Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Vyriad Inc, Rochester, Minnesota, USA.
mBio. 2024 Feb 14;15(2):e0292823. doi: 10.1128/mbio.02928-23. Epub 2024 Jan 9.
Serum titers of SARS-CoV-2-neutralizing antibodies (nAbs) 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 lifelong 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 the potent induction of high titer nAbs in measles-immune mice and confirmed the significant contributions to overall potency afforded by prefusion stabilization, trimerization, and miniferritin display of the SARS-CoV-2 spike glycoprotein. In animals primed and boosted with a measles virus (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 by engineering the antigen, we can develop potent measles-based vaccine candidates against SARS-CoV-2.IMPORTANCEAlthough the live-attenuated measles virus (MeV) is one of the safest and most efficacious human vaccines, a measles-vectored COVID-19 vaccine candidate expressing the SARS-CoV-2 spike failed to elicit neutralizing antibody (nAb) responses in a phase-1 clinical trial, especially in measles-immune individuals. Here, we constructed a comprehensive panel of MeV-based COVID-19 vaccine candidates using a MeV with extensive modifications on the envelope glycoproteins (MeV-MR). We show that artificial trimerization of the spike is critical for the induction of nAbs and that their magnitude can be significantly augmented when the spike protein is synchronously fused to a dodecahedral scaffold. Furthermore, preexisting measles immunity did not abolish heterologous immunity elicited by our vector. Our results highlight the importance of antigen optimization in the development of spike-based COVID-19 vaccines and therapies.
血清中 SARS-CoV-2 中和抗体(nAb)滴度与预防有症状 COVID-19 密切相关,但在接种或感染后数月内迅速下降。相比之下,麻疹疫苗接种后麻疹保护性 nAb 滴度终生存在,这可能是由于活减毒病毒在淋巴组织中持续存在。因此,我们试图开发一种能够产生高 SARS-CoV-2 nAb 反应的活重组麻疹疫苗。由于之前对编码 SARS-CoV-2 刺突糖蛋白的活麻疹疫苗进行的临床测试导致抗刺突抗体滴度不理想,因此我们新的载体设计用于编码融合前稳定的 SARS-CoV-2 刺突糖蛋白,通过插入的肽结构域三聚化,并在十二面体小铁蛋白支架上展示。此外,为了避免预先存在的抗麻疹抗体削弱疫苗的功效,我们对麻疹表面糖蛋白进行了广泛修饰。全面的小鼠测试证明,在麻疹免疫小鼠中强烈诱导了高滴度的 nAb,并证实了融合前稳定、三聚化和 SARS-CoV-2 刺突糖蛋白的小铁蛋白显示对整体效力的重要贡献。在用编码 SARS-CoV-2 刺突的原始麻疹病毒(MeV)疫苗进行初次免疫和加强免疫的动物中,针对原始病毒株的高滴度 nAb 反应仅与奥密克戎变体呈弱交叉反应。然而,在接受编码奥密克戎 BA.1 刺突的 MeV 疫苗加强免疫的初次免疫动物中,对原始和奥密克戎株的抗体滴度均显著升高,并且从这些动物中被动转移的血清可保护 K18-ACE2 小鼠免受 BA.1 和 WA1/2020 株感染和发病。我们的结果表明,通过对抗原进行工程改造,我们可以开发针对 SARS-CoV-2 的有效麻疹疫苗候选物。
重要性
虽然活减毒麻疹病毒(MeV)是最安全和最有效的人类疫苗之一,但在一项 1 期临床试验中,表达 SARS-CoV-2 刺突的基于麻疹的 COVID-19 疫苗候选物未能引起中和抗体(nAb)反应,特别是在麻疹免疫个体中。在这里,我们使用包膜糖蛋白经过广泛修饰的 MeV(MeV-MR)构建了一个全面的基于麻疹的 COVID-19 疫苗候选物小组。我们表明,刺突的人工三聚化对于诱导 nAb 至关重要,并且当刺突蛋白与十二面体支架同步融合时,其数量可以显著增加。此外,预先存在的麻疹免疫力并没有消除我们载体引起的异源免疫力。我们的结果强调了在开发基于刺突的 COVID-19 疫苗和疗法中抗原优化的重要性。
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