Mabrouk Moustafa T, Zidan Asmaa A, Aly Nihal, Mohammed Mostafa T, Ghantous Fadi, Seaman Michael S, Lovell Jonathan F, Nasr Mahmoud L
Division of Engineering in Medicine and Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
Vaccines (Basel). 2023 Oct 28;11(11):1655. doi: 10.3390/vaccines11111655.
The emergence of vaccine-evading SARS-CoV-2 variants urges the need for vaccines that elicit broadly neutralizing antibodies (bnAbs). Here, we assess covalently circularized nanodiscs decorated with recombinant SARS-CoV-2 spike glycoproteins from several variants for eliciting bnAbs with vaccination. Cobalt porphyrin-phospholipid (CoPoP) was incorporated into the nanodisc to allow for anchoring and functional orientation of spike trimers on the nanodisc surface through their His-tag. Monophosphoryl-lipid (MPLA) and QS-21 were incorporated as immunostimulatory adjuvants to enhance vaccine responses. Following optimization of nanodisc assembly, spike proteins were effectively displayed on the surface of the nanodiscs and maintained their conformational capacity for binding with human angiotensin-converting enzyme 2 (hACE2) as verified using electron microscopy and slot blot assay, respectively. Six different formulations were prepared where they contained mono antigens; four from the year 2020 (WT, Beta, Lambda, and Delta) and two from the year 2021 (Omicron BA.1 and BA.2). Additionally, we prepared a mosaic nanodisc displaying the four spike proteins from year 2020. Intramuscular vaccination of CD-1 female mice with the mosaic nanodisc induced antibody responses that not only neutralized matched pseudo-typed viruses, but also neutralized mismatched pseudo-typed viruses corresponding to later variants from year 2021 (Omicron BA.1 and BA.2). Interestingly, sera from mosaic-immunized mice did not effectively inhibit Omicron spike binding to human ACE-2, suggesting that some of the elicited antibodies were directed towards conserved neutralizing epitopes outside the receptor binding domain. Our results show that mosaic nanodisc vaccine displaying spike proteins from 2020 can elicit broadly neutralizing antibodies that can neutralize mismatched viruses from a following year, thus decreasing immune evasion of new emerging variants and enhancing healthcare preparedness.
逃避疫苗的严重急性呼吸综合征冠状病毒2(SARS-CoV-2)变体的出现促使人们需要能够引发广泛中和抗体(bnAbs)的疫苗。在此,我们评估了用来自几种变体的重组SARS-CoV-2刺突糖蛋白装饰的共价环化纳米盘用于通过疫苗接种引发bnAbs的情况。将钴卟啉-磷脂(CoPoP)掺入纳米盘中,以便通过其组氨酸标签使刺突三聚体在纳米盘表面锚定并实现功能定向。将单磷酸脂质A(MPLA)和QS-21作为免疫刺激佐剂掺入以增强疫苗反应。在优化纳米盘组装后,刺突蛋白有效地展示在纳米盘表面,并分别通过电子显微镜和狭缝印迹分析验证,保持了它们与人类血管紧张素转换酶2(hACE2)结合的构象能力。制备了六种不同的配方,它们包含单一抗原;四种来自2020年(野生型、贝塔、拉姆达和德尔塔),两种来自2021年(奥密克戎BA.1和BA.2)。此外,我们制备了一种展示2020年四种刺突蛋白的嵌合纳米盘。用嵌合纳米盘对CD-1雌性小鼠进行肌肉内接种诱导了抗体反应,这些反应不仅中和了匹配的假型病毒,还中和了与2021年后期变体(奥密克戎BA.1和BA.2)相对应的不匹配假型病毒。有趣的是,来自嵌合免疫小鼠的血清没有有效地抑制奥密克戎刺突与人类ACE-2的结合,这表明一些引发的抗体针对的是受体结合域之外的保守中和表位。我们的结果表明,展示2020年刺突蛋白的嵌合纳米盘疫苗可以引发能够中和下一年不匹配病毒的广泛中和抗体,从而减少新出现变体的免疫逃逸并增强医疗准备。