Chinese Scientists Discovered Therapeutic Antibodies for Rift Valley Fever Virus

Rift Valley fever virus (RVFV) belongs to the genus Bacillus virus of the genus Fibriovirus. It is transmitted by mosquitoes and can infect animals and people. RVFV can cause ruminant abortion, and the mortality rate of sick cubs is nearly 100%. Historically, RVFV has caused many heavy losses to the livestock industry. People often have symptoms such as fever, headache, hemorrhage, shock, etc. after infection, and even death. From 2000 to June 2018, the world informed the WHO of 4,830 cases of severe cases of RVFV infection, including 967 deaths, with a mortality rate of nearly 20%. However, since the identification in 1931, there are currently no commercial human vaccines and specific therapeutic drugs. The prevalence of RVFV is mainly concentrated in Africa, but in 2000, RVFV broke through geographical restrictions and landed on the Arabian Peninsula, causing widespread outbreaks in Saudi Arabia and Yemen. In 2016, China also reported an imported case. Therefore, RVFV is a typical high-risk pathogen that can cause new outbreaks of infectious diseases.

Yan Jinghua, a researcher at the Key Laboratory of Microbial Physiology and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, has long been engaged in the research of therapeutic antibodies and novel vaccines. He has developed a new vaccine against MERS coronavirus (MERS-CoV) and has preventive and protective effects on animal models. MERS-CoV humanized antibody. Yan Jinghua collaborated with Gao Fu, an academician of the Chinese Academy of Sciences and a researcher at the Key Laboratory of Microbiology and Immunology of the Institute of Microbiology, and was the first to screen out Zika virus human-derived neutralizing antibodies. The two teams worked together again to address the country's major needs, and in one case of RVFV-infected rehabilitation patients, the monoclonal antibodies that efficiently neutralize RVFV infection were first isolated. The antibody is effective in treating RVFV infection in a mouse model and is expected to be a candidate for treatment of its infection. On April 1st, the results of the study were published in Nature Microbiology under the topic Neutralization mechanism of humanized monoclonal antibodies against Rift Valley fever virus.

The surface of RVFV virus contains two envelope proteins, Gn and Gc, which are key proteins responsible for virus-cell adhesion and membrane fusion. The Gaofu team has taken the lead in analyzing the structure of the Gn of the genus Plasmovirus with severe thrombocytopenia syndrome virus (SFTSV) and RVFV. In response to RVFV infection, the team first detected a high level of Gn and Gc binding antibodies in patients with RVFV infection, indicating that Gn and Gc can simultaneously stimulate the body's immune response. Therefore, with Gn and Gc as “bait”, the research team screened 8 antibodies that bind Gn and 1 Gc-binding antibody from the recovered patients. Then, through cell-level neutralization experiments, the team found that antibodies targeting Gn have extremely high neutralizing activity. In contrast, the isolated Gc antibody showed weaker neutralizing activity. Accordingly, in the mouse infection model, Gn-epitope specific antibody also showed good effects in preventing and treating RVFV infection, while Gc antibodies showed no significant protective effect. The research team further analyzed by flow analysis that Gn antibody can block the adhesion of Gn protein and RVFV virions to susceptible cells, while Gc antibody has no such effect. These results indicate that the Gn antibody blocks the adhesion of the virus to the cells by binding to Gn on the virions, thereby neutralizing the infection of RVFV. The research team separately analyzed the complex structure of Gn and 4 neutralizing antibodies, and identified three neutralizing antibody binding sites (A, B and C) on domain I (domain I, DI) of Gn, in which antigen Sites A and B are binding hotspots for neutralizing antibodies, and more than half of Gn antibodies target A and B.

This study reveals for the first time that Gn is the dominant antigen when RVFV is infected in humans, and there are at least two binding hotspots of neutralizing antibodies on Gn, which provides an important theoretical basis for the design of RVFV vaccine. More importantly, the highly effective human neutralizing antibodies screened and isolated by the research team will be important candidates for the prevention and treatment of RVFV infection.

Yan Qihua, associate researcher Wang Qihui, master student Ma Tong, Wu Yan, associate researcher of the Beijing Institute of Biological Sciences, Chinese Academy of Sciences, and Chen Zhihai, chief physician of the Infectious Diseases Treatment and Treatment Center of Ditan Hospital, shared the first author of the article. The study also received Professor Zeng Hui from the Institute of Infectious Diseases of Beijing Ditan Hospital, Wang Weiji, a researcher at the Shanghai Pasteur Institute of the Chinese Academy of Sciences, Professor An Zhiqiang from the University of Texas Health Medicine Center (Houston), Wang Junzhi, a researcher at the China Food and Drug Administration Institute, and Liang Mifang, a researcher at the China CDC. Qin Chuan, professor of the Chinese Academy of Medical Sciences, assisted and supported. The research was supported by the Chinese Academy of Sciences' Strategic Pilot Science and Technology Special (Class B) and the National Science and Technology Major Project. Yan Jinghua and Gao Fu were also supported by the National Natural Science Foundation's innovative research community.