Grewe Ilka, Friedrich Monika, Dieck Marie-Louise, Spohn Michael, Ly My Linh, Krähling Verena, Mayer Leonie, Mellinghoff Sibylle C, Rottstegge Monika, Kraemer Rebekka, Volz Asisa, Becker Stephan, Fathi Anahita, Dahlke Christine, Weskamm Leonie M, Addo Marylyn M
Institute for Infection Research and Vaccine Development (IIRVD), Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department for Clinical Immunology of Infectious Diseases, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Front Immunol. 2024 Dec 19;15:1500615. doi: 10.3389/fimmu.2024.1500615. eCollection 2024.
Vaccine platforms such as viral vectors and mRNA can accelerate vaccine development in response to newly emerging pathogens, as demonstrated during the COVID-19 pandemic. However, the differential effects of platform and antigen insert on vaccine immunogenicity remain incompletely understood. Innate immune responses induced by viral vector vaccines are suggested to have an adjuvant effect for subsequent adaptive immunity. Integrating data on both innate and adaptive immunity, systems vaccinology approaches can improve the understanding of vaccine-induced immune mechanisms.
Two vaccine candidates against SARS-CoV-2, both based on the viral vector Modified Vaccinia virus Ankara (MVA) and encoding the native (MVA-SARS-2-S) or prefusion-stabilized spike protein (MVA-SARS-2-ST), were evaluated in phase 1 clinical trials (ClinicalTrials.gov: NCT04569383, NCT04895449). Longitudinal dynamics of innate and early adaptive immune responses induced by vaccination in SARS-CoV-2-naïve individuals were analyzed based on transcriptome and flow cytometry data, in comparison to the licensed ChAd and mRNA vaccines.
Compared to MVA-SARS-2-S, MVA-SARS-2-ST (encoding the prefusion-stabilized spike protein) induced a stronger transcriptional activation early after vaccination, as well as higher virus neutralizing antibodies. Positive correlations were observed between innate and adaptive immune responses induced by a second MVA-SARS-2-ST vaccination. MVA-, ChAd- and mRNA-based vaccines induced distinct immune signatures, with the overall strongest transcriptional activation as well as monocyte and circulating T follicular helper (cTFH) cell responses induced by ChAd.
Our findings suggest a potential impact of the spike protein conformation not only on adaptive but also on innate immune responses. As indicated by positive correlations between several immune parameters induced by MVA-SARS-2-ST, the distinct transcriptional activation early after vaccination may be linked to the induction of classical monocytes and activation of cTFH1 cells, which may in turn result in the superior adaptive immunogenicity of MVA-SARS-2-ST, compared to MVA-SARS-2-S. Overall, our data demonstrate that both the vaccine platform and antigen insert can affect innate immune responses and subsequent vaccine immunogenicity in humans.
在新冠疫情期间所展现的那样，诸如病毒载体和信使核糖核酸等疫苗平台能够加速针对新出现病原体的疫苗研发。然而，平台和抗原插入物对疫苗免疫原性的不同影响仍未被完全理解。据推测，病毒载体疫苗诱导的先天免疫反应对后续的适应性免疫具有佐剂作用。整合先天免疫和适应性免疫的数据，系统疫苗学方法能够增进对疫苗诱导免疫机制的理解。
两种针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的候选疫苗在1期临床试验中进行了评估（ClinicalTrials.gov：NCT04569383，NCT04895449），这两种疫苗均基于病毒载体安卡拉痘苗病毒（MVA），并编码天然（MVA-SARS-2-S）或预融合稳定刺突蛋白（MVA-SARS-2-ST）。与已获许可的腺病毒载体疫苗和信使核糖核酸疫苗相比，基于转录组和流式细胞术数据，分析了在未接触过SARS-CoV-2的个体中接种疫苗后诱导的先天免疫和早期适应性免疫反应的纵向动态变化。
与MVA-SARS-2-S相比，MVA-SARS-2-ST（编码预融合稳定刺突蛋白）在接种疫苗后早期诱导了更强的转录激活以及更高的病毒中和抗体。在第二次接种MVA-SARS-2-ST后诱导的先天免疫和适应性免疫反应之间观察到正相关。基于MVA、腺病毒载体和信使核糖核酸的疫苗诱导了不同的免疫特征，其中腺病毒载体疫苗诱导的转录激活以及单核细胞和循环滤泡辅助性T细胞（cTFH）反应总体最强。
我们的研究结果表明刺突蛋白构象不仅对适应性免疫反应而且对先天免疫反应都有潜在影响。正如MVA-SARS-2-ST诱导的几个免疫参数之间的正相关所表明的那样，接种疫苗后早期不同的转录激活可能与经典单核细胞的诱导和cTFH1细胞的激活有关，这反过来可能导致MVA-SARS-2-ST与MVA-SARS-2-S相比具有更强的适应性免疫原性。总体而言，我们的数据表明疫苗平台和抗原插入物都可以影响人类的先天免疫反应和随后的疫苗免疫原性。
