AAV-mediated delivery of a broadly neutralizing anti-flavivirus antibody protects against dengue and Zika viruses in a mouse model.

IF 12 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-09-09 DOI:10.1016/j.ymthe.2025.09.007

Hui-Ying Ko,Ya-Yuan Li,Yogy Simanjuntak,Han-Peng Yu,Ming-Tsai Chiang,Che-Yu Lee,Jian-Jong Liang,Yi-Ling Lee,Cheng-Pu Sun,Po-Sheng Wang,Pei-Yun Shu,Tsai-Ying Yen,Mi-Hua Tao,Yi-Ling Lin

{"title":"AAV-mediated delivery of a broadly neutralizing anti-flavivirus antibody protects against dengue and Zika viruses in a mouse model.","authors":"Hui-Ying Ko,Ya-Yuan Li,Yogy Simanjuntak,Han-Peng Yu,Ming-Tsai Chiang,Che-Yu Lee,Jian-Jong Liang,Yi-Ling Lee,Cheng-Pu Sun,Po-Sheng Wang,Pei-Yun Shu,Tsai-Ying Yen,Mi-Hua Tao,Yi-Ling Lin","doi":"10.1016/j.ymthe.2025.09.007","DOIUrl":null,"url":null,"abstract":"Flaviviruses contain many important human pathogens such as dengue virus (DENV) and Zika virus (ZIKV), for which effective and safe vaccines are still lacking, mainly because pre-existing cross-reactive non-neutralizing antibodies may exacerbate subsequent infections with related flaviviruses. To overcome this challenge, we explore Vectored ImmunoProphylaxis (VIP), which involves the passive transfer of protective antibody genes via viral vectors for in vivo expression. We utilized a recombinant adeno-associated virus (rAAV) to express a broad anti-flavivirus neutralizing human monoclonal antibody, bnAb 752-2C8, and tested its protection against four serotypes of DENV and ZIKV. The bnAb 752-2C8 antibody gene was cloned into an AAV plasmid and the recombinant AAV (rAAV) was successfully generated to express bnAb 752-2C8. After a single dose of rAAV administration into AGB6 mice, the human antibody concentrations increased to ∼1000 μg/mL and remained elevated for at least 48 weeks. VIP-treated mice were completely protected from a lethal challenge of DENVs and ZIKV, while control mice without bnAb 752-2C8 all succumbed to infection. Our results demonstrate the effectiveness of rAAV in delivering bnAb 752-2C8 for long-term protection against multiple flaviviruses, providing a potential strategy to control flavivirus infections and possibly other viral diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"49 1","pages":""},"PeriodicalIF":12.0000,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2025.09.007","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Flaviviruses contain many important human pathogens such as dengue virus (DENV) and Zika virus (ZIKV), for which effective and safe vaccines are still lacking, mainly because pre-existing cross-reactive non-neutralizing antibodies may exacerbate subsequent infections with related flaviviruses. To overcome this challenge, we explore Vectored ImmunoProphylaxis (VIP), which involves the passive transfer of protective antibody genes via viral vectors for in vivo expression. We utilized a recombinant adeno-associated virus (rAAV) to express a broad anti-flavivirus neutralizing human monoclonal antibody, bnAb 752-2C8, and tested its protection against four serotypes of DENV and ZIKV. The bnAb 752-2C8 antibody gene was cloned into an AAV plasmid and the recombinant AAV (rAAV) was successfully generated to express bnAb 752-2C8. After a single dose of rAAV administration into AGB6 mice, the human antibody concentrations increased to ∼1000 μg/mL and remained elevated for at least 48 weeks. VIP-treated mice were completely protected from a lethal challenge of DENVs and ZIKV, while control mice without bnAb 752-2C8 all succumbed to infection. Our results demonstrate the effectiveness of rAAV in delivering bnAb 752-2C8 for long-term protection against multiple flaviviruses, providing a potential strategy to control flavivirus infections and possibly other viral diseases.

查看原文本刊更多论文

在小鼠模型中，aav介导的广泛中和性抗黄病毒抗体的递送可预防登革热和寨卡病毒。

黄病毒含有许多重要的人类病原体，如登革热病毒（DENV）和寨卡病毒（ZIKV），目前仍缺乏有效和安全的疫苗，主要是因为预先存在的交叉反应性非中和抗体可能加剧相关黄病毒的后续感染。为了克服这一挑战，我们探索了载体免疫预防（VIP），它涉及通过病毒载体被动转移保护性抗体基因进行体内表达。我们利用重组腺相关病毒（rAAV）表达广泛的抗黄病毒中和人单克隆抗体bnAb 752-2C8，并测试了其对四种血清型DENV和ZIKV的保护作用。将bnAb 752-2C8抗体基因克隆到AAV质粒中，成功生成表达bnAb 752-2C8的重组AAV （rAAV）。在给AGB6小鼠单次注射rAAV后，人抗体浓度升高至~ 1000 μg/mL，并保持升高至少48周。vip处理的小鼠完全免受denv和ZIKV的致命攻击，而不含bnAb 752-2C8的对照组小鼠全部死于感染。我们的研究结果证明了rAAV递送bnAb 752-2C8对多种黄病毒的长期保护的有效性，为控制黄病毒感染和其他可能的病毒性疾病提供了潜在的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.