Esteban Ignasi, Pastor-Quiñones Carmen, Usero Lorena, Aurrecoechea Elena, Franceschini Lorenzo, Esprit Arthur, Gelpí Josep Lluís, Martínez-Jiménez Francisco, López-Bigas Núria, Breckpot Karine, Thielemans Kris, Leal Lorna, Gómez Carmen Elena, Sisteré-Oró Marta, Meyerhans Andreas, Esteban Mariano, Alonso María José, García Felipe, Plana Montserrat
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, 08036 Barcelona, Spain.
Laboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
Vaccines (Basel). 2023 Dec 22;12(1):15. doi: 10.3390/vaccines12010015.
The COVID-19 pandemic has brought significant changes and advances in the field of vaccination, including the implementation and widespread use of encapsidated mRNA vaccines in general healthcare practice. Here, we present two new mRNAs expressing antigenic parts of the SARS-CoV-2 spike protein and provide data supporting their functionality. The first mRNA, called RBD-mRNA, encodes a trimeric form of the virus spike protein receptor binding domain (RBD). The other mRNA, termed T-mRNA, codes for the relevant HLA I and II spike epitopes. The two mRNAs (COVARNA mRNAs) were designed to be used for delivery to cells in combination, with the RBD-mRNA being the primary source of antigen and the T-mRNA working as an enhancer of immunogenicity by supporting CD4 and CD8 T-cell activation. This innovative approach substantially differs from other available mRNA vaccines, which are largely directed to antibody production by the entire spike protein. In this study, we first show that both mRNAs are functionally transfected into human antigen-presenting cells (APCs). We obtained peripheral blood mononuclear cell (PBMC) samples from three groups of voluntary donors differing in their immunity against SARS-CoV-2: non-infected (naïve), infected-recovered (convalescent), and vaccinated. Using an established method of co-culturing autologous human dendritic cells (hDCs) with T-cells, we detected proliferation and cytokine secretion, thus demonstrating the ability of the COVARNA mRNAs to activate T-cells in an antigen-specific way. Interestingly, important differences in the intensity of the response between the infected-recovered (convalescent) and vaccinated donors were observed, with the levels of T-cell proliferation and cytokine secretion (IFNγ, IL-2R, and IL-13) being higher in the vaccinated group. In summary, our data support the further study of these mRNAs as a combined approach for future use as a vaccine.
新冠疫情给疫苗接种领域带来了重大变革与进展，包括在一般医疗实践中包膜mRNA疫苗的应用与广泛使用。在此，我们展示了两种表达严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白抗原部分的新型mRNA，并提供了支持其功能的数据。第一种mRNA称为RBD-mRNA，编码病毒刺突蛋白受体结合域（RBD）的三聚体形式。另一种mRNA称为T-mRNA，编码相关的HLA I类和II类刺突表位。这两种mRNA（COVARNA mRNA）设计用于联合递送至细胞，其中RBD-mRNA是主要抗原来源，T-mRNA通过支持CD4和CD8 T细胞活化作为免疫原性增强剂。这种创新方法与其他现有mRNA疫苗有很大不同，其他疫苗主要针对整个刺突蛋白产生抗体。在本研究中，我们首先表明两种mRNA均能有效转染至人抗原呈递细胞（APC）。我们从三组对SARS-CoV-2免疫状态不同的自愿捐赠者中获取外周血单个核细胞（PBMC）样本：未感染（初免）、感染后康复（恢复期）和接种疫苗者。使用将自体人树突状细胞（hDC）与T细胞共培养的既定方法，我们检测到了增殖和细胞因子分泌，从而证明了COVARNA mRNA以抗原特异性方式激活T细胞的能力。有趣的是，观察到感染后康复（恢复期）捐赠者和接种疫苗捐赠者之间反应强度存在重要差异，接种疫苗组的T细胞增殖水平和细胞因子分泌（IFNγ、IL-2R和IL-13）更高。总之，我们的数据支持进一步研究这些mRNA作为未来联合疫苗的应用。
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