Heterologous mRNA/MVA delivering trimeric-RBD as effective vaccination regimen against SARS-CoV-2: COVARNA Consortium.

IF 8.4 2区 医学 Q1 IMMUNOLOGY Emerging Microbes & Infections Pub Date : 2024-12-01 Epub Date: 2024-08-08 DOI:10.1080/22221751.2024.2387906
Laura Marcos-Villar, Beatriz Perdiguero, María López-Bravo, Carmen Zamora, Laura Sin, Enrique Álvarez, Carlos Óscar S Sorzano, Pedro J Sánchez-Cordón, José M Casasnovas, David Astorgano, Juan García-Arriaza, Shubaash Anthiya, Mireya L Borrajo, Gustavo Lou, Belén Cuesta, Lorenzo Franceschini, Josep L Gelpí, Kris Thielemans, Marta Sisteré-Oró, Andreas Meyerhans, Felipe García, Ignasi Esteban, Núria López-Bigas, Montserrat Plana, María J Alonso, Mariano Esteban, Carmen Elena Gómez
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Abstract

Despite the high efficiency of current SARS-CoV-2 mRNA vaccines in reducing COVID-19 morbidity and mortality, waning immunity and the emergence of resistant variants underscore the need for novel vaccination strategies. This study explores a heterologous mRNA/Modified Vaccinia virus Ankara (MVA) prime/boost regimen employing a trimeric form of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein compared to a homologous MVA/MVA regimen. In C57BL/6 mice, the RBD was delivered during priming via an mRNA vector encapsulated in nanoemulsions (NE) or lipid nanoparticles (LNP), followed by a booster with a replication-deficient MVA-based recombinant virus (MVA-RBD). This heterologous mRNA/MVA regimen elicited strong anti-RBD binding and neutralizing antibodies (BAbs and NAbs) against both the ancestral SARS-CoV-2 strain and different variants of concern (VoCs). Additionally, this protocol induced robust and polyfunctional RBD-specific CD4 and CD8 T cell responses, particularly in animals primed with mLNP-RBD. In K18-hACE2 transgenic mice, the LNP-RBD/MVA combination provided complete protection from morbidity and mortality following a live SARS-CoV-2 challenge compared with the partial protection observed with mNE-RBD/MVA or MVA/MVA regimens. Although the mNE-RBD/MVA regimen only protects half of the animals, it was able to induce antibodies with Fc-mediated effector functions besides NAbs. Moreover, viral replication and viral load in the respiratory tract were markedly reduced and decreased pro-inflammatory cytokine levels were observed. These results support the efficacy of heterologous mRNA/MVA vaccine combinations over homologous MVA/MVA regimen, using alternative nanocarriers that circumvent intellectual property restrictions of current mRNA vaccine formulations.

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异源 mRNA/MVA 提供三聚体-RBD 作为预防 SARS-CoV-2 的有效疫苗方案:COVARNA 联盟。
尽管目前的 SARS-CoV-2 mRNA 疫苗在降低 COVID-19 发病率和死亡率方面具有很高的效率,但免疫力的下降和抗药性变种的出现凸显了新型疫苗接种策略的必要性。本研究探讨了一种异源 mRNA/改良安卡拉疫苗(MVA)的原体/增强方案,该方案采用了 SARS-CoV-2 棘波(S)蛋白受体结合域(RBD)的三聚体形式,并与同源 MVA/MVA 方案进行了比较。在 C57BL/6 小鼠中,RBD 通过封装在纳米乳剂(NE)或脂质纳米颗粒(LNP)中的 mRNA 载体在启动过程中递送,然后用复制缺陷的 MVA 重组病毒(MVA-RBD)进行强化。这种异源 mRNA/MVA 方案可针对 SARS-CoV-2 祖毒株和不同的相关变异株(VoCs)激发强效的抗 RBD 结合抗体和中和抗体(BAbs 和 NAbs)。此外,该方案还能诱导强大的多功能 RBD 特异性 CD4 和 CD8 T 细胞反应,尤其是在使用 mLNP-RBD 的动物中。在 K18-hACE2 转基因小鼠中,与 mNE-RBD/MVA 或 MVA/MVA 方案观察到的部分保护相比,LNP-RBD/MVA 组合可在活体 SARS-CoV-2 挑战后提供完全的发病和死亡保护。虽然 mNE-RBD/MVA 方案只能保护一半的动物,但它除了能诱导 NAbs 外,还能诱导具有 Fc 媒介效应功能的抗体。此外,呼吸道中的病毒复制和病毒载量明显减少,促炎细胞因子水平也有所下降。这些结果表明,异源 mRNA/MVA 疫苗组合比同源 MVA/MVA 方案更有效,其使用的替代纳米载体规避了当前 mRNA 疫苗配方的知识产权限制:试验注册:ClinicalTrials.gov identifier:NCT05226390.
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
Emerging Microbes & Infections
Emerging Microbes & Infections IMMUNOLOGY-MICROBIOLOGY
CiteScore
26.20
自引率
2.30%
发文量
276
审稿时长
20 weeks
期刊介绍: Emerging Microbes & Infections is a peer-reviewed, open-access journal dedicated to publishing research at the intersection of emerging immunology and microbiology viruses. The journal's mission is to share information on microbes and infections, particularly those gaining significance in both biological and clinical realms due to increased pathogenic frequency. Emerging Microbes & Infections is committed to bridging the scientific gap between developed and developing countries. This journal addresses topics of critical biological and clinical importance, including but not limited to: - Epidemic surveillance - Clinical manifestations - Diagnosis and management - Cellular and molecular pathogenesis - Innate and acquired immune responses between emerging microbes and their hosts - Drug discovery - Vaccine development research Emerging Microbes & Infections invites submissions of original research articles, review articles, letters, and commentaries, fostering a platform for the dissemination of impactful research in the field.
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