Bukreyev Alexander, Meyer Michelle, Gunn Bronwyn, Pietzsch Colette, Subramani Chandru, Saphire Erica, Crowe James, Alter Galit, Himansu Sunny, Carfi Andrea
University of Texas Medical Branch.
Washington State University.
Res Sq. 2024 Mar 26:rs.3.rs-4087897. doi: 10.21203/rs.3.rs-4087897/v1.
The first-ever recent Marburg virus (MARV) outbreak in Ghana, West Africa and Equatorial Guinea has refocused efforts towards the development of therapeutics since no vaccine or treatment has been approved. mRNA vaccines were proven successful in a pandemic-response to severe acute respiratory syndrome coronavirus-2, making it an appealing vaccine platform to target highly pathogenic emerging viruses. Here, 1-methyl-pseudouridine-modified mRNA vaccines formulated in lipid nanoparticles (LNP) were developed against MARV and the closely-related Ravn virus (RAVV), which were based on sequences of the glycoproteins (GP) of the two viruses. Vaccination of guinea pigs with both vaccines elicited robust binding and neutralizing antibodies and conferred complete protection against virus replication, disease and death. The study characterized antibody responses to identify disparities in the binding and functional profiles between the two viruses and regions in GP that are broadly reactive. For the first time, the glycan cap is highlighted as an immunoreactive site for marburgviruses, inducing both binding and neutralizing antibody responses that are dependent on the virus. Profiling the antibody responses against the two viruses provided an insight into how antigenic differences may affect the response towards conserved GP regions which would otherwise be predicted to be cross-reactive and has implications for the future design of broadly protective vaccines. The results support the use of mRNA-LNPs against pathogens of high consequence.
西非加纳和赤道几内亚首次爆发马尔堡病毒（MARV）疫情，由于尚未批准任何疫苗或治疗方法，这使得人们重新将努力聚焦于治疗药物的研发。信使核糖核酸（mRNA）疫苗在应对严重急性呼吸综合征冠状病毒2的大流行中被证明是成功的，这使其成为针对高致病性新兴病毒的一个有吸引力的疫苗平台。在此，开发了以脂质纳米颗粒（LNP）配制的1-甲基-假尿苷修饰的mRNA疫苗，用于对抗马尔堡病毒和密切相关的拉夫恩病毒（RAVV），这些疫苗基于这两种病毒糖蛋白（GP）的序列。用这两种疫苗对豚鼠进行接种引发了强烈的结合抗体和中和抗体，并对病毒复制、疾病和死亡提供了完全保护。该研究对抗体反应进行了表征，以确定两种病毒之间以及GP中具有广泛反应性的区域在结合和功能谱方面的差异。糖基帽首次被突出显示为马尔堡病毒的一个免疫反应位点，可诱导依赖于病毒的结合抗体和中和抗体反应。分析针对这两种病毒的抗体反应，有助于深入了解抗原差异如何影响对保守GP区域的反应，否则这些区域预计会有交叉反应，这对未来广泛保护性疫苗的设计具有重要意义。研究结果支持使用mRNA-LNP来对抗具有严重后果的病原体。
