脂质体递送的活减毒 CHIKV 疫苗 RNA 基因组加强免疫方案可预防小鼠感染基孔肯雅病毒病。

A booster regime of liposome-delivered live-attenuated CHIKV vaccine RNA genome protects against chikungunya virus disease in mice.

机构信息

The Emerging Viruses, Inflammation and Therapeutics Group, Menzies Health Institute Queensland, Griffith University, Gold Coast, Southport, QLD 4215, Australia; School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Southport, 4215 Queensland, Australia; Global Virus Network (GVN) Centre for Excellence in Arboviruses, Australia.

Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, 4222 Queensland, Australia.

出版信息

Vaccine. 2023 Jun 19;41(27):3976-3988. doi: 10.1016/j.vaccine.2023.05.032. Epub 2023 May 23.

DOI:10.1016/j.vaccine.2023.05.032

PMID:37230889

Abstract

Mosquito-transmitted chikungunya virus (CHIKV) is the causal pathogen of CHIKV disease and is responsible for global epidemics of arthritic disease. CHIKV infection can lead to severe chronic and debilitating arthralgia, significantly impacting patient mobility and quality of life. Our previous studies have shown a live-attenuated CHIKV vaccine candidate, CHIKV-NoLS, to be effective in protecting against CHIKV disease in mice vaccinated with one dose. Further studies have demonstrated the value of a liposome RNA delivery system to deliver the RNA genome of CHIKV-NoLS directly in vivo, promoting de novo production of live-attenuated vaccine particles in vaccinated hosts. This system, designed to bypass live-attenuated vaccine production bottlenecks, uses CAF01 liposomes. However, one dose of CHIKV-NoLS CAF01 failed to provide systemic protection against CHIKV challenge in mice, with low levels of CHIKV-specific antibodies. Here we describe CHIKV-NoLS CAF01 booster vaccination regimes designed to increase vaccine efficacy. C57BL/6 mice were vaccinated with three doses of CHIKV-NoLS CAF01 either intramuscularly or subcutaneously. CHIKV-NoLS CAF01 vaccinated mice developed a systemic immune response against CHIKV that shared similarity to vaccination with CHIKV-NoLS, including high levels of CHIKV-specific neutralising antibodies in subcutaneously inoculated mice. CHIKV-NoLS CAF01 vaccinated mice were protected against disease signs and musculoskeletal inflammation when challenged with CHIKV. Mice given one dose of live-attenuated CHIKV-NoLS developed a long lasting protective immune response for up to 71 days. A clinically relevant CHIKV-NoLS CAF01 booster regime can overcome the challenges faced by our previous one dose strategy and provide systemic protection against CHIKV disease.

摘要

基孔肯雅病毒（CHIKV）通过蚊子传播，是基孔肯雅热的病原体，可引发全球范围的关节炎疾病流行。CHIKV 感染可导致严重的慢性和衰弱性关节炎，显著影响患者的活动能力和生活质量。我们之前的研究表明，一种减毒活的 CHIKV 疫苗候选物 CHIKV-NoLS，在单次接种的小鼠中对 CHIKV 疾病具有保护作用。进一步的研究表明，脂质体 RNA 递药系统在体内直接递呈 CHIKV-NoLS 的 RNA 基因组具有重要价值，可促进接种宿主中减毒活疫苗颗粒的从头产生。该系统旨在绕过减毒活疫苗生产瓶颈，使用 CAF01 脂质体。然而，单次接种 CHIKV-NoLS CAF01 并不能为小鼠提供针对 CHIKV 挑战的全身保护，CHIKV 特异性抗体水平较低。在此，我们描述了旨在提高疫苗效力的 CHIKV-NoLS CAF01 加强免疫方案。C57BL/6 小鼠通过肌肉或皮下途径接种三剂 CHIKV-NoLS CAF01。CHIKV-NoLS CAF01 接种的小鼠对 CHIKV 产生了全身性免疫反应，与 CHIKV-NoLS 接种具有相似性，包括皮下接种的小鼠中高水平的 CHIKV 特异性中和抗体。CHIKV-NoLS CAF01 接种的小鼠在受到 CHIKV 攻击时免受疾病症状和肌肉骨骼炎症的影响。单次接种减毒活的 CHIKV-NoLS 的小鼠产生了长达 71 天的持久保护免疫反应。一种具有临床相关性的 CHIKV-NoLS CAF01 加强免疫方案可以克服我们之前的单剂策略所面临的挑战，为 CHIKV 疾病提供全身保护。