S-309

New research shows that the recently emerged BA.2.86 omicron subvariant of the virus that causes COVID-19 can be neutralized by bivalent mRNA vaccine-induced antibodies in the blood, which explains why this variant did not cause a widespread surge as previously feared. New research shows that the recently emerged BA.2.86 omicron subvariant of the virus that causes COVID-19 can be neutralized by bivalent mRNA vaccine-induced antibodies in the blood, which explains why this variant did not cause a widespread surge as previously feared. However, the study in cell cultures showed this SARS-CoV-2 variant can infect human cells that line the lower lung and engage in virus-host cell membrane fusion more efficiently, two features linked to severe disease symptoms. The study is published today (Jan. 8, 2024) in the journal Cell. The BA.2.86 variant of omicron is the ancestor of the currently dominating JN.1 and has about 60 more spike protein mutations than the original, or parent, coronavirus, including over 30 more than its close omicron relatives -- the early BA.2 variant and the recently dominant XBB.1.5 variant among them. These mutations led scientists to worry that so many changes would make the variant as tough to contain as the initial omicron outbreak in 2021-22. "We found that, surprisingly, despite all those 60 mutations combined together, BA.2.86 is not as immune-evasive as the XBB.1.5 variant, which until recently had been dominating the pandemic for months. That's good news," said Shan-Lu Liu, senior author the study and a virology professor in the Department of Veterinary Biosciences at The Ohio State University. "But BA.2.86 appears to have increased infectivity of human lung epithelial cells compared to all omicron variants, so that's a little worrisome. And, consistent with infectivity, it also has increased fusion activity with human lung epithelial cells," said Liu, also a professor in the Department of Microbial Infection and Immunity. "That raises a potential concern about whether or not this virus is more pathogenic compared to recent omicron variants." The published findings coincide with reports from the Centers for Disease Control and Prevention that after a brief increase in BA.2.86 infections, its derived sublineage JN.1 rapidly gained ground in the United States, responsible for an estimated 44% of COVID-19 cases as of Dec. 23, 2023. First detected in July in Europe and the Middle East, BA.2.86 and its sublineages have since been spreading with increasing frequency in different parts of the world. On Nov. 22, the World Health Organization classified BA.2.86 and sublineages as "variants of interest." The Ohio State researchers analyzed neutralizing antibodies in blood serum samples from health care professionals who had received three monovalent vaccine doses or two monovalent vaccines followed by one bivalent vaccine booster, and from first responders who had COVID-19 infections during the wave dominated by the XBB.1.5 variant. They compared the ability of neutralizing antibodies to block infection by BA.2.86, an XBB-derived variant known as FLip, the parent virus and several omicron variants. Overall, antibodies produced by serum from the bivalent vaccine-dosed health care professionals were more efficient at neutralizing BA.2.86 than they were at neutralizing other omicron variants, including XBB.1.5. In contrast, the three monovalent vaccines and previous XBB.1.5 infection were barely effective in blocking infection by BA.2.86. "People who have had a COVID-19 infection should remember that omicron variants are less virulent compared to prior variants such as delta, meaning they don't make most people very sick," Liu said. "If you have less severe disease, the antibodies generated by infection are low -- almost 10-fold lower than vaccine-induced antibodies. That is why you cannot rely on natural infection alone for immunity. "While bivalent vaccine can still neutralize BA.2.86, the efficiency is clearly reduced. Therefore, it is important to get the newest booster vaccine, which is formulated with only XBB.1.5 and has been shown to be effective against BA.2.86," Liu added. However, the researchers were surprised to find that a monoclonal antibody known as S309, which has been shown to inhibit almost all other major omicron variants, does not neutralize BA.2.86. Molecular modeling revealed that some of the BA.2.86 mutations in the spike protein might have changed the conformation and rendered S309 unable to neutralize the new variant, Liu said. Additional experiments pointed to the potential for BA.2.86 to be more likely to cause severe disease than its omicron relatives. Researchers found BA.2.86 was more efficient at infecting a cell line derived from the human lower airway epithelium in the lung. Infection of these cells is greatly facilitated through a cell surface protein, known as TMPRSS2, to promote membrane fusion, and this protein is a known contributor to SARS-CoV-2 infection and disease symptoms in the respiratory tract. First author Panke Qu, a graduate student in Liu's lab, conducted the cell-culture studies using pseudoviruses -- a non-infectious viral core surrounded by different SARS-CoV-2 spike proteins on the surface structured to match known variants. "Because we used a pseudovirus, we need to confirm these findings using the real virus," said Liu, also associate director of Ohio State's Center for Retrovirus Research and a program co-director of the Viruses and Emerging Pathogens Program in Ohio State's Infectious Diseases Institute. "But from our past experience, we know that the infectivity in human epithelial cell lines provides very important information. The concern is whether or not this variant, as well as its descendants including JN.1, will have an increased tendency to infect human lung epithelial cells similar to the parental virus that launched the pandemic in 2020." Liu noted that other labs have recently suggested that JN.1, one of fastest-growing descendants of BA.2.86, is much more resistant to neutralizing antibodies that are effective against BA.2.86. "We know that coronaviruses are prone to viral recombination, which can lead to new variants with huge numbers of mutations that could have increased immune evasion but also disease severity," he said. "That's why surveillance of the variants is still very important, even though we are in the end of year four of the pandemic." This work was supported by anonymous donor funds, the National Institutes of Health, the National Center for Advancing Translational Sciences, the Glenn Barber Fellowship from Ohio State's College of Veterinary Medicine, the Robert J. Anthony Fund for Cardiovascular Research, and Ohio State's Comprehensive Cancer Center and Center for Clinical and Translational Science. Additional co-authors, all from Ohio State, are Kai Xu, Julia Faraone, Negin Goodarzi, Yi-Min Zheng, Claire Carlin, Joseph Bednash, Jeffrey Horowitz, Rama Mallampalli, Linda Saif, Eugene Oltz, Daniel Jones and Richard Gumina.

目前，针对SARS - CoV - 2 S蛋白受体结合域( receptor binding domain，RBD )的单克隆抗体根据其结合表位分为7类。然而，这些抗体大多受到SARS - CoV - 2 Omicrom及其亚变种的严重损害，尤其是最近的BQ.1 . 1、XBB及其衍生物。鉴定针对目前流行的变异体的广谱中和MAbs是必要的。2023年12月18日，中国科学院天津工业生物技术研究所高峰及中国科学院微生物研究所高福共同通讯在PNAS 上在线发表题为“Defining a de novo non-RBM antibody as RBD-8 and its synergistic rescue of immune-evaded antibodies to neutralize Omicron SARS-CoV-2”的研究论文，该研究在S蛋白中发现了一个"呼吸"的隐秘表位，将其命名为RBD-8。该研究分离到2株识别该抗原表位的人源单克隆抗体BIOLS56和IMCAS74，它们对SARS - CoV、穿山甲来源的冠状病毒以及所有检测到的SARS - CoV - 2变异株均具有广泛的中和能力。BIOLS56通过制备双特异性MAb来中和BQ.1和BQ.1 . 1，从而拯救出免疫逃逸抗体RBD - 5 MAb IMCAS-L4.65，从而制备出能够覆盖目前所有流通的O μm亚变异体的MAb。结构分析表明，RBD - 8抗体的中和作用取决于表位暴露的程度，而表位暴露的程度受抗体结合角度和血管紧张素转化酶2结合诱导的上调RBD数量的影响。这种识别非受体结合基序( non-receptor binding motif，non-RBM )的隐匿性表位为COVID - 19通用治疗性抗体和疫苗的研发提供了指导。自2020年3月世界卫生组织( WHO的)宣布大流行以来，2019冠状病毒病( COVID-19 )大流行已持续3年，仍对全球构成威胁。严重急性呼吸综合征冠状病毒2 (severe acute respiratory syndrome coronavirus 2( SARS-CoV-2 ))，COVID-19 )与SARS - CoV同属于冠状病毒科β冠状病毒属，引起两种严重的人类疾病。SARS - CoV - 2病毒粒子主要由基因组核酸和蛋白质组成，即刺突( S )、膜( M )、囊膜( E )和核衣壳( N )蛋白，其中S、M和E蛋白镶嵌在病毒囊膜中，N蛋白保护病毒基因组。值得注意的是，编码S蛋白的基因是各种变异的重要突变热点。尽管已有多种治疗性抗体和疫苗应用于临床，但由于SARS - CoV - 2变异株的不断出现，特别是VOCs ( variant of concern )的不断出现，使得这些治疗方法的疗效大打折扣，防疫工作仍然面临着巨大的挑战。因此，迫切需要开发广谱的保护性抗体和通用型疫苗。SARS - CoV和SARS - CoV - 2均通过其S蛋白识别血管紧张素转换酶2 ( ACE2 )介导病毒进入。S蛋白主要由S1和S2两个亚结构域组成，其中S1含有负责识别ACE2进入宿主细胞的受体结合结构域( receptor binding domain，RBD )。因此，阻断RBD与ACE2的结合是中和抗体研究的重点。然而，随着VOCs的出现，这些中和抗体的疗效往往被大大削弱甚至消融，其中包括以抗体为基础的药物etesevimab (又名CB6)、REGN10933和LY - CoV555。另一方面，由于SARS - CoV - 2的RBD与SARS - CoV具有75 %的序列一致性，也有一些针对SARS - CoV - 2和SARS - CoV的RBD的交叉中和抗体的研究，以S309 为代表。同样，S309对变体的中和能力也受到了明显的削弱，尤其是对VOCs的中和能力。BIOLS56和IMCAS74被定义为RBD-8类抗体（图源自PNAS ）Hastie等利用基于表面等离子共振( surface plasmon resonance，SPR )的竞争实验，将冠状病毒免疫治疗联盟中针对SARS - CoV - 2 RBD的抗体分为RBD - 1、RBD - 2、RBD - 3、RBD - 4、RBD - 5、RBD - 6和RBD - 7七类。RBD - 1、RBD - 2和RBD - 3类抗体以不同的角度与RBD的受体结合基序结合，而" up "的RBD构象是结合所必需的。当RBD处于"上"或"下"状态时，RBD - 4和RBD - 5类抗体结合在RBD外表面的不同位置。对于RBD - 6和RBD - 7类抗体，它们都与RBD的内表面结合，而RBD的内表面通常被称为隐秘表位，两个" up "的RBD是必需的。基于此，该研究报道了两株针对一个隐匿表位的人源单克隆抗体( hMAbs ) BIOLS56和IMCAS74，并将其命名为RBD - 8。重要的是，该隐秘表位包含了沙粒病毒间的保守残基。因此，靶向RBD - 8的抗体具有广谱中和杆状病毒的能力。虽然BIOLS56的中和作用较弱，但它拯救了免疫逃逸抗体IMCAS - L4.65以中和BQ.1和BQ.1 . 1，扩大了双特异性抗体以中和所有已知的待测VOCs。文献检索显示，许多RBD - 8 MAb已被不同的研究组发现，但尚未被正式命名为新的研究组。此外，该研究提供了一个模型，通过结构分析来解释为什么不同的RBD - 8抗体对sarbecoviruses表现出不同程度的中和作用。这些发现表明，暴露的隐匿性表位RBD - 8是开发通用疫苗和抗体的一个有前途的靶点。利用该表位设计的双特异性抗体，结合其他表位，是避免病毒逃逸的良好候选者。参考信息：https://doi.org/10.1073/pnas.2314193120识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场