and other tissues of adult mice. All mice immunized with the vaccine survived after ZIKV challenge. The vaccine remarkably reduces placenta damage and levels of pro-inflammatory cytokines, and it fully protects fetuses from damage. CD8+ CTLs are essential in protection, as demonstrated via depletion experiments. Our study provides a strategy to develop safe and effective vaccines against viral infections. [Display omitted] •Vaccine of modified ZIKV NS3 induces specific CTLs with little antibody response•The vaccine fully protects adult mice against ZIKV and greatly reduces viral titers•The vaccine protects fetuses against ZIKV challenge and reduces placental damage•Depletion of CD8+ T cells abrogates vaccine protection in animal models Non-neutralizing antibodies have been shown to enhance viral infection in flaviviruses. Gambino et al. sought a vaccine strategy that protects against ZIKV without inducing antibodies. They demonstrate that a ZIKV vaccine inducing solely NS3-specific CTLs provides full protection against ZIKV challenge and protects against fetal damage in pregnant mice.