Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Henry M. Jackson Foundation for the Advancement of Military Medicine, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Nat Immunol. 2019 Mar;20(3):362-372. doi: 10.1038/s41590-018-0305-x. Epub 2019 Feb 11.
The present vaccine against influenza virus has the inevitable risk of antigenic discordance between the vaccine and the circulating strains, which diminishes vaccine efficacy. This necessitates new approaches that provide broader protection against influenza. Here we designed a vaccine using the hypervariable receptor-binding domain (RBD) of viral hemagglutinin displayed on a nanoparticle (np) able to elicit antibody responses that neutralize H1N1 influenza viruses spanning over 90 years. Co-display of RBDs from multiple strains across time, so that the adjacent RBDs are heterotypic, provides an avidity advantage to cross-reactive B cells. Immunization with the mosaic RBD-np elicited broader antibody responses than those induced by an admixture of nanoparticles encompassing the same set of RBDs as separate homotypic arrays. Furthermore, we identified a broadly neutralizing monoclonal antibody in a mouse immunized with mosaic RBD-np. The mosaic antigen array signifies a unique approach that subverts monotypic immunodominance and allows otherwise subdominant cross-reactive B cell responses to emerge.
目前的流感病毒疫苗不可避免地存在疫苗与流行株之间抗原性不一致的风险，从而降低了疫苗的效力。这就需要新的方法来提供更广泛的流感保护。在这里，我们设计了一种使用病毒血凝素的超变受体结合域 (RBD) 展示在纳米颗粒 (np) 上的疫苗，该疫苗能够引发中和跨越 90 年的 H1N1 流感病毒的抗体反应。随着时间的推移，来自多个毒株的 RBD 共展示，使相邻的 RBD 具有异型性，为交叉反应性 B 细胞提供了亲和力优势。用嵌合 RBD-np 免疫可引起比用包含相同 RBD 集合的纳米颗粒混合物作为单独的同型阵列的混合物引起更广泛的抗体反应。此外，我们在用嵌合 RBD-np 免疫的小鼠中鉴定出一种广谱中和单克隆抗体。这种嵌合抗原阵列标志着一种独特的方法，可以颠覆单型免疫优势，并允许出现否则处于次要地位的交叉反应性 B 细胞反应。
