A human monoclonal antibody targeting the monomeric N6 neuraminidase confers protection against avian H5N6 influenza virus infection

Affiliations

• CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
• Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People’s Hospital, Shenzhen, China
• Faculty of Health Sciences, University of Macau, Macau, China
• BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health; Southern Medical University, Guangzhou, China
• Medical School, University of Chinese Academy of Sciences, Beijing, China
• Beijing Life Science Academy, Beijing, China
• Health Science Center, Ningbo University, Ningbo, China

PMID:  39402031  DOI: 10.1038/s41467-024-53301-6

Abstract

The influenza neuraminidase (NA) is a potential target for the development of a next-generation influenza vaccine, but its antigenicity is not well understood. Here, we isolate an anti-N6 human monoclonal antibody, named 18_14D, from an H5N6 avian influenza virus (AIV) infected patient. The antibody weakly inhibits enzymatic activity but confers protection in female mice, mainly via ADCC function. The cryo-EM structure shows that 18_14D binds to a unique epitope on the lateral surface of the N6 tetramer, preventing the formation of tightly closed NA tetramers. These findings contribute to the molecular understanding of protective immune responses to NA of AIVs in humans and open an avenue for the rational design of NA-based vaccines.

流感病毒的神经氨酸酶（NA）是开发下一代流感疫苗的潜在靶点，但其抗原性尚不完全清楚。在这里，我们从一名感染H5N6禽流感病毒（AIV）的患者中分离出了一种抗N6的人源单克隆抗体，命名为18_14D。该抗体对酶活性的抑制作用较弱，但在雌性小鼠中提供了保护，主要通过抗体依赖性细胞介导的细胞毒性（ADCC）功能实现。冷冻电镜（cryo-EM）结构显示，18_14D与N6四聚体侧面上的一个独特表位结合，防止了紧密闭合的NA四聚体的形成。这些发现有助于我们对禽流感病毒神经氨酸酶的保护性免疫反应的分子理解，并为合理设计基于NA的疫苗开辟了新的途径。

结果：18_14D对H5N6神经酰胺酶(N6)亲和力高，有较强的ADCC活性，但是无法抑制H5N6病毒复制；体内实验显示，18_14D对小鼠模型具有较好的预防感染和一定的感染后治疗效果，其预防和治疗效果高度依赖抗体的ADCC活性。