An inactivated trivalent virion-based vaccine protects against aerosol challenge with encephalitic alphaviruses in mice and macaques

IF 14.6 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-10-01 DOI:10.1126/scitranslmed.adv7079

L. K. Metthew Lam, Theron Gilliland Jr., Matthew Dunn, Maria D. Alcorn-Burckhardt, Yutaka Terada, Chengqun Sun, Shauna Vasilatos, Morgan Midgett, Connor Williams, Amanda Laughlin, Jeneveve Lundy, Christina L. Gardner, Archana Thomas, Hans-Peter Raué, Hans P. Gertje, Aoife K. O’Connell, Nicholas A. Crossland, Douglas S. Reed, Michael S. Diamond, Mark K. Slifka, William B. Klimstra

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Abstract

Venezuelan (VEEV), Eastern (EEEV), and Western (WEEV) equine encephalitis viruses are mosquito-transmitted alphaviruses in the family Togaviridae with the potential to cause fatal neuroinvasive disease in humans. These viruses can also be infectious when aerosolized and, thus, are potential biothreat agents. Human infection can progress rapidly to encephalitis, with fatality rates of 1 to 10% in symptomatic VEEV and WEEV infections and 30 to 70% in symptomatic EEEV infections. Currently, there are no antiviral agents or vaccines approved for encephalitic alphaviruses. An investigational live-attenuated VEEV vaccine was generated more than 40 years ago but is highly reactogenic, poorly immunogenic, and causes disease in up to 20% of recipients. Formalin-inactivated vaccines for EEEV and WEEV are also poorly immunogenic and no longer available. Here, we developed a trivalent vaccine against VEEV, EEEV, and WEEV using a combination of attenuated chimeric Sindbis-VEEV/EEEV/WEEV viruses to streamline production and an H₂O₂ inactivation treatment for enhanced safety and virion surface epitope preservation. The vaccines were adjuvanted with alum and tested for immunogenicity and protection in mouse and nonhuman primate models of lethal, aerosolized alphavirus infection. Two doses conferred complete protection in mice, and a similar regimen showed substantial or complete protection in nonhuman primates when administered at low and high doses, respectively. These results suggest that this inactivated vaccine is effective against the three encephalitogenic alphaviruses and may meet the need to counter the public health threat and biothreat posed by these viruses.

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一种灭活的基于三价病毒粒子的疫苗可以保护小鼠和猕猴免受脑炎甲病毒的气溶胶攻击

委内瑞拉（VEEV）、东方（EEEV）和西方（WEEV）马脑炎病毒是托加病毒科（Togaviridae）中由蚊子传播的甲病毒，有可能在人类中引起致命的神经侵袭性疾病。这些病毒在雾化时也具有传染性，因此是潜在的生物威胁剂。人类感染可迅速发展为脑炎，有症状的VEEV和WEEV感染的死亡率为1%至10%，有症状的EEEV感染的死亡率为30%至70%。目前，尚无批准用于脑炎甲病毒的抗病毒药物或疫苗。一种实验性的VEEV减毒活疫苗是在40多年前研制出来的，但它的反应性很强，免疫原性很差，导致多达20%的接种者发病。针对eev和WEEV的福尔马林灭活疫苗免疫原性也很差，不再可用。在这里，我们开发了一种针对VEEV， EEEV和WEEV的三价疫苗，使用减毒嵌合Sindbis-VEEV/EEEV/WEEV病毒的组合来简化生产，并进行h2o2灭活处理以提高安全性和病毒粒子表面表位保存。用明矾作为佐剂，在小鼠和非人类灵长类动物模型中对致命的雾化甲型病毒感染进行了免疫原性和保护试验。两种剂量对小鼠具有完全的保护作用，当分别给予低剂量和高剂量时，类似的方案在非人灵长类动物中显示出实质性或完全的保护作用。这些结果表明，该灭活疫苗对三种致脑性甲病毒有效，可以满足应对这些病毒构成的公共卫生威胁和生物威胁的需要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.