Gómez-Carballa Alberto, Albericio Guillermo, Montoto-Louzao Julián, Pérez Patricia, Astorgano David, Rivero-Calle Irene, Martinón-Torres Federico, Esteban Mariano, Salas Antonio, García-Arriaza Juan
Genetics, Vaccines and Infectious Diseases Research Group (Genvip), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain; Unidade de Xenética, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Hospital Clínico Universitario de Santiago de Compostela (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Galicia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología (CNB), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
Antiviral Res. 2023 Dec;220:105760. doi: 10.1016/j.antiviral.2023.105760. Epub 2023 Nov 21.
Unravelling the molecular mechanism of COVID-19 vaccines through transcriptomic pathways involved in the host response to SARS-CoV-2 infection is key to understand how vaccines work, and for the development of optimized COVID-19 vaccines that can prevent the emergence of SARS-CoV-2 variants of concern (VoCs) and future outbreaks. In this study, we investigated the effects of vaccination with a modified vaccinia virus Ankara (MVA)-based vector expressing the full-length SARS-CoV-2 spike protein (MVA-S) on the lung transcriptome from susceptible K18-hACE2 mice after SARS-CoV-2 infection. One dose of MVA-S regulated genes related to viral infection control, inflammation processes, T-cell response, cytokine production and IFN-γ signalling. Down-regulation of Rhcg and Tnfsf18 genes post-vaccination with one and two doses of MVA-S may represent a mechanism for controlling infection immunity and vaccine-induced protection. One dose of MVA-S provided partial protection with a distinct lung transcriptomic profile to healthy animals, while two doses of MVA-S fully protected against infection with a transcriptomic profile comparable to that of non-vaccinated healthy animals. This suggests that the MVA-S booster generates a robust and rapid antigen-specific immune response preventing virus infection. Notably, down-regulation of Atf3 and Zbtb16 genes in mice vaccinated with two doses of MVA-S may contribute to vaccine control of innate immune system and inflammation processes in the lungs during SARS-CoV-2 infection. This study shows host transcriptomic mechanisms likely involved in the MVA-S vaccine-mediated immune response against SARS-CoV-2 infection, which could help in improving vaccine dose assessment and developing novel, well-optimized SARS-CoV-2 vaccine candidates against prevalent or emerging VoCs.
通过参与宿主对SARS-CoV-2感染反应的转录组途径来阐明COVID-19疫苗的分子机制，是理解疫苗作用方式以及开发能够预防SARS-CoV-2关注变体（VoCs）出现和未来疫情爆发的优化COVID-19疫苗的关键。在本研究中，我们调查了用表达全长SARS-CoV-2刺突蛋白的基于安卡拉痘苗病毒（MVA）的载体（MVA-S）对易感的K18-hACE2小鼠在感染SARS-CoV-2后肺部转录组的影响。一剂MVA-S调节了与病毒感染控制、炎症过程、T细胞反应、细胞因子产生和IFN-γ信号传导相关的基因。接种一剂和两剂MVA-S后，Rhcg和Tnfsf18基因的下调可能代表了控制感染免疫和疫苗诱导保护的一种机制。一剂MVA-S为健康动物提供了具有独特肺部转录组特征的部分保护，而两剂MVA-S则以与未接种的健康动物相当的转录组特征完全保护免受感染。这表明MVA-S加强针产生了强大而快速的抗原特异性免疫反应，预防病毒感染。值得注意的是，接种两剂MVA-S的小鼠中Atf3和Zbtb16基因的下调可能有助于在SARS-CoV-2感染期间对肺部先天免疫系统和炎症过程进行疫苗控制。本研究显示了可能参与MVA-S疫苗介导的针对SARS-CoV-2感染的免疫反应的宿主转录组机制，这有助于改进疫苗剂量评估，并开发针对流行或新出现的VoCs的新型、优化良好的SARS-CoV-2候选疫苗。
