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What has Wuhan Institute of Virology, Chinese Academy of Sciences done since the COVID-19 outbreak?

Since the COVID-19 outbreak, researchers of Wuhan Institute of Virology, Chinese Academy of Sciences (CAS) have been fighting on the front line against the pandemic, undertaking a number of researches on COVID-19 prevention and control. However, rumors that "the new coronavirus is the result of artificial synthesis" and that "the virus escaped from a lab" have been spreading online and attracted rapt attention of people from all sectors of society.

In order to fully reveal the scientific and technological research conducted by the researchers of Wuhan Institute of Virology, CAS on COVID-19 prevention and control, and to tell their frontline research stories, Science and Technology Daily interviewed Yuan Zhiming, director of CAS Wuhan Branch and Wuhan National Biosafety Laboratory, and Guan Wuxiang, deputy director of Wuhan Institute of Virology, CAS.

Scientific research on COVID-19 started on Dec. 30, 2019.

Science and Technology Daily: When did Wuhan Institute of Virology, CAS start its scientific research on COVID-19? What was your first task?

Guan Wuxiang: Wuhan Institute of Virology, CAS started doing scientific research on COVID-19 on Dec. 30, 2019. After receiving samples of pneumonia of unknown cause from Wuhan Jinyintan Hospital, we organized a team of researchers specialized in the area overnight to conduct pathogen detection and identification. We reported the results to relevant government departments immediately after we got them.

Science and Technology Daily: Since the COVID-19 outbreak, what scientific research has Wuhan Institute of Virology, CAS undertaken? How's your research proceeding?

Guan Wuxiang: Since the COVID-19 outbreak, Wuhan Institute of Virology, CAS has conducted research in virus isolation and identification, pathogen detection, development of antiviral drugs and vaccine, evaluation of the neutralizing antibody in plasma of convalescents, establishment of animal model, and study of pathogenic mechanism. We provided the front lines with scientific and technological support, and we've made considerable progress.

In terms of virus isolation and identification, we've made continuous efforts to obtain the complete genome sequence of the virus. We isolated the virus strain, identified it as a novel coronavirus, and completed the standardized storage of the virus. On Jan. 11, as one of the institutions designated by the National Health Commission, we submitted the genome sequence of COVID-19 to the World Health Organization.

In terms of virus detection, we promptly organized research and development of nucleic acid testing and serological testing technologies and products. In cooperation with Shenzhen Uni-medica Co. Ltd., we developed a COVID-19 nucleic acid detection kit, which has been going through the emergency review and approval process of National Medical Products Administration (NMPA). We also developed a COVID-19 serological test kit in cooperation with Zhuhai Livzon Diagnostics Inc. It was approved by NMPA and received a medical device registration certificate on March 14. As one of the designated institutions in Wuhan, we participated in the etiological examination of COVID-19, and have tested more than 6,500 samples of throat swabs from suspected COVID-19 patients since Jan. 26.

We also conducted screening and evaluation of marketed drugs, clinical drugs and drug candidates jointly with the National Engineering Research Center for Emergency Prevention and Control Drugs of the Academy of Military Medicine of the Academy of Military Sciences PLA China, and we found that chloroquine phosphate and Favipiravir could effectively inhibit the infection of COVID-19 at cellular level in vitro. In the meantime, we cooperated with the Wuhan Institute of Biological Products under the China National Pharmaceutical Group (Sinopharm) to develop an inactivated vaccine, which was approved for clinical trials by NMPA on April 12.

In cooperation with the Wuhan Institute of Biological Products under Sinopharm, we evaluated the neutralizing antibody titer in plasma of some convalescent patients, and found that the antibody titer could reach 1:640. Corresponding clinical work was carried out by our partner in accordance with set procedure after further evaluation.

In terms of the establishment of animal models, we've established a rhesus macaque model for COVID-19. The evaluation of animal models for COVID-19 organized by the Ministry of Science and Technology regarded the rhesus macaque model as successfully established, and concluded it can be used for relevant research on pathogenesis and transmission route, and it provided an important platform for COVID-19 vaccine and drug evaluation.

Science and Technology Daily: How has previous virological research of Wuhan Institute of Virology helped the research on COVID-19?

Guan Wuxiang: As early as the SARS outbreak in 2003, Wuhan Institute of Virology was assigned the task of building the Wuhan National Biosafety Laboratory (Wuhan P4 Laboratory). Wuhan Institute of Virology has focused on the research in medical virology, especially the highly pathogenic viruses, and conducted basic research on various viruses, and developed technologies for their prevention and control. These efforts have laid the foundation and formed a reserve for dealing with the outbreak of new infectious diseases.

In particular, relevant research teams of Wuhan Institute of Virology have been studying coronaviruses for more than a decade, and have reserved universal nucleic acid detection methods for coronaviridae, universal nucleic acid testing and antibody testing methods for SARS-like coronaviruses, and methods for virus isolation and cultivation. These methods have played important roles in the early stage of pathogen identification of COVID-19.

Science and Technology Daily: Based on years of research on coronaviruses, is it possible to predict the COVID-19 outbreak?

Guan Wuxiang: After the SARS outbreak in 2003, China has improved its infectious diseases surveillance system. It also further improved its ability to prevent and control infectious diseases through special support for major infectious diseases. The existing system mainly aims at the surveillance and early warning of infectious diseases, and cannot make active prediction at present.

The prediction of virus outbreak is a universal problem that is difficult to solve. Our knowledge of viruses existing in nature and the laws of their occurrence, development, transmission and pathogenesis is far from sufficient. In order to proceed from passive early warning to active prediction of infectious diseases, we need a batch of researchers who can stick to long-term basic research and technological development. The long-term surveillance and background investigation of virus-carrying wild animals is an important component in the surveillance of infectious diseases.

12 scientific research teams have been set up.

Science and Technology Daily: How many teams in Wuhan Institute of Virology are now conducting scientific research on COVID-19 prevention and control? What exactly are these teams doing?

Guan Wuxiang: With the development of the epidemic situation and in accordance with the tasks undertaken, the institute concentrated its superior forces, broke the setup of traditional subject groups, and formed 12 research teams with a total of more than 120 people. Among them, nearly 20 researchers have been doing pathogen detection, nearly 20 people doing virus surveillance, 17 people doing drug screening. We also have 6 supporting teams with more than 40 people offering support to the research. The National Virus Resource Bank is responsible for the collection and standardization of COVID-19 samples. Biosafety Level 3 (P3) Laboratory and Biosafety Level 4 (P4) Laboratory are mainly responsible for the normal operation of the laboratory and the safety protection of the scientific personnel. The Analysis and Testing Center and the Laboratory Animal Center are responsible respectively for the analysis and testing of various large-scale instruments and the provision of laboratory animal support.

Science and Technology Daily: What is the state of the day-to-day work of these researchers?

Guan Wuxiang: Since the COVID-19 outbreak, scientific researchers of Wuhan Institute of Virology have been fighting on the front line against the epidemic. All of them voluntarily gave up the Chinese New Year holiday vacation, overcame such difficulties as inconveniences in daily lives, and devoted themselves whole-heartedly to scientific research on COVID-19.

On each single shift, researchers work in the laboratory for a 5-hour to 6-hour session, during which they have no access to food, water, or toilet. Taking into account the time they spend preparing and processing data, their average working day lasts about 10 to 12 hours. In order to make full use of the facilities, several teams entered the P3 laboratories of Xiaohongshan and Zhengdian, taking turns to tackle key problems. The pathogen detection team dealing with enormous samples was divided into two groups and rotated in P3 and P2 laboratories.

Take our team of COVID-19 pathogen detection for example. The size of the pathogen detection team in our institute is limited, it cannot detect a large number of samples, so lots of young CPC members working in our institute volunteered to participate in pathogen detection.

What has the P4 Laboratory done?

Science and Technology Daily: Can you tell us something about the research and its progress at the P4 Laboratory?

Yuan Zhiming: The P4 Laboratory is a part of the Wuhan National Biosafety Laboratory. Wuhan National Biosafety Laboratory consists of one P4 laboratory and two P3 laboratories. These three laboratories, along with the multiple P2 laboratories, general laboratories, laboratory animal facilities and related supporting facilities of the Wuhan Institute of Virology, form the biosecurity laboratory cluster platform.

On Dec. 30, we received unidentified pneumonia samples from Wuhan, and later successfully isolated the virus causing COVID-19. Since then, Wuhan National Biosafety Laboratory has urgently launched laboratory accreditation and applied for laboratory activity qualification to conduct scientific research on COVID-19. The laboratory obtained activity qualifications for COVID-19 research in culturing cell, operating glire infection and non-human primate infection. And we have made sure relative research was conducted in accordance with corresponding law and rules. At the same time, the Scientific Research Ethics Review Committee and the Laboratory Animal Management Committee of our institute approved, managed, supervised and reviewed the conduct of animal experiments in accordance with set procedure, so as to ensure the animals' welfare in the course of the experiments.

Since then, Wuhan National Biosafety Laboratory has conducted research on purification and multiplication of COVID-19, evaluation of neutralizing antibody in plasma of convalescents, evaluation of disinfectant efficacy, establishment of non-human primate animal models, evaluation of antiviral drug, development of inactivated vaccine and animal protection tests. At present, a standard process of virus proliferation and inactivation has been established, a new disinfectant has been developed and its inactivation activity against COVID-19 has been evaluated. A rhesus macaque infection model has been established. Evaluation of candidate antiviral drugs and inactivated vaccine has been conducted. The establishment of animal models provides an important basis for the study of viral infections and the evaluation of other candidate antiviral drugs and new vaccine.

Various measures have been taken to prevent the virus from escaping the laboratory.

Science and Technology Daily: As the highest-level biosafety laboratory, what protective measures do you take?

Yuan Zhiming: All researchers performing experimental operations at the P4 Laboratory must receive systematic theoretical and practical operation training. They also need to pass annual physical and mental health assessments. They will not be allowed to enter the laboratory until obtaining qualification accreditation and approval by the laboratory director.

Each time before researchers enter the laboratory, biosafety workers must confirm their basic physical conditions, including blood pressure and body temperature, are normal and meet the needs of experimental operation. In the actual experimental process, only qualified and authorized laboratory personnel can enter the P4 ring corridor through the access control system, check the running status of the laboratory, fill out the registration form for the entry and exit of laboratory personnel, and inform the monitoring center.

Then, experiment operators need to go through the access control system to enter the first changing room of the laboratory. They need to take off their own clothes and change for disposable inside protective suits. They need to check the status of positive-pressure protective suits, and then put them on and connect the breathing hose. After completing all the steps above, they can enter the core laboratory through the chemical shower room to conduct experiment. To ensure biosafety and biosecurity, the laboratory requires no fewer than two staff members at one time, and no one can enter the laboratory to work alone.

In general, researchers exit the laboratory the same way they enter. Before exiting, they need to use chemical disinfectant and water to thoroughly disinfect the positive-pressure protective suits in the chemical shower room. After taking off the inner protective clothing, all the researchers need to take a sanitary shower, then put on their own clothes and exit the laboratory. After filling out the laboratory personnel entry and exit registration form, they complete a laboratory activity.

Inside the laboratory, all communications with the outside is made via the monitoring center, which will be the first to be contacted if anything goes wrong. When there is experimental activity going on, the monitoring center will be staffed with biosafety, biosecurity and equipment support workers to ensure they have the ability to deal with all kinds of emergencies.

Science and Technology Daily: What kind of special protective measures have you employed at the P4 Laboratory to prevent the viruses from escaping?

Yuan Zhiming: The core of the P4 laboratory in Wuhan is surrounded entirely by a stainless steel enclosure to form a "box-in-box" structure. The enclosure structure of the core laboratory can ensure sufficient structural strength and leakproofness to form a static seal. Negative pressure technology is used to ensure strict and orderly pressure gradients among the functional areas, so as to prevent the air polluted by infectious pathogens from spreading to the low pollution probability areas and the outside environment.

As for gases discharged from the laboratory, a two-stage high-efficiency filter is used to treat the gases and ensure the safety of the laboratory exhaust. Waste water from the laboratory is discharged after high-temperature treatment by the sewage treatment system. The polluted wastes in the laboratory will be safely removed after high-temperature and high-pressure treatment with a double-door high-pressure sterilizer, and will be handed over to a medical wastes centralized disposal unit with corresponding qualifications. The positive pressure protective clothing of the experimental personnel will be disinfected with chemical shower devices when the personnel passes through the entry-exit passage to ensure the safety of the passage. The measures above ensure that the virus in the laboratory cannot escape.

There're not only high-standard biosafety facilities in the laboratory, but also a strict biosafety management system, including a series of procedures, protocols and standardized operating manuals covering such aspects as scientific research projects, personnel, laboratory animals, wastes treatment, and infectious materials management, so as to ensure the safe and efficient operation of the laboratory. The physical facilities of the laboratory shall be tested by a third-party institution every year, and the operation of the laboratory is subject to the supervision and assessment of the China National Accreditation Committee for Conformity Assessment and annual inspections by relevant government departments.

Science and Technology Daily: Research on COVID-19 needs to be continued over the long term. What follow-up work will be undertaken?

Guan Wuxiang: The institute will continue to respond to the urgent needs of rapid disposition and emergency response in terms of science and technology. Future research on COVID-19 will focus on pathogen detection, antiviral drugs and vaccine development, evaluation of neutralizing antibody in plasma of convalescents, animal models, and pathogenesis research.

To meet the long-term needs of prevention and control of infectious diseases, the institute will continue to carry out basic research and development of technologies for disease prevention and control in the fields of biosafety and public health, providing scientific and technological support and decision-making advices for the maintenance of biosafety.

[ Editor: SRQ ]