“Now, in American hospitals, if someone has a respiratory illness, a lung infection and a fever, the doctor will have to ask them a question: ‘Have you been to China recently?’ ‘If the answer is yes, then what you need to do is put on a mask, isolate them in the isolation room, and then contact the CDC. The quote comes from an interview with Anthony Farhi, an infectious disease expert at the National Institutes of Health (NIH), and the editor-in-chief of the Journal of the American Medical Association (JAMA) on January 23.
From Hubei Province, in the middle of the Chinese map, to Washington, d.C., across the Atlantic, from Thailand in Southeast Asia to Australia in the southern hemisphere, an outbreak of pneumonia in China has attracted widespread global attention.
The starting point for all this was a new type of coronavirus, the largest known rna virus, which has caused two major outbreaks: more than 8,000 people were infected with SARS coronavirus in 2003, with a fatality rate of nearly 10 percent. In 2012, the Middle East Respiratory Syndrome (MERS) had 851 deaths and a 37 percent fatality rate of nearly 2,500 infections.
The new coronavirus in Hubei is similar to SARS symptoms, the virus invades the human body, infected people will be fever, cough, muscle aches or weakness or even breathing difficulties … A study based on 425 infected people found that before January 1, Wuhan downtown, the South China seafood wholesale market is the main site of the virus “boom”, after which people carrying the virus began to become more of a source of infection, the virus spread from person to person, sneezing, coughing, talking close lying and so on, it began to become a dangerous act.
Former FDA Director Scott Gottlieb told the media on January 24th that the new coronavirus appears to be milder than SARS, but may be more contagious because the outbreak is faster than SARS. In the early hours of January 31, Beijing time, the World Health Organization (WHO) announced that China’s new coronavirus outbreak constituted an “international public health emergency of concern” (PHEIC), the highest level of whoise infectious disease emergency response mechanism.
The WHO Emergency Committee met in the morning and said there was no need to announce PHEIC for the time being, to observe it for about 10 days, but that afternoon it changed its decision. One of the main reasons is that the first human-to-human case was found in the United States, confirming that the virus infection is strong. Lu Shan, a professor at the University of Massachusetts School of Medicine, said. At the time of the announcement, there were 98 new coronavirus infections in 18 countries outside China, including eight human-to-human cases in four countries: Germany, Japan, Vietnam and the United States.
Scientists and doctors are beginning to gain more and more insight into the virus and the characteristics of the outbreak it has caused, but it remains unclear exactly where and when it began to infect humans, and in particular, to determine how the outbreak will end.
New corona virus, know and don’t know
Laurie Garrett, a former senior fellow on global health at the Council on Foreign Relations, is also a Pulitzer Prize-winning fellow, saying, “At this time 17 years ago, I was reporting a SARS outbreak that killed 774 people and affected 37 countries, so on December 12, 2019, When I read about the cluster pneumonia infection at Wuhan Seafood Market, I had a striking similarity. “In virology, this is really two related viruses.
At the end of December 2019, several local medical institutions in Wuhan City, Hubei Province, reported a group of unexplained pneumonia patients, and on December 27, three adult patients with severe pneumonia symptoms were admitted to Jinyintan Hospital in Wuhan. Three days later, the researchers collected the four patients’ alveolar irrigation fluid and isolated the same virus from their bodies — a new coronavirus that was later named “2019-nCoV” by the World Health Organization. The process was published January 25 in the New England Journal of Medicine (NEJM) by Gao Fu, director of the China Center for Disease Control and Prevention. Coronary viruses are divided into four genus alpha, beta, gamma and radon, and new coronaviruses are classified as sub-nucleogen. So far, there are six known types of coronavirus estovirus infection in humans, four of which are less pathogenic, but the other two coronaviruses can cause serious respiratory diseases, high infection rate, high mortality rate, they are SARS and MERS virus.
When the first available sequence of viral genes became public, the scientists placed it on the coronavirus family tree– a rich lying virus that infects many species and found it closely related to the virus from bats. On January 23, Shi Zhengli’s team at the Wuhan Virus Research Institute of the Chinese Academy of Sciences found that the new coronavirus is 96% similar to bat coronavirus, with a sequence consistency of 79.5% with SARS coronavirus, and she speculates that the new coronavirus may have originated in bats.
Similarly, on January 29th, Cdc Tan Wenjie and others published in The Lancet, pointing out that the new coronavirus is more similar to the two bat coronaviruses collected in Zhoushan, Zhejiang Province, with the same characteristics of 88%. The article points out that analysis of the history of animal and plant species suggests that bats may be the original hosts of the virus, while some animal sold at the South China Seafood Market in Wuhan may be intermediate hosts of transmission between the virus and humans.
Another analysis suggests that snakes are the intermediate hosts most likely to carry the new coronavirus, though this claim has been almost unanimously blasted by genetic analysts. “From our research and the work of other academics, it is very clear that there is no evidence that the virus came from snakes,” David Robertson, a professor at the Centre for Virus Research at the University of Glasgow, told China Newsweek. But that doesn’t mean bats spread directly, and the bigger possibility is that an as-yet-undetermined mammal is the intermediate host. “
“In the early stages of an outbreak, it is important to identify the pathogens that cause the outbreak and to know if multiple strains are spreading simultaneously, and the latter can complicate identification.” ‘Fortunately, these viruses are very similar, which makes them more likely to be locked and shows that they have only just been introduced to humans,” Peter Bogner, president of the Global Initiative for the Sharing of Avian Influenza Data (GISAID), told China Newsweek.
There is a lot of speculation about the source, but it’s likely to be related to bats, because it’s clear that in the coronavirus family of known genomes, all precursor cells of the virus currently come from bats. “To know more details, it would require animal samples on the market at the time, but everything has been disposed of and disinfected – of course, it’s an appropriate response to an unknown threat. GISAID Chairman Peter Bogner said. At the same time, the search for the virus in animals is under way, as this identification is important in preventing the transmission of new viruses to humans in the future.
There is indeed a strong correlation between this market and the new coronavirus. Several epidemiological studies based on Wuhan cases have found that some infected people have a history of exposure to the seafood market. The most direct evidence came from the CDC Virus Disease Prevention and Control Institute, which said at a briefing on January 26that that 33 positive samples were detected from 585 environmental samples from the South China Seafood Market, 31 of which were distributed in the Western District of the South China Seafood Market. There are a number of wildlife traders in the area of 7th and 8th Streets in the West End, near the inside of the market, and there are 14 positive specimens in this area, suggesting that the virus originated from wild animals sold in the South China seafood market.
However, an article published in the Lancet on January 24th by Huang Zhaolin and others at Wuhan Jinyintan Hospital analyzed 41 infected people who had received the hospital before January 2nd and found that only 27 of them had a history of exposure to the South China seafood market, and no epidemiological link was found between the first patient and the patient son after. Explain that the market may not be the only source of the epidemic. Later, Cao Bin, author of the paper and medical physician in respiratory and critical care at the Sino-Japanese Friendship Hospital, said in a reply to Science magazine, “It seems clear now that the South China seafood market is not the only source of the epidemic, but to be honest, we don’t know where the virus came from.” “
At the same time, even the natural host of the virus is still uncertain. “It’s hard to decide which is a natural host until you isolate the virus from a single species,” Christian Anderson, an evolutionary biologist at the Scripps Institute in San Diego, told Science. “
In the GISAID database, scientists are sharing more and more complete virus sequences from patients — at least 53 so far. By delving into the genetic sequences of these viruses, the researchers tried to understand the source of the new coronavirus and the chromatic relationship between the viruses it found in bats and other animals, as well as to see how it looked, mutated and even stopped spreading. However, scientists still have many unsolved mysteries about the new virus, which has now caused more than 10,000 infections and 260 deaths.
Pandemic: Why the number of infections far outnumbers SARS
When officials reported 62 infections by January 18, academics from imperial institutes of technology and the University of Hong Kong School of Medicine predicted that the number of people infected with the virus in Wuhan could exceed 4,000; They estimate there are about 3,500 cases of infection in Wuhan. The latest forecast comes from Professor Leung Chuo-wei of the University of Hong Kong, who, in an article published in The Lancet, estimated that as of January 25, there could be 75,800 people in Wuhan infected with the new coronavirus.
Although these projections differ from the initial official advisory data, the outbreak quickly spread. On January 25th Laurie Garrett wrote on CNN that the new epidemic appeared to be about to surpass the 2003 SARS epidemic, and four days later, on January 29th, the number of confirmed cases nationwide was close to 6,000, surpassing the 5,327 confirmed infections in the country during SARS. From The Wuhan Health and Health Commission disclosed the outbreak from December 31 to this time, only the past month or so.
According to the paper “The Early Spreading Dynamics of New Coronary Virus Infection Pneumonia in Wuhan, China” published on January 29th in NEJM by the CDC, Hubei CDC, the University of Hong Kong and other institutions, the data of the earliest 425 confirmed cases in Wuhan were analyzed. It is estimated that R0 (basic infection) is about 2.2, i.e. an average of 2.2 people will be passed on to each infected person. This is close to the WHO’s preliminary estimate, which gives R0 values of 1.4 to 2.5.
What is the severity of the outbreak? In an interview with China Newsweek, Mr. Goben, a professor at the School of Public Health at the University of Hong Kong, points out that severity has two implications. First, clinical performance, the risk of hospitalization of infected people is high? How many of the inpatients are seriously ill? What is the probability of death? In this regard, Mr Gobben said he did not have enough information, but an article he and colleagues had just published estimated that the risk of death in hospital is about 14 per cent. This is similar to the conclusion of Zhang Li et al. of Wuhan Jinyintan Hospital: An article published in The Lancet on January 29th found that the mortality rate was 11% among 99 patients with new coronary pneumonia.
“What is known is that many of the infections in the new crown are mild, which is very different from SARS. However, the rate of mild to severe lying is not clear, as the vast majority of cases of mild symptoms have not been tested and laboratory confirmed. Goburn said. Zhang Wenhong, head of the Shanghai Medical Treatment Expert Group and director of the infection department of Huashan Hospital, recently wrote that, taking the situation of Shanghai patients as an example, the number of seriously ill patients may be 15%, the mortality rate is significantly lower than SARS, and critically ill patients are mainly seen in the elderly with basic diseases such as cardiopulmonary.
On the other side of the coin, a large number of mild or asymptomatic patients may become the source of infection. Vincent Munster, a virologist at the NIH National Institute of Allergy and Infectious Diseases, said in an editorial in NEJM that if a viral infection does not cause a serious illness, the infected person is likely not to seek medical attention – instead, they will go to work, move, and may spread the virus to contacts, or even internationally. This complicates the tracing of the chain of infection.
Symptoms are mild, but spreadable, is the biggest difference between the new crown and SARS, but also the difficulty of epidemic prevention and control. According to a microbiologist who did not want to be named, SARS infection after the emergence of fever, pneumonia and other symptoms after a strong infectious, and this new coronavirus has 12 days or even longer incubation period, the onset is not acute, not necessarily high fever, obvious respiratory symptoms, some patients are a little weak, headache, Accompanied by digestive tract symptoms. “These patients are not easy to find hidden in the crowd, and they are not going to be tested for medical treatment, and even doctors are not easy to identify. “This is a difficult problem to solve, ” Tong Zhaoxuan, vice president of Chaoyang Hospital in Beijing and a respiratory specialist, told China Newsweek. Only through continuous publicity and education, let them aware of their dangers, protect themselves, protect their families, but also responsible to society. “
However, for the infection of people who have been asymptomatic, Professor Lushan of the University of Massachusetts School of Medicine explains that if it is not in the incubation period, then the clinical belief that the infected person, even if there is a virus in the body, should be very small, and therefore very low infectious. “This is a basic concept of virology, i.e. infection is directly related to the load in the virus. “
At present, the number of infections is rapidly increasing. “The next four to five weeks are crucial. It would be a real tightrope – if it spread too widely, it wouldn’t end like SARS. “The NIH’s Anthony Farhi believes that the next step is either to peak and then fall, or it will become a global outbreak. However, Lushan should be optimistic, “the overall out-of-control epidemic, the development of the national development of this situation will not happen, because other areas outside Hubei has few cases, there is sufficient manpower and resources to deal with new cases.” “
Vaccines and drug development
A 35-year-old man who returned to the U.S. on january 15 this year after returning from a family visit in Wuhan was diagnosed with the new coronavirus, the first u.S. infection. On the seventh day of his hospital stay, doctors decided to offer him an as-yet-unapproved drug, the antiviral drug Remdesivir (RDV), developed by Gilead, and the next day his condition improved dramatically, based on the U.S. principle of “sympathetic medication.” The article on the diagnosis and treatment of the first confirmed case in the United States was published January 31 in the New England Journal of Medicine.
RDV is a new nucleoside analogue antiviral drug that can be used to resist viral therapy by inhibiting the synthesis of viral nucleic acids. Lu Hongzhou, party secretary of the Shanghai Public Health Clinical Center, said that from the current research data, RDV may be the most promising anti-new coronavirus drugs, but there is no research on the safety and efficacy of RDV in the human body. Merdad Parsey, Gilead’s global chief medical officer, also issued a carefully worded statement on January 31st saying that RDV had not been approved for listing in any country and its safety and effectiveness had not been proven.
Dozens of new coronavirus nucleic acid detection reagents are placed in the savings box, these raw liquids from more than a dozen manufacturers, during the Spring Festival, often encountered a shortage of supply. Photography/Yang Lihuai
To determine whether RDV is safe and effective for new coronavirus infection, Gilead is working with the China-Japan Friendship Hospital on a three-stage randomized double-blind controlled trial. The trial was conducted from February 3 to April 27 and included 270 patients with mild and moderate levels.
Wang Guangfa, director of respiratory and critical care medicine department at Peking University First People’s Hospital and a member of the new crown expert group, was previously exposed to the new coronavirus and recovered from treatment. In response, he revealed that the anti-HIV drug Lopinavir/Litonavir (commonly known as Creech) was very effective for him, after taking only a day of body temperature to improve.
The “New Coronary Virus Infection Pneumonia Treatment Program (Trial 4th Edition)” issued by the National Health and Reform Commission on January 27th proposed that there was “no effective antiviral drug” for the new coronavirus, but that alpha-interferon atomized inhalation or the drug Lopinavir/Litonavir could be tried. “Clinically, it was effective, especially in early patients, who sat down quickly and did not deteriorate further. Lu Hongzhou said.
Ding Sheng, the first dean of Tsinghua Institute of Pharmacy and director of the Global Health Drug Research and Development Center, told China Newsweek that alpha-interferon, an immune-boosting drug, is a mechanism by which human self-cells can resist foreign pathogens. “Lopinavir/Litonavir” is a combination of two drugs that act as an inhibitor of hydrolysis in HIV, which causes the virus to lose function by blocking its activity.
But he noted that the similar protease in the new coronavirus is still quite different from the enzyme of HIV, so the efficacy is uncertain. Anthony Farhi also said that in SARS and MERS, some historical control data showed that Creech had some benefits for terminally ill patients; Moreover, he stressed that these were drugs used on the basis of the “compassion principle” without any proven benefits.
After SARS and MERS, why did the special antiviral drugs against them be late? Ding Sheng explained that, in general, these coronaviruses are not common. “A lot of diseases are like this, the patient population is small, and then there are no new cases, which makes it difficult to do clinical trials, and the developed drugs have no market, the big drug companies obviously have no incentive to invest.” “
On January 26, Xu Wenbo, director of the Cdc’s virus disease institute, said they had started research and development of a new coronavirus vaccine, which has been successfully isolated and is sifting for seed strains. At the same time, several foreign research teams are stepping up research and development of the new coronavirus vaccine, but the use of different methods. Zhang Linxuan, director of Tsinghua University’s Center for Global Health and Infectious Diseases Research, who has been involved in the development of the MERS vaccine, said the principle of the new corona vaccine is to induce antibodies with a strong comprehensive capability to the virus, which is now one of the most important goals of all vaccine strategies.
The National Institute of Allergy and Infectious Diseases, part of NIH, is working with Us biotech company Moderna on the development of a new nucleic acid-based coronavirus vaccine. At the University of Queensland in Australia, scientists commissioned by the Global Health Emergency Response Group’s Alliance for Epidemic Prevention and Innovation (CEPI) say they are using a technique called “molecular pliers”, which adds a gene to proteins encoded in the virus genome to stabilize proteins. Let the body treat it as a live virus and produce antibodies.
“Nucleic acids, especially RNA-based or DNA-based, produce relatively quickly, but the weakness is that the immune response after entering the body is relatively poor. Zhang said the U.S. will adopt this new technology faster than it can, but there is still a long way to go to really use the new technology, while another idea is protein-based vaccine development, which is currently used by all approved vaccines.
In the face of a pandemic, the problem of continued investment in drugs is also a dilemma for vaccine development. During the SARS outbreak in 2003, scientists spent 20 months on the first human trial, from obtaining genetic sequences to the first human trial of the vaccine, but the vaccine against the SARS virus is still not available.
Anthony Fahey, an infectious disease expert at the NIH who led the study, and others believe that advances in academic understanding of coronaviruses since SARS have significantly reduced vaccine development time. So, from getting a genetic sequence to moving toward phase 1 clinical trials, Anthony Farhi hopes the process could be shortened to three months. Zhang said that this length of time is possible if fully advanced, “especially from sars and MERS outbreaks of research and development experience, coupled with some technology updates, this prediction is possible.” “
However, Anthony Fahey told China Newsweek that even after completing the first phase of the trial in three months, it would take another three months to get the results and then move on to Phase II for clinical trials in a larger population. “Even if we get an emergency license, it is unlikely that the vaccine will be put into practice for at least a year.” “
Ding Sheng said that at that time, sars vaccine has made initial progress, also did some human trials, but because there are no patients, no one to invest, so it can not go on. In addition, because the vaccine is very high safety requirements, so do not rule out technical problems, for example, HIV vaccine has not yet been, other parasites, many of the bacteria are not available vaccine.
“Even if we find ourselves developing a SARS vaccine that cross-prevents new coronaviruses, we still need funding for safety testing and human clinical trials. As a result, we are months away from the available vaccine. Vaccine scientist Peter Holtz told China Newsweek. He is working with Fudan University and other institutions to develop a prototype vaccine for SARS coronavirus at Baylor University School of Medicine in Houston. Because BOTH SARS and the new coronavirus belong to the same ACE2 receptor, and the amino acid composition is 80% similar, they want to see if the vaccine can also work against the new coronavirus.
“The most pressing thing about the future is the question of time. Ding Sheng said that in the long run, the disease can certainly be solved, but we hope to have a short-term contribution, long-term can also have reserves, in order to respond to future emergencies.