Muñoz-Alía Miguel Á, Nace Rebecca A, Balakrishnan Baskar, Zhang Lianwen, Packiriswamy Nandakumar, Singh Gagandeep, Warang Prajakta, Mena Ignacio, Narjari Riya, Vandergaast Rianna, García-Sastre Adolfo, Schotsaert Michael, Russell Stephen J
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
Vyriad Inc, Rochester, MN, USA.
bioRxiv. 2022 Dec 16:2022.12.16.520799. doi: 10.1101/2022.12.16.520799.
Serum titers of SARS-CoV-2 neutralizing antibodies (nAb) correlate well with protection from symptomatic COVID-19, but decay rapidly in the months following vaccination or infection. In contrast, measles-protective nAb titers are life-long after measles vaccination, possibly due to persistence of the live-attenuated virus in lymphoid tissues. We therefore sought to generate a live recombinant measles vaccine capable of driving high SARS-CoV-2 nAb responses. Since previous clinical testing of a live measles vaccine encoding a SARS-CoV-2 spike glycoprotein resulted in suboptimal anti-spike antibody titers, our new vectors were designed to encode prefusion-stabilized SARS-CoV-2 spike glycoproteins, trimerized via an inserted peptide domain and displayed on a dodecahedral miniferritin scaffold. Additionally, to circumvent the blunting of vaccine efficacy by preformed anti-measles antibodies, we extensively modified the measles surface glycoproteins. Comprehensive mouse testing demonstrated potent induction of high titer nAb in measles-immune mice and confirmed the significant incremental contributions to overall potency afforded by prefusion stabilization, trimerization, and miniferritin-display of the SARS-CoV-2 spike glycoprotein, and vaccine resurfacing. In animals primed and boosted with a MeV vaccine encoding the ancestral SARS-CoV-2 spike, high titer nAb responses against ancestral virus strains were only weakly cross-reactive with the omicron variant. However, in primed animals that were boosted with a MeV vaccine encoding the omicron BA.1 spike, antibody titers to both ancestral and omicron strains were robustly elevated and the passive transfer of serum from these animals protected K18-ACE2 mice from infection and morbidity after exposure to BA.1 and WA1/2020 strains. Our results demonstrate that antigen engineering can enable the development of potent measles-based SARS-CoV-2 vaccine candidates.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）中和抗体（nAb）的血清滴度与预防有症状的2019冠状病毒病（COVID-19）密切相关，但在接种疫苗或感染后的几个月内会迅速下降。相比之下，麻疹疫苗接种后，具有麻疹保护作用的nAb滴度可终身维持，这可能是由于减毒活病毒在淋巴组织中持续存在。因此，我们试图研发一种能够引发高SARS-CoV-2 nAb反应的重组活麻疹疫苗。由于先前对编码SARS-CoV-2刺突糖蛋白的活麻疹疫苗进行的临床试验产生的抗刺突抗体滴度不理想，我们设计了新的载体，以编码经预融合稳定的SARS-CoV-2刺突糖蛋白，该蛋白通过插入的肽结构域三聚化，并展示在十二面体微型铁蛋白支架上。此外，为了规避预先形成的抗麻疹抗体对疫苗效力的削弱，我们对麻疹表面糖蛋白进行了广泛修饰。全面的小鼠试验表明，在对麻疹免疫的小鼠中能有效诱导高滴度nAb，并证实了SARS-CoV-2刺突糖蛋白的预融合稳定、三聚化和微型铁蛋白展示以及疫苗表面重塑对整体效力有显著的增量贡献。在用编码原始SARS-CoV-2刺突的麻疹病毒（MeV）疫苗进行初免和加强免疫的动物中，针对原始病毒株的高滴度nAb反应与奥密克戎变体的交叉反应较弱。然而，在用编码奥密克戎BA.1刺突的MeV疫苗进行加强免疫的初免动物中，针对原始毒株和奥密克戎毒株的抗体滴度均显著升高，并且这些动物血清的被动转移保护K18-ACE2小鼠在接触BA.1和WA1/2020毒株后免受感染和发病。我们的结果表明，抗原工程能够推动基于麻疹的高效SARS-CoV-2候选疫苗的研发。
Zotero 插件
