García-Arriaza Juan, Garaigorta Urtzi, Pérez Patricia, Lázaro-Frías Adrián, Zamora Carmen, Gastaminza Pablo, Del Fresno Carlos, Casasnovas José M, Sorzano Carlos Óscar S, Sancho David, Esteban Mariano
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología (CNB), Consejo Superior de Investigaciones Científicas (CSIC), 28049 Madrid, Spain;
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología (CNB), Consejo Superior de Investigaciones Científicas (CSIC), 28049 Madrid, Spain.
J Virol. 2021 Mar 10;95(7). doi: 10.1128/JVI.02260-20. Epub 2021 Jan 7.
Vaccines against SARS-CoV-2, the causative agent of the COVID-19 pandemic, are urgently needed. We developed two COVID-19 vaccines based on modified vaccinia virus Ankara (MVA) vectors expressing the entire SARS-CoV-2 spike (S) protein (MVA-CoV2-S); their immunogenicity was evaluated in mice using DNA/MVA or MVA/MVA prime/boost immunizations. Both vaccines induced robust, broad and polyfunctional S-specific CD4+ (mainly Th1) and CD8+ T-cell responses, with a T effector memory phenotype. DNA/MVA immunizations elicited higher T-cell responses. All vaccine regimens triggered high titers of IgG antibodies specific for the S, as well as for the receptor-binding domain; the predominance of the IgG2c isotype was indicative of Th1 immunity. Notably, serum samples from vaccinated mice neutralized SARS-CoV-2 in cell cultures, and those from MVA/MVA immunizations showed a higher neutralizing capacity. Remarkably, one or two doses of MVA-CoV2-S protect humanized K18-hACE2 mice from a lethal dose of SARS-CoV-2. In addition, two doses of MVA-CoV2-S confer full inhibition of virus replication in the lungs. These results demonstrate the robust immunogenicity and full efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic. The continuous dissemination of the novel emerging SARS-CoV-2 virus, with more than 78 million infected cases worldwide and higher than 1,700,000 deaths as of December 23, 2020, highlights the urgent need for the development of novel vaccines against COVID-19. With this aim, we have developed novel vaccine candidates based on the poxvirus modified vaccinia virus Ankara (MVA) strain expressing the full-length SARS-CoV-2 spike (S) protein, and we have evaluated their immunogenicity in mice using DNA/MVA or MVA/MVA prime/boost immunization protocols. The results showed the induction of a potent S-specific T-cell response and high titers of neutralizing antibodies. Remarkably, humanized K18-hACE2 mice immunized with one or two doses of the MVA-based vaccine were 100% protected from SARS-CoV-2 lethality. Moreover, two doses of the vaccine prevented virus replication in lungs. Our findings prove the robust immunogenicity and efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic.
迫切需要针对2019年冠状病毒病（COVID-19）大流行的病原体严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的疫苗。我们基于表达完整SARS-CoV-2刺突（S）蛋白的改良安卡拉痘苗病毒（MVA）载体开发了两种COVID-19疫苗（MVA-CoV2-S）；使用DNA/MVA或MVA/MVA初免/加强免疫在小鼠中评估了它们的免疫原性。两种疫苗均诱导了强大、广泛且多功能的S特异性CD4+（主要是Th1）和CD8+ T细胞应答，具有T效应记忆表型。DNA/MVA免疫引发了更高的T细胞应答。所有疫苗方案均触发了针对S以及受体结合域的高滴度IgG抗体；IgG2c同种型占优势表明存在Th1免疫。值得注意的是，来自接种疫苗小鼠的血清样本在细胞培养物中中和了SARS-CoV-2，并且来自MVA/MVA免疫的样本显示出更高的中和能力。值得注意的是，一剂或两剂MVA-CoV2-S可保护人源化K18-hACE2小鼠免受致死剂量的SARS-CoV-2感染。此外，两剂MVA-CoV2-S可完全抑制肺部的病毒复制。这些结果证明了基于MVA的COVID-19疫苗在动物模型中具有强大的免疫原性和完全的效力，并支持将其转化至临床。新型SARS-CoV-2病毒持续传播，截至2020年12月23日，全球感染病例超过7800万例，死亡人数超过170万，这凸显了迫切需要开发针对COVID-19的新型疫苗。为此，我们基于表达全长SARS-CoV-2刺突（S）蛋白的痘病毒改良安卡拉痘苗病毒（MVA）株开发了新型候选疫苗，并使用DNA/MVA或MVA/MVA初免/加强免疫方案在小鼠中评估了它们的免疫原性。结果显示诱导了强大的S特异性T细胞应答和高滴度的中和抗体。值得注意的是，用一剂或两剂基于MVA的疫苗免疫的人源化K18-hACE2小鼠100%免受SARS-CoV-2致死性感染。此外，两剂疫苗可防止病毒在肺部复制。我们的研究结果证明了基于MVA的COVID-19疫苗在动物模型中具有强大的免疫原性和效力，并支持将其转化至临床。
