Structural insights into the broad protection against H1 influenza viruses by a computationally optimized hemagglutinin vaccine.

Influenza virus poses an ongoing human health threat with pandemic potential. Due to mutations in circulating strains, formulating effective vaccines remains a challenge. The use of computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) proteins is a promising vaccine strategy to protect against a wide range of current and future influenza viruses. Though effective in preclinical studies, the mechanistic basis driving the broad reactivity of COBRA proteins remains to be elucidated. Here, we report the crystal structure of the COBRA HA termed P1 and identify antigenic and glycosylation properties that contribute to its immunogenicity. We further report the cryo-EM structure of the P1-elicited broadly neutralizing antibody 1F8 bound to COBRA P1, revealing 1F8 to recognize an atypical receptor binding site epitope via an unexpected mode of binding. Structural studies of a computationally optimized broadly reactive antigen hemagglutinin in complex with a broadly neutralizing antibody reveal its immunogenic properties and provide insights into flu vaccine design.

流感病毒对人类健康构成持续威胁，具有引发大流行的潜力。由于流行毒株的突变，研制有效的疫苗仍然是一项挑战。使用计算机优化的广泛反应性抗原（COBRA）血凝素（HA）蛋白是一种有前景的疫苗策略，可预防多种当前及未来的流感病毒。尽管在临床前研究中有效，但驱动COBRA蛋白广泛反应性的机制基础仍有待阐明。在此，我们报道了名为P1的COBRA HA的晶体结构，并确定了有助于其免疫原性的抗原和糖基化特性。我们还报道了P1诱导的广泛中和抗体1F8与COBRA P1结合的冷冻电镜结构，揭示1F8通过一种意想不到的结合模式识别一个非典型的受体结合位点表位。 计算机优化的广泛反应性抗原血凝素与广泛中和抗体复合物的结构研究揭示了其免疫原性特性，并为流感疫苗设计提供了见解。