A few days ago, a “mysterious 40 degrees north latitude” picture was circulated on the Internet. Is 40 degrees north latitude really prone to new outbreaks? On March 26th, Niu Junqi, deputy director of the Institute of Translational Medicine of the First Hospital of Jilin University, launched the third “Understanding the Future” scientific lecture: Virus and Human Health-Special Science Popularization in the Future Forum of Scientific Public Welfare Organizations. The origin and distribution of various new infectious diseases. It is concluded that the lower the latitude, the higher the incidence.
In the 1960s, people had a good record against infectious diseases. One Nobel laureate led a report saying that “infectious diseases are no longer an important public problem that threatens human health.” Half a century later, we are worried whether the COVID-19 virus will persist in humans for a long time, and we are more worried about the emergence of new infectious diseases.
In order to control emerging infectious diseases, Niu Junqi believes that research on target animals, monitoring of “human sentries” and monitoring of the general population are needed. He also explained the difficulties and opportunities of rapid testing, vaccine development, new drug development, and vaccine and drug development for emerging infectious diseases.
The full text of Niu Junqi’s speech was organized by Guo Lijie and Li Min, PhD students of the Institute of Biophysics, Chinese Academy of Sciences. The surging news is organized and released twice after being authorized.
Coping strategies for emerging infectious diseases
Niu Junqi: I came from an infectious disease doctor and have been in clinical practice for 38 years. In the past two decades, he has been engaged in the diagnosis and treatment of various infectious diseases. In the past ten years, he has mainly engaged in the research and treatment of viral hepatitis, and also participated in the clinical evaluation of new drugs and vaccines. Below I share with you from my learning experience and my work experience.
Today’s topic is about coping and strategies for emerging infectious diseases.
What is an emerging infectious disease? In the 1960s, people have made great achievements in the fight against infectious diseases. Some traditional and ancient infectious diseases have been controlled, such as smallpox can even be eliminated. In the 1960s, these achievements were encouraged, with one Nobel laureate leading a report that stated that “infectious diseases are no longer an important public issue that threatens human health.” But soon after the report was published, a series of new infectious diseases appeared, such as “legion disease”, which have not received widespread attention. It was not until the emergence of AIDS that people realized that new infectious diseases were still an important issue that seriously threatened human life. Subsequently, a variety of infectious diseases such as influenza, SARS, and Bunya virus infections broke out.
Emerging infectious diseases include the following: the first is an emerging species or strain that has never infected humans before but now has infected humans, such as HIV, SARS virus, and this time COVID-19 virus. The second is a disease that was prevalent in a small group of people and then spread to a new group of people. This is also called a new infectious disease. The third is that the scope of influence was not too large in the past, but because of changes in the ecological environment (such as extensive forest cover in the United States, forestry), some infectious diseases have caused widespread infections, such as Lyme disease. Now Lyme The disease also has a higher incidence in China. The fourth is that the disease can be treated in the past, but the existing antibiotics are not effective against it and cause resistance, such as drug-resistant tuberculosis infection, which is also called recurrent infectious disease.
So what causes the epidemic of new infectious diseases? The first is a change in microorganisms, such as influenza A virus, whose genetic variation has caused a new epidemic. The second is the change in human susceptibility. For example, AIDS destroys the human immune system, so it causes human infection. The third is the change in weather. Due to climate change (warming), zoonotic diseases caused by mosquito and tick bites have increased. For example, West Nile disease is transmitted by mosquitoes and is spreading from tropical to subtropical. The fourth is the change in population and trade. The convenience of transportation enables a disease to spread rapidly worldwide. If a locally transmitted disease spreads to intercontinental or global transmission, we also call it an emerging infectious disease. Fifth, changes in bacteria or viruses caused by economic activities, such as the addition of a large number of antibiotics in the aquaculture industry, have caused a widespread increase in drug-resistant bacteria in humans and animals. The sixth is the collapse of national public health systems, such as Zimbabwe. Seventh, poverty and social inequity will cause the spread of tuberculosis-based infectious diseases. Eighth, war, famine, and bioterrorism all bring outbreaks of infectious diseases. Ninth, the construction of dams and irrigation systems will also lead to changes in the reproduction of organisms and thus the emergence of new infectious diseases.
There have been dozens of new infectious diseases since 1980. First, coronavirus pneumonia, SARS and Middle East respiratory syndrome, these are very typical new infectious diseases. In the past, we thought it might be an infectious disease, but the pathogen has not been confirmed. After confirmation, we also call it a new infectious disease, such as hepatitis C and hepatitis E. Secondly, for example, hand, foot and mouth disease was originally transmitted in a small area, or it no longer seriously threatened human health after many years, but it has reappeared in recent years. We call it a recurring infectious disease. Finally, infectious diseases brought about by bioterrorism, such as anthrax. Anthrax used to be widely spread among humans in the past, but almost disappeared. Now it is caused by bioterrorism.
What types of diseases are these diseases? How do they spread? The “Nature” magazine summarizes the types of new infectious diseases from 1940 to 2000. We see that the types of these new infectious diseases include bacteria, viruses, molds, parasites, etc. Among them, the number of bacteria is the largest, accounting for all 54% of infectious diseases. However, many bacterial diseases can be predicted, such as the detection of bacterial strains in the hospital. If it is resistant, we consider it to be a new infectious disease. Therefore, people are not too panic about this bacterial infectious disease. In addition, there is another type of zoonotic disease, which accounts for 60% of new infectious diseases. It is transmitted from animals to humans. 71.8% of zoonotic diseases come from wild animals. Wild animals are an important source of emerging infectious diseases. In addition, some diseases are caused by the bite of mosquitoes and ticks, which are called arboviruses. This proportion is not particularly high. Bacterial diseases can be predicted, but zoonotic diseases are difficult to predict, and they occur very suddenly. This is also the focus of research on emerging infectious diseases.
Look at the global distribution of the relative risks of emerging infectious diseases. Red is a high fever area. Picture a is a hot spot for emerging infectious diseases of wild animal origin. In eastern China, Bangladesh, India, Pakistan, some Africa, and some European regions are all high incidence areas. Figure b is also an infectious disease of animal origin, but mainly poultry and livestock. In response to this type of infectious diseases, China and the Indian-Pakistani subcontinent are still high-incidence areas. Figure c This category is a new infectious disease caused by drug-resistant bacteria. It is a hot spot in China, India and Pakistan, and parts of Europe. Figure d is a vector-borne infectious disease. China is still a hot spot, including the Indian-Pakistani subcontinent and some African countries.
Why are we Chinese people suffering so many disasters? What is the reason for this? A few days ago, a picture on the Internet, “Heaven is hard to do”, everyone thought of the mysterious 30 degrees north latitude. There was an ancient and glorious civilization at 30 degrees north latitude, but I don’t know why it disappeared. For example, the Sanxingdui civilization in Sichuan, so far no one knows what caused these civilizations to disappear. Some people speculate that it may be caused by infectious diseases, and of course, much research is needed.
In fact, the picture circulated on the Internet is not quite right. It is believed that these countries with high incidence of infectious diseases are all 40 degrees north latitude. In fact, Wuhan is 30 degrees north latitude. These new infectious diseases mostly occur at 30 degrees north latitude and 30 degrees south latitude, that is, the higher the area near the equator, the higher the incidence. We see that this is a high-incidence area in China, some of which have expanded to 60 degrees north latitude, so generally the lower the latitude, the higher the incidence.
why? What factors are related to the emergence of new infectious diseases? In fact, it is obviously related to human activities, animal activities, and the natural environment. For example, the impact of human activities on zoonotic diseases includes tree planting, grazing, changes in cultivated land, and urbanization. Among animals, the diversity of mammals has the largest impact on the outbreak of infectious diseases. In addition, the number of livestock and poultry is also an important factor in the occurrence of new infectious diseases. In addition, it is the environment. The biggest impact is the forest, especially the evergreen broad-leaved forest, which affects animal activities and animal diversity. Quantitative analysis of these factors has led to the conclusion that human economic activities, environment and ecological factors provide the basis for the most likely origin of new infectious diseases. These factors explain why China and the India-Pakistan subcontinent are regions with high incidence of zoonotic diseases, because in low-dimensional areas, the polymorphisms of broad-leaved evergreen plants, animals, and mammals are most abundant. of. However, this figure shows that the newly discovered and reported infectious diseases are precisely in European and American countries, and more are found in areas with relatively low risk. Therefore, we must note that the prevention and prediction of emerging infectious diseases and the early detection measures taken by European and American countries are better than ours. It also shows that the global investment in the prevention and control of emerging diseases and the allocation of resources are obviously insufficient. The investment in high-incidence areas is small, and the investment in low-incidence areas is relatively sufficient.
Recently, the world has experienced several dramatic outbreaks of infectious diseases. These are the zoonotic diseases that have caused public health emergencies in humans. Coronavirus caused SARS in 2003, and most people still remember it. It is a new pathogen and a zoonotic disease. The Middle East Respiratory Syndrome is also a zoonotic disease, and the virus host comes from the unimodal camel. The 2009 H1N1 flu, which first occurred in Mexico, was caused by mutations in the influenza virus, and the earliest mutations occurred in pigs, so it is also called “swine flu”, which is also a zoonotic disease. Ebola virus is a zoonotic disease that caused the attention of scientists in the United States and Canada at the time in the 1970s. Early and pioneering research on the disease was made, and the disease did not appear in humans for a long time. Until 2013-2016, it broke out again. Zika virus occurs in Brazil, a zoonotic disease. The origin of these diseases is all countries and regions below 30 degrees latitude.
Will there be new infectious diseases in the future and where will they occur? It could be the area we mentioned above. Does the new coronavirus come back in the short or long term? China has basically achieved a decisive victory today. This virus has many characteristics very similar to SARS and very similar to Middle East Respiratory Syndrome. So if we want to get a good control, we must find the host of the earliest pathogen and cut off this route, and the virus will not come again or will not come again in a short time. However, some of the zoonotic diseases are long-term in humans after infection, such as HIV, which has a characteristic of chronic infection. From this perspective, are we too optimistic about the new coronavirus? My point of view was more optimistic before, but now it has formed a worldwide pandemic. If the outbreak is adequately controlled in various countries, the spread of the virus could be cut off this year. However, there have been outbreaks in more than 100 countries, and some countries have insufficient medical resources or public health management capabilities, so the spread of the virus will be more widespread, especially when the southern hemisphere winter is approaching, causing the virus to spread more widely. presence.
How to prevent new outbreaks of infectious diseases? Where do we control it is the most economical and effective? We look at the spread of zoonotic diseases. Initially it spreads in animals, then it spills over to humans. For example, bird flu and swine flu. Avian flu sometimes comes from chickens, and swine flu comes from pigs. The longest contact person is a chicken breeder or pig breeder. After the virus infects them, it spreads among the general population. Suppose we found and controlled the earliest host, so the investment is the most economical and the cost is the least. This time, Professor Shi Zhengli of Wuhan Virus Research Institute has been working for a long time to find the source of the virus, and finally found the coronavirus in bats. Later, researchers found the virus in pangolin. If animal origin studies are clear, the investment in virus prevention is minimal. Once the virus overflows, it may pass through intermediate hosts or it may spread directly to humans. The earliest humans who were exposed to the virus, taking this epidemic as an example, as “human sentries” are actually these people in the South China seafood market. If these people are monitored well, they will not spread to the majority of Wuhan citizens, and they will not be transmitted to the whole country and global. So early control is very important.
Surveillance of the general population is difficult now, and the US test kits are in short supply. Therefore, the control of new infectious diseases is best controlled at the source. Our country should increase virological research, especially the research on the etiology of zoonotic diseases. Some are already transmitted to humans, and some may be transmitted to humans. Increasing investment in this area is a very cost-effective preventive measure.
In addition to researching and blocking these three goals (research of target animals, monitoring of human sentinels for spill events, and monitoring of the general population), there are two important points that cannot be ignored, one is the intermediate host, so far We dare not finalize that it is from a bat. But pangolins or civets of the SARS virus are intermediate hosts, and we can find the exact intermediate host to cut off the transmission route. The other is the transmission vector. For example, malaria is mainly transmitted through mosquito bites. If you strengthen mosquito control or prevent mosquito bites, you can also block infectious diseases. At present, the incidence of malaria in the world has decreased significantly. The most effective measure is not artemisinin, but mosquito nets. After the mosquito nets are commonly used by people, the incidence of malaria has decreased significantly.
So in addition to these measures, what other strategies can we develop to prevent and mitigate the outbreak? One is to improve the ability to detect pathogens. It took us a short time to get the entire gene sequence of the coronavirus, and then established PCR detection methods and antibody detection methods. These technological advancements have improved the ability to detect pathogens. The other is that most people are paying attention to the research and development of vaccines and drugs. Obviously, vaccine research is the best way to deal with emerging infectious diseases. But we need to know that the vaccine goes through four stages from laboratory to human application. The beginning is the discovery phase. First we have to find a suitable source of immunity, which can be all of the pathogen, or it can be an effective antigenic part of the pathogen, which can stimulate humans to produce neutralizing antibodies. At present, you have seen some new news about our country’s research in the news. These are all in the early stages of the development of candidate vaccines. To my knowledge, it has not been verified in animal experiments. Therefore, it should be said that China’s vaccine research or global vaccine research and development is at a very early stage. A valid antigen has been found, and human safety and efficacy tests can only be performed after animal test verification. The safety and effectiveness requirements for verifying vaccines are very high, and this stage still takes a long time. Mass production can only take place after verification. It needs to be accumulated and stored after production, and then delivered to the people at risk, so this is a long process.
Some time ago, the Chinese Ministry of Science and Technology said that it would support the development of five vaccines, including inactivated vaccines, genetically engineered vaccines, adenovirus vector vaccines, nucleic acid vaccines and vaccines prepared from attenuated influenza virus vaccine vectors. There is an international epidemic prevention and innovation alliance (CEPI), which is supported and funded by the Bill Gates Foundation and others, and has successively supported the development of some new vaccines. It focuses on supporting new technology platforms, including DNA vaccines, RNA vaccines and molecular clamp vaccines.
In history, the influenza virus has caused 34 outbreaks in humans worldwide. Everyone is more impressed by the Spanish flu of 1918, but this is actually the most data left for people this time. At present, about 300,000 people die of influenza every year in the peak year, far exceeding the 3,000 deaths of the COVID-19 epidemic in China, so the research on influenza vaccines is very important and relatively mature. These influenza viruses, if attenuated, such as after being soaked in formalin or formaldehyde, have reduced activity and are not pathogenic. This is a live vaccine. If you soak the virus for a long time with high fever or formalin, it becomes an inactivated vaccine. Hepatitis A virus is available in both live and inactivated vaccines. There are also split vaccines that break the virus and no longer survive. There is also a virus-like particle vaccine, which does not have viral nucleic acid but retains the immunogenicity of the virus. At most, attenuated vaccines are used. With the advancement of technology in recent years, DNA vaccines, synthetic peptide vaccines and subunit vaccines have been gradually developed. Synthetic peptide vaccines are similar to subunit vaccines, except that synthetic peptides are synthetic antigens, and subunit vaccines are extracted antigens.
In addition to these vaccines, there are genetically engineered vaccines. Genetically engineered vaccines are those that insert the effective antigen of the virus into a plasmid, which is then transfected into other cells to replicate and culture. After extraction, it is injected into humans. This technology is very mature It is applied to the preparation of HPV vaccine and hepatitis B vaccine.
In addition, the DNA vaccine is a plasmid made of viral DNA, which is then replicated in large quantities and injected directly into human muscle. At this time, muscle is equivalent to yeast cells or E. coli. The plasmid is replicated in muscle cells and then transcribed into RNA then expresses antigens that stimulate the body to produce antibodies.
We have done clinical trials of HBV DNA vaccine and found that it is difficult to get into muscle cells by injection alone, so we need to use gene gun, so the transfection efficiency will be higher. Even so, the amount of antigen expressed by DNA vaccines is not sufficient, so although DNA vaccines are the easiest to develop vaccines from the perspective of production, preparation, and early research and development, how to generate sufficient antigens remains to be solved. So someone asks if direct injection of mRNA is OK? In recent years, some researchers have also developed mRNA vaccines, which may be simpler to express in vivo than DNA vaccines, so the amount of expressed antigens will be more mature. However, the technology of RNA vaccine is still at an early stage, and there are still many problems to be solved.
Ebola virus now has several approved vaccines, including those approved in the United States and China. China has approved an adenovirus vaccine. Adenovirus is a large group of viruses that cause upper respiratory tract infections and some cause pneumonia. Most adenoviruses are non-pathogenic. They are very large and have a size of 40 kb. If an antigen of a virus is incorporated into the adenovirus and then the virus is replicated, it will induce the body to produce comprehensive antibodies. But the problem is that this adenovirus has been widely infected in humans. In previous studies, it was found that almost 100% of Chinese people have been infected with adenovirus. Therefore, after the adenovirus vaccine is injected, the antibodies produced quickly clear the adenovirus with the antigen, so its expression time in the body is relatively short. Adenovirus vaccines are relatively easy to prepare in the early stages, but the use of adenoviruses to prepare therapeutic hepatitis B vaccines does not provide sufficient immunological expression. In addition, there are several other vectors for the Ebola vaccine, such as VSV (vesicular stomatitis virus) and HPIV3 (human parainfluenza virus 3).
It should be said that the development of vaccines requires very high safety and effectiveness. Not only is vaccine development difficult, but approval is not easy. The US FDA has formulated an animal rule for emerging infectious diseases, that is, animal experiments can be approved if they are successfully performed. This is only suitable for situations where safety and effectiveness research cannot be done in humans but the disease seriously threatens human health, such as The anthrax vaccine is approved for marketing based on the safety and effectiveness obtained from animal experiments. Our country also approved the marketing of the Ebola virus vaccine. Academician Chen Wei conducted a clinical trial with Tianjin Kangsino. For this coronavirus, she and Kansino also jointly conducted a vaccine research. Although this vaccine is made in Africa, Part of the study, but no large-scale clinical validation.
The development of vaccines should be said to be very difficult. Since the SARS outbreak, people have invested a lot of enthusiasm and energy in developing SARS vaccines in the early days. Now 17 years have passed, and there has been little progress. Why is this so? A vaccine study needs about $ 500 million to $ 1 billion to support, and a decade or so. Many people now say that the vaccine we have developed is about to enter the human body, but it is still very early. Another problem is that human infectious diseases require many vaccines. Between 600,000 and 700,000 patients die each year from AIDS, tuberculosis, and hepatitis B. These diseases require vaccines. However, currently there is no vaccine for AIDS, BCG for tuberculosis is not completely effective, the hepatitis B vaccination procedure is also complicated, and the influenza vaccine needs to be vaccinated every year. In this way, for governments or enterprises, they are more willing to invest human and material resources in these vaccines, and their enthusiasm for sudden infectious diseases is not high enough.
There is a gold standard in the industry for developing a drug and vaccine, which is an average of 11.9 years and an investment of $ 800 million. These two figures are more accurate. In 2003 Dimasi calculated that the development of a new drug or vaccine required US $ 800 million, with a success rate of 21%. In 2004, Kola calculated that R & D investment was about 900 million US dollars, and the success rate was 11%. Gilbert estimates that R & D investment is about 1.7 billion, but the success rate is 8%. So the success of a drug or vaccine development is related to capital investment, but it is also affected by many other complex factors. Overall, the success rate of investment is around 10% -40%, which means that it may not be successful after investment.
Even if the company invests money, it may not be able to develop a vaccine, and the company needs to be profitable, so it needs government and charitable funds to make investments in this area. What has done better in this regard is the Bill and Melinda Gates Foundation, the World Economic Forum, the Wellcome Trust, and the Epidemic Prevention and Innovation Alliance established by the Norwegian and Indian governments in 2016 ( CEPI), the German and Japanese governments also joined as investors. What diseases do they study? In 2018, WHO experts listed diseases that were prioritized for development, such as Marburg pneumonia, Middle East respiratory syndrome, SARS, and disease X, which are unknown diseases. It seems that the COVID-19 epidemic is one of the X diseases, and there may be other diseases.
The alliance invested some funds, but it was far from enough. I hope the Chinese government will also consider joining such a fund organization. I believe that China’s enthusiasm for investment in this area is very high. We also look forward to the earliest vaccine development in China.
In addition to the above, vaccine development faces many complex factors. Take the SARS virus vaccine as an example. After it was developed, the epidemic would be gone. There is no way to conduct Phase II and Phase III clinical trials. Clinical verification must be performed during the epidemic to prove it is effective, but the disease is no longer epidemic. There is no way to continue. So what should this test do? Prepare clinical trials as early as possible, and once the sudden illness returns, it can perform on-site effect certification, so as to scientifically and comprehensively test the effectiveness and safety of the vaccine.
We just mentioned the development of vaccines, but we also need to find some drugs. During the epidemic of the COVID-19 virus, there were more than 200 drugs starting clinical research registered on the Chinese New Drug Registration Website. Will these more than 200 be successful? The vast majority are doomed to failure. What kind of drugs should we study? To learn from antibiotics, there are broad-spectrum antibiotics. Ribavirin and interferon in antiviral drugs are broad-spectrum antiviral drugs. The remaining drugs are very specific. The treatment of hepatitis B is hepatitis B, and the treatment of influenza is influenza. Will not treat other diseases. However, there are exceptions. For example, AIDS drugs are also effective in treating hepatitis B. If there is such a broad-spectrum antiviral drug, even if a new virus is outbreaked, this broad-spectrum antiviral drug can also work. This is the most ideal situation. . In the past, a drug was used to treat a disease. The target of treatment can be viral proteases, but can a drug inhibit all viral proteases? That’s one medicine for multiple uses. In addition to proteases, such as polymerases, RNA-directed polymerases, or DNA-directed polymerases are all possible. As long as these enzymes are inhibited, one drug can be used for multiple purposes. These drugs are targeted at viruses. If the body’s antiviral ability is improved, can it also inhibit all viruses? This is another way of thinking, so that it becomes “one medicine and multiple uses” or “one stone and more birds”.
There are many other ideas for this method, such as overlapping infections. If a virus that is harmless to humans first infects people, it is possible to prevent the infection of another virus. The other is targeted host therapy. Toll-like receptor agonists can now treat hepatitis B and AIDS. If these drugs mature in the future, they may also treat new diseases. In this outbreak, the most prominent and most hopeful is Rhedivevir. Through early research, it was found that it is a broad-spectrum coronavirus drug, which has effects on the treatment of MERS and SARS. Because SARS and MERS are both coronaviruses, this time people applied it to the research of new coronaviruses. We look forward to its successful research at an early date. If successful, it will be a very good inspiration for broad-spectrum antiviral drugs. Hepatitis C virus polymerase inhibitors have been found to inhibit caliciviruses, hemorrhagic fever viruses, etc., and may also become a broad-spectrum antiviral drug.
In addition, it can be tested whether the old drugs can be used as new antiviral drugs. Due to the prevalence of hand, foot and mouth disease, the French director of the Shanghai Pasteur Institute did a study. He found a very old antiviral drug, suramin, which played an antiviral effect both in vivo and in vitro. Antiviral drugs actually have many different targets. So we can find approved drugs in the database to try to treat new viruses. Their early animal experiments, human experiments, and safety have been confirmed, as long as their effectiveness is confirmed during the epidemic of the new virus, so the new use of old drugs is a fast and economical treatment. These small molecule drugs are contained in various databases, such as 1280 drugs in the Prestwick Library, more than 2000 drugs in the Bioactive Compound Library, and more than 7,000 drugs in the NIH Clinical Collection database. These drugs can be used as new drugs Filter. For example, this time it was discovered that chloroquine hydrochloride, which is used to treat malaria, has an antiviral effect. Because this is an old drug, phase IV clinical trials can be applied. Many approved drugs, such as interleukin 6 inhibitors, have been found to have the potential to suppress inflammatory storms, so they may play a good role in this viral infection treatment.
To sum up, the new coronavirus infection is an emerging infectious disease, and our country is a hot spot for outbreaks of new infectious diseases. This new infectious disease is mainly zoonotic. New infectious diseases face huge challenges in the development of vaccines and drugs, but also face opportunities. It is worthwhile to develop new applications of broad-spectrum drugs and old drugs. Pay attention to R & D strategies.