Recruitment of volunteers for clinical trials has aroused concern; China independently develops and has complete intellectual property rights; for one of the most infected HIV strains in China
At 9:00 a.m. on June 15, four early volunteers, including post-90s students, post-80s young mothers and Post-70s medical enthusiasts, sat in a conference room of Youan Hospital in Beijing. The common purpose of their trip is to become clinical volunteers for the AIDS vaccine. At the moment, they are looking at the informed consent in their hands.
On March 24, 2016, a condom dispenser was installed on the outside wall of a dormitory building on the campus of Zhengzhou University. Information Picture/Visual China
Advice for recruiting volunteers for clinical trials of HIV vaccines in Youan Hospital, Beijing.
In June this year, the Center for AIDS Prevention and Control of China CDC released a recruitment information. China independently developed and fully intellectual property rights of the AIDS vaccine (DNA-rTV) recruited 160 Phase II clinical volunteers, who were required to be between 18 and 55 years old, healthy and HIV-negative, with a trial cycle of 2 years.
In recent years, the research and development of AIDS vaccine is one of the hotspots in medical research. Since the first AIDS vaccine entered clinical trials in 1987, more than 300 clinical trials have been carried out worldwide. In China, many research teams from many institutions, including CDC, Tsinghua University, Jilin University and Shanghai Public Health Clinical Center, are challenging this world problem. However, progress has not been smooth.
In fact, its not easy to get to the stage of human experimentation. The research of authoritative experts in the industry is laughed at asseeing rats die, and the animal experimentation will fail as soon as it comes to the stage of animal experimentation. An AIDS vaccine expert, who declined to be named, said.
The recruited volunteer HIV vaccine DNA-rTV is the worlds first replicated virus vector HIV vaccine to enter phase II clinical trial stage. The four clinical trials completed in the earlier stage were all ideal.
According to the plan, we should be able to see data on the protection rate of the vaccine by 2025. Professor Shao Yiming, Chief Expert of AIDS Prevention and Control of CDC and Chief Leader of DNA-rTV Project, told Xinjing News.
HIV vaccination no possibility of infection
After the recruitment information was released, the public reaction was very enthusiastic, and even went on the microblog hot search. This surprised Dr. Xia, who is in charge of receiving consultants in Beijing Youan Hospital. We have been recruiting like this all the time, but I didnt expect that this time we would suddenly be hot search. Dr. Xia said that many people came to consult recently. At most, there are about 20 people a day. There are more young people and there are all kinds of industries.
Clinical trials were launched at the same time in Beijing Youan Hospital and the First Affiliated Hospital of Medical College of Hangzhou Zhejiang University. Shao Yiming said that on the one hand, considering that the two hospitals have the foundation of AIDS research and treatment, on the other hand, two clinical centers, one south and one north, can also help to collect data of people in different areas.
According to the recruitment information, participants in the whole project will receive a subsidy of 15,000 yuan, which will be distributed to the bank card in stages.
However, financial aid is not the focus of volunteersconsideration. A volunteer from the Post-70s who came to consult with Xinjing Daily said that he was interested in medicine at ordinary times. He came after seeing the recruitment information and wanted to make some contribution to the progress of medicine. A post-90s student volunteer said he wanted to unlock new experiences in life, so he also called friends to participate.
The volunteers who participated in the project were also members of Xiangyang Blossom, a non-governmental public welfare community from concerned minorities. We also hope to contribute to the research. Volunteers rush to say.
It is not easy to become a clinical volunteer. They need to sign an informed consent after understanding the purpose, process and potential risks of the trial, and pass a series of screening including inquiry and physical examination. Participation in clinical trials is only possible if it meets the criteria and is voluntary.
Zhang Tong, deputy director of Beijing Youan Hospital Infection Center, told Beijing News that during the recruitment process, the most frequently asked question is whether people will be infected with AIDS because of vaccination. In fact, there is no real HIV virus in the vaccine, only some synthetic HIV gene fragments, there is no possibility of infection.
Generally speaking, new drugs and vaccines need to pass Phase I, II and III clinical trials before they are put on the market. Generally speaking, the purpose of these three phases is to test whether the product is safe, effective and generally effective. According to Dr. Xia, this clinical trial belongs to stage A of phase II. The main purpose is to test how long the vaccination interval is the best.
According to the informed consent, previous trials of DNA-rTV vaccine were completed in 2009, 2014 and 2017, with a total of 232 subjects. Experiments have proved that the vaccine has good safety and effectiveness in human body.
For this phase of clinical trials, volunteers need to visit the hospital regularly for examination and follow-up in the next two years. Owing to frequent business trips and lack of timely follow-up, the Post-70s volunteer interviewed by Beijing News reporters did not sign the informed consent.
This is quite normal. Zhang Tong told the Beijing News that volunteers quit the test after passing the physical examination, even after vaccination. The reasons for quitting include job changes, personal emergencies or simply not wanting to participate. Withdrawal at any time during the experiment is the right of the subjects.
There were volunteers who came to participate in the experiment without telling their families, and then quit because the informed consent they brought home was turned out by their families. There are also volunteers who ask to deposit their informed consent with us. Dr. Xia said.
As of June 20, Zhejiang Medical Hospital has recruited 56 subjects, Youan Hospital has recruited more than 80 people, and the remaining 20 places will be re-recruited later.
A boat with HIV gene fragments installed
Shao Yiming, 62 years old, has been studying AIDS vaccine for nearly 40 years. He is also one of the earliest researchers concerned about AIDS in China. In 1993, he carried out the earliest clinical trials of AIDS vaccine in developing countries in Yunnan with a number of experts, but the results were not satisfactory.
Now, his second AIDS vaccine project, DNA-rTV vaccine, has become the worlds most advanced HIV vaccine using replicative vectors.
The so-called replicative vector vaccine can be imagined as installing HIV gene fragments like a board into a small boat, which is vaccinia virus, a vaccine widely vaccinated in China as smallpox vaccine.
After entering the human body, the boat will continue to reproduce within two weeks to stimulate the human immune system and produce antibodies, so it is called live vaccine. Compared with the dead vaccine which does not reproduce and only decays gradually, the live vaccine has stronger and more lasting immune effect.
The use of replicative vaccinia virus is one of the biggest differences between this vaccine and other international AIDS vaccines. Shao Yiming said.
The selection of small boats, i.e. vaccine vectors, is crucial. Historically, other companies have tried different types of boats and failed.
American pharmaceutical giant Mercks Ad5 has been called the star of hope in the AIDS vaccine. The carrier boat chosen for this vaccine is adenovirus, the well-known cold virus.
However, when the vaccine was tested in Thailand, it not only effectively prevented HIV infection or reduced the level of HIV in blood of AIDS patients, but also increased the risk of HIV infection in some volunteers. In 2009, the experiment was called off.
This is the only test that has been proved ineffective and harmful in many clinical trials of AIDS vaccine. Since then, the technical route of AIDS using adenovirus as vector has failed.
Volunteers need to sign informed consents. New Beijing News reporter Han Qinke
No research can be harmful to subjects. Shao Yiming explained to the Beijing News that the failure of the test was mainly due to the wrong choice of vaccine vectors. Because some of the subjects had been infected with the cold virus, the immune system had a memory response to it, so when the cold virus boat sailed into the human body, it triggered a response, and a large number of white blood cells proliferated, which just provided a hotbed for the reproduction of HIV virus.
The vector chosen for DNA-rTV vaccine is vaccinia virus. Since smallpox has been extinct for many years, people will not be infected from nature, and the immune system will not have a memory response. Even the last batch of smallpox vaccinated people in China are now 40 years old. After such a long time, the memory response has been minimal.
No one should have been vaccinated after 1980. During the consultation, Dr. Xia said that here, several volunteers rolled up their sleeves at the same time, revealing elliptical marks about the size of the small nail cap on their arms. He explained with a laugh, You are the marks of BCG vaccination. At this time, just an older female doctor pushed the door in. As Chinas last batch of vaccinators, she left an almost invisible flower-like mark on the outside of her left upper arm.
DNA-rTV vaccine takes the technical route of live vaccine, which may be more effective, but at the same time, it also brings greater security challenges. To further ensure safety, Shao Yimings team removed a virulence gene board from the vaccinia virus boat and replaced it with an HIV gene fragment. This has reduced the virulence of vaccinia virus by more than 500-1000 times. It also stipulates that only those with a fully healthy immune system can be vaccinated. Shao Yiming said that only one case of low fever occurred in more than 200 subjects who participated in previous clinical trials, which lasted less than two days. By contrast, nearly a third of people had moderate to low fever after smallpox vaccination.
AIDS vaccine research and development like a road in the dark
Researchers have compared the development of AIDS vaccine to the road in the dark, which is particularly difficult.
Because of the high risk of HIV, researchers can not directly use attenuated or inactivated HIV virus in vaccines, but can only use genetic engineering technology to synthesize. According to the requirements of the Food and Drug Administration of the United States (FDA), the current level of laboratory technology can not even be verified if the level of HIV virus killing should reach a single killing of 1 trillion viruses.
Researchers often use influenza viruses that are more familiar to the public as analogies. Influenza viruses vary, requiring new vaccines every year to prevent them, but they are still insignificant compared with changes in HIV.
Professor Xu Jianqing, Clinical Center of Public Health of Shanghai (affiliated to Fudan University), said, A person with AIDS may carry more viruses than influenza viruses worldwide. Considering that there are different epidemic strains in different parts of the world, it is very difficult to develop a vaccine that can target all strains.
The DNA-rTV vaccine developed by Shao Yimings team is also only suitable for some strains. The vaccine targets one of the most HIV strains in China, which is infected by about 40% of people living with HIV in China.
What we are currently doing is conceptual validation. As long as it is scientifically proven to be effective, vaccines targeting the remaining 60% of the epidemic strains in China are expected to be completed in a year or two. Shao Yiming said.
Moreover, there is no need for all strains to have corresponding vaccines. In general, the establishment of an immune barrier can achieve effective prevention as long as it exceeds a certain proportion. That is to say, if no one around us is infected with the virus, it is not so important whether an individual carries the virus or is vaccinated.
In Xu Jianqings view, the process in which preventive vaccines work is like shooting at a target with a gun. The last centurys extinct smallpox virus is like a fixed target, only need to adjust and optimize to hit the target center, while HIV virus is equivalent to multiple moving targets, it is difficult to hit multiple targets at the same time.
Where is the bulls eye has been a difficult problem for researchers for many years. To solve this problem, Xu Jianqing was one of the first researchers to put forward the idea of attacking virus conservative areas. In his view, the mutation of HIV virus is caused by random mutation caused by the deficiency of reverse transcriptase function. The conservative region in the viral sequence may be the key point to maintain the survival of the virus, and this conservative region, like the heel of Achilles, may become the key to destroy the good body of Diamonds.
Snakes hit seven inches, Xu said, perhaps by attacking conservative areas of HIV, more extensive protective effects can be achieved. In the past few years, Xu Jianqings team has also been optimizing their AIDS vaccine. However, the whole development process takes a very long time, plus the observation of animal response time, each round of vaccine optimization takes about four months. There may be only three rounds of optimization in a year.
In addition, the lack of appropriate animal models is also one of the obstacles in the development of AIDS vaccine. HIV can only replicate in chimpanzees and gibbons that are similar to humans. AIDS was first transmitted to humans by chimpanzees. Shao Yiming mentioned it. But as key protected animals, these animals are forbidden to be used in medical experiments.
Difficulties make the development of AIDS vaccine long and difficult. Nearly 40 years have passed since the first case of AIDS was discovered in the United States in 1981. As of June 2018, 302 clinical trials have been conducted worldwide, but so far, no AIDS vaccine has been on the market.
In the research and development of AIDS vaccine, Chinese researchers have a certain advantage.
In the world, China is one of the few countries with independent technology route, independent research capability and good disease resources for AIDS vaccine. Shao Yiming said, The new HIV infection rate among gay men in China is one of the highest in the world. The higher the first HIV infection rate, the fewer samples needed in phase III clinical trials, which is conducive to accelerating the research and development process. In addition, volunteers in clinical trials in China have strong ability to recruit and manage, which is also helpful for the development of new vaccines.
Some people used to use the metaphor of climbing Mount Everest to evaluate the progress of AIDS vaccine research and development. In the past, we can only look at it from a distance, but now we are close, see the way up the mountain, and probably know how to go.
What else can we do besides waiting for a vaccine?
Shao Yimings right index finger has a very shallow trace, which was carelessly scratched 30 years ago when he studied lymphatic sections of AIDS patients. At that time, there were no measures or medicines, but they were resigned to fate. Fortunately, it was all right.
Many years ago, due to the lack of effective ways to prevent, interrupt and treat AIDS, high-risk groups often had nothing to do after exposure, and could only wait for infection grief or uninfected joy like gambling.
Even now, peoples fear of AIDS still exists. Some respondents said that parents of graduate students had come to consult with their tutors to try not to expose their children to live HIV, while some researchers found it difficult to find girlfriends because of their research on HIV.
In the 1990s, the Cocktail Therapy came into being, which combined three or more antiviral drugs to change AIDS from lethal to controllable. Now, AIDS can be seen as a chronic disease requiring long-term or lifelong medication, just like hypertension and diabetes. Zhang Tong said.
With the gradual maturity of treatment methods, the medical and health departments began to focus on the prevention and protection of high-risk groups.
Controlling the source of infection, cutting off the channels of transmission and protecting the susceptible population are the main ideas for the prevention and control of infectious diseases. AIDS vaccine is used to protect the susceptible population. Once the vaccine comes out, it will bring great changes to the prevention and control of AIDS, Zhang Tong said.
But before the emergence of vaccines, a variety of prevention programs were also under study. Zhang Fujie, Director of Clinical and Research Center of AIDS Infection in Beijing Ditan Hospital, told Xinjing News that for healthy people, unsafe behaviors and unsafe sexual behaviors such as drug abuse should be avoided; for high-risk groups, besides regular testing, it can also be prevented before exposure (that is, PrEP, made by taking two kinds of drugs every day). Compound preparations to reduce the risk of HIV infection in high-risk groups) for AIDS prevention.
Participants were concerned about the price and side effects of PrEP drugs at several seminars advocating cooperation between Xiangyanghua and hospitals. Moreover, PrEP drugs are currently lacking of legal purchasing channels in China. A volunteer said, Its all friends who bring back bottles when they go out to play, or find a special agent to buy them.
We still recommend minimizing risk behaviors. Even if the AIDS vaccine is developed successfully, it can only prevent AIDS, but not reduce the risk of infection with other viruses. Researchers have mentioned this point.
Source: New Beijing Daily Responsible Editor: Youyuan Garden_NO4712