维也纳医科大学进一步开发的COVID疫苗显示出针对奥密克戎的有希望的效果

诸平

据奥地利维也纳医科大学（Medical University of Vienna简称MedUni Vienna, Vienna, Austria）2024年3月11日提供的消息，维也纳医科大学进一步开发的COVID疫苗，显示出针对新冠病毒变体——奥密克戎（Omikron）的有希望的效果（Further developed COVID vaccine from MedUni Vienna shows promising results against Omikron）。

维也纳医科大学病理生理学、传染病学和免疫学中心（Center for Pathophysiology, Infectiology and Immunology at the Medical University of Vienna）的研究人员，进一步开发了他们的COVID-19疫苗，该疫苗现在在对抗新冠病毒的奥密克戎变体（Omikron variant）方面显示出希望。相关研究结果于2024年2月23日已经在《疫苗》（Vaccines）杂志网站发表——Pia Gattinger, Bernhard Kratzer, Al Nasar Ahmed Sehgal, Anna Ohradanova-Repic, Laura Gebetsberger, Gabor Tajti, Margarete Focke-Tejkl, Mirjam Schaar, Verena Fuhrmann, Lukas Petrowitsch, Walter Keller, Sandra Högler, Hannes Stockinger, Winfried F. Pickl, Rudolf Valenta. Vaccine Based on Recombinant Fusion Protein Combining Hepatitis B Virus PreS with SARS-CoV-2 Wild-Type- and Omicron-Derived Receptor Binding Domain Strongly Induces Omicron-Neutralizing Antibodies in a Murine Model. Vaccines, 2024, 12(3): 229. DOI: 10.3390/vaccines12030229. Published: 23 February 2024. https://www.mdpi.com/2076-393X/12/3/229

参与此项研究的除了来自奥地利维也纳医科大学（MedUni Vienna）的研究人员之外，还有来自奥地利卡尔·兰德斯坦纳健康科学大学（Karl Landsteiner University of Health Sciences, Krems, Austria）、奥地利格拉茨大学（University of Graz, Graz, Austria）；俄罗斯谢切诺夫第一莫斯科国立医科大学（Sechenov First Moscow State Medical University, Moscow, Russia）以及俄罗斯联邦医学生物机构(FMBA)国家研究中心(NRC)免疫学研究所{National Research Center (NRC) Institute of Immunology Federal Medical-Biological Agency (FMBA) of Russia, Moscow, Russia}的研究人员。

由SARS-CoV-2病毒引起的COVID-19现已在全球蔓延。自2021年11月以来，奥密克戎变体及其亚型占主导地位。为了预防疾病的严重进程，需要疫苗来诱导对奥密克戎有效的抗体。

由鲁道夫·瓦伦塔（Rudolf Valenta）和皮亚·哥廷格（Pia Gattinger）领导的维也纳医科大学团队，改进了由乙型肝炎病毒(hepatitis B virus简称HBV)的PreS蛋白（PreS protein）和SARS-CoV-2的两种RBD蛋白组成的新冠病毒疫苗（COVID-19 vaccine），使其对奥密可戎具有很高的效果。在他们的研究中，开发、生产和比较了不同的疫苗变体。

动物模型结果显示，由原SARS-CoV-2病毒和奥密可戎组成的嵌合PreS-RBD亚单位疫苗(W-PreS-O)诱导的针对奥密可戎的中和抗体滴度（neutralizing antibody titers）最高。有趣的是，不同疫苗诱导的RBD特异性抗体水平（RBD-specific antibody levels）具有可比性，但W-PreS-O诱导的针对奥密可戎的病毒中和效价比菌株特异性和二价疫苗高7倍。这表明W-PreS-O是一个特别有希望进行进一步临床前和临床研究的候选者。

研究负责人鲁道夫·瓦伦塔解释说:“我认为这是一项非常重要的工作，因为目前对由当前病毒变异引起的COVID-19几乎没有任何保护选择，特别是对易感患者而言。值得注意的是，联合疫苗对奥密可戎的效果比‘仅’针对奥密可戎的疫苗更好。特别有趣的是，不仅抗体水平起作用，而且联合疫苗的中和效果更好。”

研究结果是持续抗击COVID-19的重要一步，可能有助于开发更适合当前流行病毒变体的疫苗。

这项研究由奥地利科学基金（Austrian Science Fund, Grant number P 34253-B）和下奥地利州资助的多瑙河过敏研究集群项目（Danube Allergy Research Cluster program funded by the Country of Lower Austria）的资助。

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Abstract

Background: COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a recurrent endemic disease affecting the whole world. Since November 2021, Omicron and its subvariants have dominated in the spread of the disease. In order to prevent severe courses of disease, vaccines are needed to boost and maintain antibody levels capable of neutralizing Omicron. Recently, we produced and characterized a SARS-CoV-2 vaccine based on a recombinant fusion protein consisting of hepatitis B virus (HBV)-derived PreS and two SARS-CoV-2 wild-type RBDs. 

Objectives: To develop a PreS-RBD vaccine which induces high levels of Omicron-specific neutralizing antibodies. Methods: We designed, produced, characterized and compared strain-specific (wild-type: W-PreS-W; Omicron: O-PreS-O), bivalent (mix of W-PreS-W and O-PreS-O) and chimeric (i.e., W-PreS-O) SARS-CoV-2 protein subunit vaccines. Immunogens were characterized in vitro using protein chemical methods, mass spectrometry, and circular dichroism in combination with thermal denaturation and immunological methods. In addition, BALB/c mice were immunized with aluminum–hydroxide-adsorbed proteins and aluminum hydroxide alone (i.e., placebo) to study the specific antibody and cytokine responses, safety and Omicron neutralization. 

Results: Defined and pure immunogens could be produced in significant quantities as secreted and folded proteins in mammalian cells. The antibodies induced after vaccination with different doses of strain-specific, bivalent and chimeric PreS-RBD fusion proteins reacted with wild-type and Omicron RBD in a dose-dependent manner and resulted in a mixed Th1/Th2 immune response. Interestingly, the RBD-specific IgG levels induced with the different vaccines were comparable, but the W-PreS-O-induced virus neutralization titers against Omicron (median VNT50: 5000) were seven- and twofold higher than the W-PreS-W- and O-PreS-O-specific ones, respectively, and they were six-fold higher than those of the bivalent vaccine. 

Conclusion: Among the tested immunogens, the chimeric PreS-RBD subunit vaccine, W-PreS-O, induced the highest neutralizing antibody titers against Omicron. Thus, W-PreS-O seems to be a highly promising COVID-19 vaccine candidate for further preclinical and clinical evaluation.