The world's first hepatitis E vaccine developed by Xiamen University

 Reporters : Xie Kaifei, Ouyang Guilian / Publisher : Science & Technology Daily

Ref : http://news.sciencenet.cn/htmlnews/2020/8/444576.shtm / Direct translation

Recently, the team of Professor Xia Ningshao of Xiamen University and the team of Associate Professor Zhu Jiang from the Scripps Research Institute in the United States published a research result in Nature Communications, revealing many "secrets" of the hepatitis E vaccine.

In 2012, the world’s first hepatitis E vaccine "Yikoning" was launched. The vaccine was developed by Xiamen University National Infectious Disease Diagnostic Reagents and Vaccine Engineering Technology Research Center and Yangshengtang Beijing Wantai Biopharmaceutical Co., Ltd. (hereinafter referred to as Yangshengtang). It is the only hepatitis E vaccine on the market so far.

Current clinical trial data and animal experiment results suggest that the hepatitis E vaccine has the potential to protect different genotypes of hepatitis E virus infection. However, how does the hepatitis E vaccine stimulate the body's antibody response after it enters the human body? Why can these antibodies prevent other genotypes of hepatitis E virus infection? For many years, these were unresolved scientific questions.

The above-mentioned research results reveal for the first time the source of protective antibodies induced by the hepatitis E vaccine, and confirm that the antibodies induced by the hepatitis E vaccine have a cross-type broad-spectrum protective effect, which will help the global promotion of the hepatitis E vaccine.

No specific medicine, vaccine is an important preventive measure

Hepatitis E is a type of viral hepatitis caused by hepatitis E virus (HEV) infection, ranking fifth in the large family of viral hepatitis. The clinical symptoms are similar to those of hepatitis A, generally manifested as flu-like prodromal symptoms such as fever and nausea, accompanied by symptoms such as jaundice, anorexia, and hepatomegaly.

The World Health Organization estimates that 20 million people worldwide are infected with the HEV virus every year, and about 3.3 million of them have hepatitis E symptoms. Among high-risk groups (pregnant women and patients with chronic liver disease), the mortality rate of hepatitis E is as high as 20%-30%, which has become an important public health problem worldwide. In my country, the annual incidence and death toll of hepatitis E has exceeded that of hepatitis A.

Currently, there is no specific treatment for hepatitis E infection in the world. Therefore, the development of effective preventive vaccines becomes the best choice.

In 1998, researchers at Xiamen University began to study hepatitis E vaccine. Through the original innovation from target to technology, Xiamen University and Yangshengtang Wantai Biotechnology finally established the world's unique prokaryotic expression virus-like particle vaccine technology system and successfully developed the world's first hepatitis E vaccine "Yikoning". It was listed in 2012. The R&D team also won the Qiushi Outstanding Technological Achievement Collective Award and the China Patent Gold Award.

What role will "Yikoning" play in the prevention and control of hepatitis E? "HEV viruses that infect humans are mainly divided into 4 genotypes, and there are big differences in epidemic trends, clinical manifestations, and infected hosts." Associate Professor Zheng Zizheng from the School of Public Health, Xiamen University said, among which, there are very few reports of genotype 2 In China, genotypes 1 and 4 are currently prevalent, and genotype 3 is more popular overseas.

The main active ingredient of the hepatitis E vaccine developed by Xiamen University is a recombinantly expressed type 1 HEV virus protective antigen, which theoretically prevents type 1 HEV virus infection. The results of phase III clinical trials conducted in my country show that the hepatitis E vaccine has a preventive effect against hepatitis caused by hepatitis E viruses of type 1 and 4 that are circulating in China, and the protection rate can reach 100%, which can be described as "two birds with one stone".

The hepatitis E vaccine can be stored at 4°C for 36 months, and its effectiveness and antigenicity remain good. Even if it is placed at 42°C for 14 days, the vaccine is still available. "This is a significant advantage for regions without vaccine cold chain transportation conditions, and it also greatly reduces the requirements for transportation costs and transportation conditions." Zheng Zizheng said.

Very effective, able to induce a broad spectrum of neutralizing antibody responses

In January 2019, the U.S. Food and Drug Administration approved an application for clinical trials of the hepatitis E vaccine in the United States. The National Institutes of Health fully funded Emory University in the United States to carry out a phase I clinical trial of hepatitis E vaccine. This is the first clinical trial of a Chinese vaccine in the United States.

Clinical trial data and animal experiment results show that genotype 1 hepatitis E vaccine can prevent genotype 4 HEV infection. In the rabbit infection model, the hepatitis E vaccine also showed a good effect on the type 3 HEV virus. However, Zheng Zizheng pointed out that this is only the result of animal models. Whether the hepatitis E vaccine can also induce antibodies that are reactive to different genotypes of HEV viruses in humans remains to be further explored.

In order to clear up doubts, Xiamen University researchers and foreign collaborators have done more detailed research. The research results released this time reveal this mystery at the molecular level. At the same time, the research reveals how the human body responds to the hepatitis E vaccine.

"The whole course of hepatitis E vaccine requires three injections. For every injection of hepatitis E vaccine, the human body will have a targeted immune response, produce antibodies and develop antibody evolution." Zheng Zizheng said. Faced with the difficulties of organizing large-scale clinical trials in foreign populations, researchers creatively use single B cell research technology, low-bias antibody panels and traditional serological analysis methods to study a small sample of hepatitis E vaccination populations The subjects, from the three levels of single cell, cell population and serology, revealed the dynamic changes of the occurrence, development and maturation of protective antibodies in the human body during vaccination.

The researchers found that after completing the three-shot vaccination, the antibodies induced by the hepatitis E vaccine can recognize the hepatitis E virus capsid proteins of type 1, type 2, type 3, and type 4, and are compatible with hepatitis E virus coats of different genotypes. The reactivity of the shell protein is comparable. Accurate analysis at the antibody molecular level revealed that the hepatitis E vaccine can effectively induce a broad-spectrum and efficient neutralizing antibody response, and has a good preventive effect on the major HEV genotypes that are circulating worldwide.

"In short, previous clinical trials have proved that the hepatitis E vaccine has the ability to prevent genotypes 1 and 4. In the latest research, through clever experimental design, it accurately reveals how the hepatitis E vaccine is in the human body. Play a role." Zheng Zizheng pointed out that the results proved that the antibodies produced by the human body by the hepatitis E vaccine can "kill" hepatitis E viruses of type 1, 2, 3, and 4, that is to say, as long as the hepatitis E vaccine is vaccinated , It will be able to "four birds with one stone" and resist the hepatitis E virus, which is the main epidemic worldwide.

Efficient and fast, different groups of people can produce antibodies

The reporter of Science & Technology Daily learned that the production of antibodies is an extremely complex process, which is rearranged, evolved, and encoded by multiple germline genes. The more diverse germline genes are from, the better antibody responses can be produced by different individuals. 

In this study, researchers found that the germline genes that the vaccine induces to produce antibodies have a wide range of sources, suggesting that they can provoke an effective antibody response in different populations around the world. The degree of somatic mutation of the hepatitis E vaccine-specific antibody gene is relatively low, and the protective antibody induced by the vaccine does not require long-term evolution and extensive maturation to obtain virus neutralization ability. "In layman's terms, the hepatitis E vaccine induces the human body to produce antibodies with high efficiency and speed, making it easy for people to obtain protection." Zheng Zizheng said.

Currently, Phase III clinical studies of vaccines are an important process for evaluating the safety and effectiveness of vaccines. Due to the diversity of the population and the complexity of the immune system response, the vaccine phase III clinical evaluation has the characteristics of large investment, large number of people, long period and high risk. How to more effectively evaluate and predict the potential safety and effectiveness of vaccines in large-scale use in small-sample studies is of great significance to vaccine development.

It is worth noting that this hepatitis E vaccine study combines single-cell antibody cloning and low-bias lineage tracing to establish a research platform for immune response analysis, which is helpful in the early stages of clinical trials (phase I or II). ) Analyze the antibody response of vaccine recipients, predict the effectiveness of the vaccine, reduce the risk of phase III clinical trials, and the evaluation results may be used as a basis for conditional approval of vaccine marketing in emergency situations.

"Currently, there is no hepatitis E screening in the routine screening of viral hepatitis in hospitals. The clinic does not pay enough attention to hepatitis E, which also makes people not understand and pay insufficient attention to hepatitis E." Zheng Zizheng suggested that in order to implement the World Health Organization 2030 the global goal of eradicating viral hepatitis in 2015 requires all sectors of society to pay attention to hepatitis E prevention, accelerate the implementation of hepatitis E prevention and control strategies, and promote high-risk groups, such as chronic liver patients, women of childbearing age, the elderly, immunosuppression, and travel to epidemic areas People and other people are vaccinated against hepatitis E. At the same time, the World Health Organization's production pre-certification of hepatitis E vaccine will be accelerated to benefit people all over the world.