Caixin
Mar 19, 2020 09:42 AM
SOCIETY & CULTURE

Exclusive: Why ‘Smart’ Covid-19 Virus May Be Here to Stay

Shao Yiming, chief HIV/AIDS expert at the Chinese Center for Disease Control and Prevention.
Shao Yiming, chief HIV/AIDS expert at the Chinese Center for Disease Control and Prevention.
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Chinese health authorities initially failed to identify and control the threats posed by Covid-19 because of faulty assumptions and weaknesses in a carefully constructed direct reporting system, according to Shao Yiming, a prominent virologist who is chief HIV/AIDS expert at the Chinese Center for Disease Control and Prevention (CDC).

The nation’s CDC lacks the resources needed to effectively do its job in a country the size of China, he said in an extensive, exclusive interview with Caixin. The Covid-19 pandemic should serve as “an opportunity to make concrete efforts to improve public hygiene and health,” he argued.

“The authority of the technology sector does not lie in how much political power it’s given but in its world-leading position,” Shao said. “Professionals should be allowed to do their jobs without administrative intervention that violates objective laws. The whole society, from the people to the leaders, should establish a culture of respect for science and regulate their behavior based on such culture. Otherwise, we all will pay big price.”

Shao, 63, has worked his entire life in disease control. He earned his Ph.D. in 1988 at the Virology Institute of the Chinese Academy of Preventive Medicine, the predecessor of the CDC. In the late 1980s, he worked at the World Health Organization in Geneva as a consultant in the biomedical research division of the Global Program on AIDS. In 2002, upon the official establishment of the CDC, he became the agency’s chief expert on AIDS and a member of the Infectious Disease Standard Committee and the Advisory Committee of Prevention and Control of Infectious Diseases at the National Health Commission, vice chairman of the Chinese Society for Microbiology, chairman of the Virology Committee and a member of the International Committee on Taxonomy of Viruses.

In the interview with Caixin, Shao said that the characteristics of the new coronavirus suggest that it may persist and recur like seasonal influenza and that it has not mutated to be stronger or weaker. Conspiracy theories notwithstanding, he said there is no sign of human manipulation in the novel coronavirus.

“Viruses are nanoscale and, with very few exceptions, cannot be seen at all under an optical microscope,” Shao said. “But they are the most abundant living things on earth, with a total of 10 to the 31st power. If you connect the world's viruses end to end, and it would be 10 billion light years long. We live in an ocean of viruses, so to speak. Don’t try to break the symbiosis that has formed in nature. Otherwise we will have the situation we have today.”

Shao said the failure of the CDC’s direct reporting system may be related to an erroneous assumption that health authorities were dealing with another avian influenza that probably wouldn’t involve human-to-human transmission. Putting the initial focus on the seafood market where the outbreak is believed to have originated was probably a mistake, he said, and an even bigger error was that the phenomenon was reported only through the health administration and not through the direct reporting system to the CDC. But giving the CDC greater administrative power probably isn’t the right solution, he argued.

“If the CDC staff become government officials, things can only be worse than now,” Shao said.

Shao said he has observed the outflow of a large amount of talent from the disease control system and a shortage of leaders in related scientific subjects, while only a third of the county-level disease control staff have college degrees. In view of the CDC’s performance in this outbreak he advocates “vertical reform to the bottom, and horizonal reform to every aspect.”

What follows is a transcript of his interview with Caixin.

‘Smart’ virus and ‘dumb’ virus

Caixin: We experienced SARS in the early 2000s, then MERS, and now Covid-19. All these outbreaks were most likely caused by cross-species transmission of coronavirus carried by bats. What is the chain of transmission?

Shao: In nature, cross-species transmission of viruses needs to overcome the species barrier. From the storage host to the intermediate host and then to humans, each crossing has a very high threshold. This is a low-chance event that doesn’t happen very often. The species barrier is designed to keep the genetic information of a species stable. Otherwise, genes will move back and forth between species, breaking the balance of nature.

The natural host, or so-called storage host, is a reservoir of viruses in nature. The viruses it carries usually do not infect humans directly. Shi Zhengli’s team at the Wuhan Institute of Virology quickly identified the natural host of Covid-19 as horseshoe bats from Yunnan, with 96% similarities in genomic sequences. Covid-19 has about 30,000 base pairs, which means about 1,200 base pairs have changed compared with the coronavirus carried by bats. Viruses mutate at a rate of about 0.1% a year. With 30,000 base pairs, about 30 will mutate each year, which means it takes about 40 years for a bat coronavirus to become Covid-19.

If a virus carried by animals needs the mutation of only about a dozen base pairs to become the same virus in humans, it’s possible to cross the species barrier to infect humans in a short time. In this case, these animals are called intermediate hosts. In the SARS epidemic, scientists found that the genomic sequences of the coronavirus in civets are 99.9% similar to the SARS virus in humans. Only when a virus has evolved this far does cross-species transmission have a high probability.

Some scientists suggested that the pangolin may be the intermediate host of Covid-19. However, the coronavirus found in pangolins shares only at most 92% of their whole genomes with Covid-19, so it shouldn’t be the intermediate host.

Caixin: But now the Huanan Seafood Market in Wuhan has been shut down and sterilized. Will that affect our search for the intermediate host?

Shao: While finding the intermediate host is very important to prevent the return of the virus, it is not the most important for controlling the current epidemic. If there are 100 kinds of wild animals in a market, and the intermediate host of the virus must be among them, then killing all of the 100 kinds of animals in an emergency response can cut off the continued transmission of the virus from animals to humans. Instead of killing them all, try to figure out which one is the intermediate host and then cut off the transmission. That’s a precision strike, but it takes time. In an emergency response, the two methods are simply the same approach to different degrees.

Prevention and research are two separate things. Ideally, they should be done in parallel. Prevention staff were right to shut down and sterilize the seafood market immediately. But it would have been better if another team of researchers were allowed to keep some samples from each vendor’s stall. I think there’s still a chance to take some make-up measures. The market administration should have registration information about where the goods sold in the market came from and what animals each vendor sold. I don’t think the chances are all gone and it’s impossible to find the intermediate host. It just may take more time and casting a bigger net to find out. A Covid-19 trace study organized by the Ministry of Science and Technology is conducting such investigations and is believed to be able to find the intermediate host eventually.

In addition to the trace investigation at the seafood market, in order to speed up the process, the virus can be experimented on target animals so as to observe which animals the virus can infect and form a healthy and stable virus-carrying state. Because only if the animal is adapted to the virus can it pass the virus to humans as an intermediate host without becoming ill itself. If the host can be infected quickly but become ill, it can’t carry the virus stably for a long time. A sick animal can’t sell, so it won’t enter the market and have the opportunity to spread the virus to humans. There are a number of experimental methods to test whether the virus can reproduce and shed in animals.

Caixin: What’s the point of finding “patient zero,” or the first person infected?

Shao: From an epidemiological perspective or just out of curiosity, many scientists are willing to spend time looking for patient zero. But for emergency response, it’s not that important. The specific significance of finding patient zero is to be able to determine the time of initial infection, and then estimate the scope of transmission and epidemic scale. The second purpose is to find the intermediate host. The animals that patient zero had contact with could be the intermediate hosts.

Finding patient zero is the ideal state for disease-tracing research. It’s easier to find in acute infections and harder in chronic ones because the incubation period (the time from initial infection to onset) is short in the former and long in the latter. For the acute infectious disease Ebola, researchers did find patient zero, but not the intermediate host. The patient zero, who delivered food to railroad workers, traveled more than 20 kilometers a day through the forest and had contact with too many animals. If the person lives in an urban environment, it is easier to trace because he may be exposed to only one or two kinds of domestic animals. So whether scientists can find the intermediate host from patient zero also depends on the range of wildlife the person has contact with.

In addition, there are cases of identifying the wrong patient zero. Take the example of U.S. patient zero of AIDS, a chronic infectious disease. Here, we’re not talking about patient zero that was infected across species, but the patient zero who first brought the virus to the U.S. I proposed to establish a WHO network for HIV isolation and identification. It took scientists more than a decade to find that the spread of HIV from chimpanzees to humans occurred about 100 years ago. Tracing studies at the time determined that patient zero was an Air Canada flight attendant who flew to many cities in North America, causing widespread human transmission. But scientists later discovered that his viral genomic sequences were not on the root of the evolutionary tree at all. He was just the earliest patient in terms of illness time. The incubation period for AIDS is on average eight to 10 years. By the time he got sick in the summer of 1981, thousands of people had already been infected.

Caixin: In the past 20 years, from SARS to MERS to Covid-19, deadly coronavirus has struck humans three times. Will there be a new coronavirus epidemic every once in a while? Is there a pattern to follow?

Shao: Every species has its rate of mutation. Knowing this rate, it is possible to calculate how far a virus has to go to cross species and eventually infect humans. For example, there are four coronaviruses that can cause illness in humans ― two α coronaviruses (229E, NL63) and two β

coronaviruses (OC43, HKU). They cause only mild respiratory illness. About 40% of common colds are caused by these four types of coronaviruses. It took 100 to 200 years for these viruses to “cross” from animals to mild viruses that can spread steadily among humans and come back every year. These are “smart” viruses, causing not too much harm to the host. Doctors and virologists don’t care about these viruses, and we don’t spend much effort destroying them. If you catch a cold and go to the hospital, the doctor may give you antibiotics to treat bacterial infection if your blood cell count is high. If not high, it may be a virus infection, and the doctor will only tell you to drink more water and rest.

Viruses like SARS, MERS and this novel coronavirus are all relatively “dumb” viruses. Because they do too much harm to the host, either killing the host or being killed by the host, they can’t survive and spread for long. Like SARS, we took great efforts to kill the virus all at once. Scientific studies estimate that there were trillions of species on earth, but 99% have become extinct due to poor adaptation to the environment. Only less than 1% have survived. This is especially true for viruses, because they are not independent organisms and must rely on the metabolic system of the host cell to reproduce. They can survive peacefully with the host only if they can find a suitable environment.

Why couldn’t Ebola spread so far? Because its incubation period is just a few days, causing 80% severe sickness and a death rate of 50%. In the years of poor transportation, infected people couldn’t travel more than 100 kilometers, which didn’t create the conditions for large-scale and long-term transmission. Therefore, since Ebola was discovered in the 1970s, it has been largely confined to central Africa. It wasn’t until 2014 that Ebola spread to west Africa, causing an epidemic of more than 20,000 infected people and sporadic cases brought back to home countries by health workers who went to treat them. Such viruses, though aggressive, have a short lifespan because they cannot form a peaceful parasitic relationship with humans. Each time, it takes a lot of effort to cross the species barrier, and it takes years to transmit from wild animals to humans.

Caixin: How does a virus mutate as it spreads across species?

Shao: After a virus spreads across species, it is definitely not the kind of peaceful coexistence with the original host, and it must mutate. There are two possibilities. One is the virus gets stronger. Avian influenza virus is very mild in the original host birds but becomes highly pathogenic after spreading to humans. SIV, the ancestor of AIDS, is also mild in chimpanzees. Infected chimpanzees can be healthy, but infected humans can get AIDS.

Some viruses become weaker after transmission across species. For example, vaccinia virus, which causes smallpox in cattle, becomes significantly less virulent after inoculation in humans, which led to a vaccine against smallpox in humans. This was discovered by a British doctor who observed that milk workers had no smallpox because they were constantly infected with the vaccinia virus. The WHO spent more than 20 years in the last century to push for global immunization of smallpox vaccinate and eradicated the disease from the planet in 1980.

Will Covid-19 stay around like flus?

Caixin: Do you think Covid-19 will make a comeback like seasonal flu?

Shao: The characteristics of Covid-19 and the three principles of the prevention and control of infectious diseases determine that it may persist like flus. First, Covid-19 is “smarter” than SARS and MERS, with a relatively low fatality rate, more mild cases and a longer incubation period. It also has a very important characteristic ― high infectivity. Studies found a specific sequence of units of DNA that a restriction enzyme recognizes and cuts into segments, making the viral proteins able to bind with cell receptors more strongly so that they can enter human cells more efficiently. This is the biggest structural difference between Covid-19 and SARS and MERS. These characteristics give Covid-19 the potential to be like flus, which means it’s difficult to eradicate at once and may come back seasonally.

In addition, we usually say that the prevention and control of infectious diseases has three principles ― control the source of infection, cut off the route of transmission, protect susceptible people. The three principles control the disease from the source, intermediate transmission and the target population. If a virus is too contagious, the first two prevention and control principles won’t be very effective, and vaccination will be an effective protection for vulnerable people. The infectious ability of SARS and MERS is not so strong, but their fatality rates are high, so we should focus on the control of the source of infection and cut off transmission. SARS suddenly disappeared in the spring and summer of 2003 because sufficient measures of the first two principles were taken. Now Covid-19 is almost like flus.

Generally speaking, virulence is negatively correlated with transmissibility. The stronger the virulence, the weaker the transmissibility, and vice versa. Two extreme examples are the highly pathogenic avian influenza virus and the common cold coronavirus. Avian influenza is very virulent and has a high fatality rate, but its transmission becomes very weak once it infects humans and doesn’t spread from human to human. For this kind of infectious disease, the main measure is to control the source of infection. The coronavirus that causes the common cold is not very virulent but spreads quickly among people. SARS, MERS and Covid-19 fall somewhere in the middle. In terms of infectious capacity, all three viruses can be transmitted from person to person. In terms of the R0 value of the basic regeneration number, which measures transmission efficiency, MERS is weak (0.3-0.8), SARS is strong (2-4), and Covid-19 is the strongest (2-5). In terms of virulence, MERS is the strongest, SARS is the second strongest and Covid-19 is the weakest.

According to the nature of the disease, the prevention and treatment strategy should be adapted accordingly. Now we can say that measures to control the source of infection and cut off the transmission route are not enough to control Covid-19, and it will be very difficult to do that globally and over a longer period. In my opinion, we have two options.

Strategy A is to strongly promote the two measures of controlling the source of infection and cutting off the transmission route so as to minimize the epidemic pressure and buy time for the implementation of measures to protect vulnerable people with vaccines. After that, the widespread use of vaccines should be vigorously promoted.

Strategy B is to advance the development of new coronavirus treatment drugs. Once a major breakthrough in drug development is achieved, the focus of prevention and control will shift to the second line of defense to stop mild cases from turning severe and reduce the fatality rate. That is a strategy to treat the Covid-19 like a flu.

If new treatments can reduce the death rate of Covid-19 to that of flu, strategy B can be implemented to significantly reduce the social and economic costs of prevention and treatment. It is worth noting that some countries have implemented strategy B in the absence of effective drugs. This is not consistent with China’s value that puts people’s life and health as priorities.

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Caixin’s coverage of the new coronavirus

Caixin: Does the sudden disappearance of SARS also, to some extent, remove the incentive to develop a vaccine? How is the development of the Covid-19 vaccine going?

Shao: Yes. To develop a vaccine, there must be at least one test to prove that it protects against infection during an epidemic. If the disease doesn’t come back, the vaccine is only half done and there is no final result because we can only conduct phase I and II clinical trials in healthy people to produce data on the safety and immunogenicity of the vaccine. But whether the vaccine provides sufficient protection against a real virus infection scenario can be determined only if the vaccine is used during an epidemic and the difference in infection rates between the experimental and control groups is observed. After the SARS epidemic, the vaccine that had gone the furthest completed a phase I clinical safety review but then could not be tested further.

Since the number of new confirmed coronavirus cases in China has dropped significantly, it is impossible to evaluate the efficacy of a vaccine in China without a major recurrence of the epidemic. The final protective verification of a vaccine may need to be carried out in highly endemic areas abroad, as with the Ebola vaccine.

‘Gene sequences don’t lie’

Caixin: We talked about virus mutation after it jumps to another species. Will it continue changing after infecting humans?

Shao: After jumping to humans, viruses could change to either become stronger or weaker. Those that turn stronger will gradually disappear by natural forces or human efforts. Natural forces means the virus is too strong and kills its host so it can’t be transmitted anymore. Some viruses become milder and won’t cause severe symptoms after infecting people. People become unaware or ignore them so they can continue spreading.

Caixin: Do we know whether the novel coronavirus is getting stronger or weaker?

Shao: Basic biological research showed that RNA viruses like SARS-CoV-2 (the name of the virus that causes the Covid-19 illness) often mutate fast. They transmit among different species and adapt quickly to different hosts.

Based on hundreds of publicly available sequences of the new coronavirus, including those collected in Wuhan in the early days of the outbreak and others from different countries, only a dozen of its 30,000 nucleotide bases changed. It shows that the virus is still in a very early stage of mutation that’s far from triggering it to turn stronger or weaker. The differences of fatality rates in different regions are mainly due to local medical resources, responsive measures and individual conditions.

Caixin: There are many debates about research on the virus. Some researchers want to trace the origin of the virus with genetic analysis while others say the virus has mutated into two strains. What’s your opinion on these studies?

Shao: There are two methods to trace an epidemic — epidemiological investigation and gene sequence analysis. The first method is to track the earliest patients, but it is very difficult due to the long transmission chain and lack of accurate information. But gene sequences do not lie, and it is the most accurate evidence to show evolutionary relationship. If the virus in one person has a similar gene structure with one in another person, the viruses must be from the same root.

Talking about the research on two strains of the novel coronavirus, it is clear that the two strains have only several different nucleotide bases, which is negligible. It will still take time and patience to monitor how the virus’s virulence and contagious ability evolve.

Caixin: You said gene sequences don’t lie. There are conspiracy theories saying the novel coronavirus was made in a lab. Will gene sequences tell us the truth?

Shao: Based on currently available gene sequences of the virus, there is no evidence of human intervention. To put it simply, if people want to create a virus, some of the “tools” that doesn’t exist in the nature will be left there. We can see it by looking. Of course, people can intentionally erase the trace, but it means massive work.

It is possible to create a virus without any visible evidence of human intervention. But it will take a huge amount of tests to prove it is viable and pathogenic. A natural virus from a patient is clearly viable and pathogenic, but it will take massive animal and human testing to know whether a lab-produced virus is viable. When the workload reaches a certain extent, it becomes a mission impossible.

Disease control system needs reform

Caixin: There are many questions on whether China’s disease surveillance systems failed to play its role in the Covid-19 outbreak. What’s your opinion?

Shao: There is no doubt that China strengthened its disease control system and emergency response capacity after the 2003 SARS outbreak. It has done well to contain previous outbreaks of avian influenza such as H7N9 and H5N1. In some cases, the efforts were made with little publicity to avoid public panic.

Although avian influenza can cause severe pneumonia, human-to-human transmission has been reported very rarely. Therefore, controlling the source of the virus ― killing the chicken and isolating the infected patients — was effective enough to contain the diseases. And that is what local disease control departments thought would be enough for controlling Covid-19 at the beginning. In Wuhan, officials closed the seafood market, where the outbreak was believed to emerge, and thought they could get the disease under control. But they ignored the need to report the disease and downplayed the severity of human-to-human transmission, leading to painful results for the public. I think officials’ old mindset for dealing with infectious disease led to misjudgments and missed opportunities for early control and public preparation.

It is a great pity that the direct reporting system to monitor infectious disease set up after the SARS outbreak didn’t play its due role during this epidemic. Under the rules, the cases should be submitted to the system whenever there are more than three unknown pneumonia cases. The system is in place with a network covering more than 70,000 reporting points across the country, and doctors can do it with a simple click. The reports will be simultaneously submitted to the national and local level of the Disease Control and Prevention Center (CDC). The idea of the direct reporting system is to reduce administrative intervention and save time in the face of an epidemic. But after 15 years of operation of this costly system, all the efforts unbelievably turned out to be in vain, and hierarchical review and administrative intervention were back in place. Why were there such actions, which violate the Law on the Prevention and Control of Infectious Diseases, could happen in government and law enforcement departments? Why didn’t local experts fulfill their duty according to the infectious disease reporting rules? And why did the National Health Commission and its experts fail to collect important information in a timely way? Whether we can find true and adequate answers to these questions will be important to future work.

Caixin: Many people compare China’s CDC with the U.S. counterpart and call for the agency to have greater authority. What’s your thought?

Shao: First, we must understand that the technical nature of the work at CDCs. They use scientific methods to carry out surveillance of infectious diseases, assess risks and send timely alerts. They also carry out intervention based on the nature of the epidemic and set up national standards and guidance to deal with diseases. But it is almost impossible for China’s CDC system to complete such tasks with their current resources and coordination capacity. The Covid-19 outbreak proves the problems and the urgent need for CDC reforms.

There are about 20,000 people working in the American CDC system, compared with only 2,000 in China, and they cover almost four times the population of the U.S. The U.S. CDC has more than 500 people focusing on research, warning, intervention, public education and emergency response related to flu virus, but the team in China is only 20.

There should be dedicated teams to track and conduct long-term studies of seasonal flu, novel influenza and respiratory infections. They need to carry out massive surveillance, sample collection, testing and analysis to study the virus and response measures. Such tasks can’t be completed with only 10 to 20 people.

China has identified 36 infectious diseases in the Law on the Prevention and Control of Infectious Diseases, but fewer than half of the diseases are under study by dedicated teams. Although the China CDC has strived to hire high-end talent over the past 10 years, it has difficulties retaining them.

There are usually two paths of disease control system reforms. The first is to make it an administrative organ, and the second is to maintain its status but reinforce its function. Personally, I think the administrative path is not a good option since it doesn’t fit the nature of its function. CDC is not a management department. Instead, it engages in the concrete job of preventing and controlling diseases. China’s CDC oversees the largest population and faces the highest risks, which requires it to be equipped with the best technological capacity. The authority of a technical department doesn’t rely on how much administrative power it has but on its technological capacity.

Making the CDC an administrative department may turn technicians into bureaucrats and lead to an even worse result.

The political system and the whole society should cultivate an environment with respect for science and scientists and let technology have a say. Allowing professionals to do things they are good at, the society will run in a better way. Opinions from technical departments should be an important reference for political decision-making, but technical departments should be allowed to remain independent. Scientific education of the general public is also important for people to make the right judgment.

Caixin: Do you have any detailed suggestion?

Shao: Institution-building should be enhanced in the disease control system. We should eliminate certain institutional barriers such as limiting CDC’s responsibility to human disease control while assigning animal disease surveillance to agricultural departments. In the U.S., the CDC regularly monitors risks from animals. The frequent outbreak of zoonotic diseases (those transmitted from animals) reminds us of the importance of cross-department cooperation.

On the other hand, the national CDC should not only function in Beijing. In countries like the U.S. and Russia, the national CDC often has branches and dispatches teams to states and cities to collect first-hand information. I think in China, while strengthening the power of the national CDC, it is also important to combine disease control departments at the provincial level with the CDC for better coordination.

With its vast territory, China can’t concentrate everything in Beijing. For disease control, it can place research centers regarding different types of diseases in different localities based on local risk levels of outbreaks to make them closer to groups at risk.

Caixin: How can we reduce the risks of zoonotic diseases in the future?

Shao: At the early stage of the Covid-19 outbreak, many community infections were not identified, and the massive gathering during the Chinese New Year holiday also resulted in high R0 — the average number of people who will catch the disease from a single infected person. After intervention measures, we found the R0 of the disease was reduced below 1, indicating that the outbreak is waning. Under such circumstance, it is time for us to gradually resume business and social activities and return to our normal lives.

Efforts can be taken on several fronts to reduce the risks of zoonotic diseases. The first is to toughen laws. The Standing Committee of the National People’s Congress recently imposed a total ban on trade and consumption of wild animals. It is an important measure to control the risks.

Our disease surveillance system should be strictly implemented according to the Law on the Prevention and Control of Infectious Diseases to prevent any cover-up. I suggest revising the law to give priority to direct reporting to the central government instead of reports to local authorities and to require hospitals to set up expert teams to verify the risks to reduce administrative intervention.

In addition, some systemic arrangements can be set up during disease control periods such as body temperature screening at public sites and gathering and providing hand sanitizer in restaurants. We should take the Covid-19 outbreak as an opportunity to make concrete efforts to improve public hygiene and health.

Contact reporter Denise Jia (huijuanjia@caixin.com) and editor Bob Simison (bobsimison@caixin.com)


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