Source: Sci-Tech News | Author: Lu Chengkuan & China.org

Since the outbreak of COVID-19, researchers at the Wuhan Institute of Virology (WIV) of the Chinese Academy of Science (CAS) have been working on the frontline, undertaking a range of R&D tasks to prevent and control the pandemic. Still, rumors swirling around the internet have spread around the world claiming that the novel coronavirus was synthesized and that the pandemic was caused by a leak from the lab.

In order to present a comprehensive overview of the work into pandemic prevention and control being done by researchers at the WIV, and to share their frontline experiences with the world, Science and Technology Daily conductedan exclusive interview with Yuan Zhiming, president of the CAS Wuhan Branch and director of Wuhan National Biosafety Laboratory,and Guan Wuxiang, deputy director general of the WIV.

Working all out since Dec. 30, 2019

Science and Technology Daily: When did the WIV begin its research and development work into COVID-19? What was the first task youreceived?

Guan Wuxiang:The WIV's efforts in this regard began on Dec. 30, 2019. Upon receiving samples of an "unknown pneumonia" from Wuhan Jinyintan Hospital, we organized our top experts in the field to conduct pathogen detection and identification overnight, and promptly reported their findings to the relevant authorities.

Science and Technology Daily:What R&D tasks have the WIV undertaken concerning the prevention and control of the pandemic since the start of the COVID-19 outbreak? How have these tasks progressed?

Guan Wuxiang:Since the outbreak began, the WIV has carried out various R&D works in an orderly manner. These include isolating and identifying the virus, detecting pathogens, developing antiviral drugs and vaccines, evaluating the titer levels of neutralizing antibodies in recovering patients' plasma, establishing animal-based models, and researching pathogenic mechanisms. The progress made in these areas has provided scientific and technological support for frontline pandemic prevention and control.

The WIV has achieved a series of breakthroughs in terms of virus isolation and identification. It has sequenced the whole genome of the virus, isolated the virus strain, identified it as a novel coronavirus, and completed standardized virus cryopreservation. On Jan. 11, as one of the designated institutes of the National Health Commission, the WIV submitted the virus' sequence to the World Health Organization.

In terms of detecting COVID-19, the WIV has quickly organized its R&D efforts to develop nucleic acid tests and serological detection technologies. COVID-19 nucleic acid testing kits, jointly developed by the WIV and Uni-medica, are currently under emergency approval by the National Medical Products Administration (NMPA). The WIV has also worked with Zhuhai Livzon Diagnostics to develop a COVID-19 serological test kit, which was approved by the NMPA on March 14 and certified for medical use. As a designated institute by Wuhan city, the WIV has participated in the task of detecting the COVID-19 pathogen. Over 6,500 throat swab samples of suspected COVID-19 cases have been tested by the WIV since Jan. 26.

The WIV has also worked with the National Engineering Research Center for Drugs of Emergency Prevention and Control of the Institute of Military Medicine under the Academy of Military Sciences to select and evaluate marketed drugs, clinical drugs and drug candidates. We found that chloroquine phosphate and favipiravir have shown fairly positive antiviral effects against the novel coronavirus at the cellular level. Other drugs have also been selected and are currently being evaluated. In the meantime, the WIV has been working with the China National Biotec Group (CNBG) of the China National Pharmaceutical Group (Sinopharm) to research and develop an inactivated whole virus vaccine. This vaccine was approved by the NMPA for clinical trials on April 12.

In addition, the WIV and the CNBG have also evaluated the titer levels of neutralizing antibodies in the plasma of recovering patients. We found that the antibody titers reached 1:640. After further evaluation, the organizations involved carried out clinical trials according to the relevant procedures.

As for establishing animal models, the WIV has completed COVID-19 modelling in rhesus monkeys. Evaluated by experts organized by the Ministry of Science and Technology, the model is considered to have been successful, and can be used to conduct research into the pathogenic mechanisms and spread of COVID-19. This provides a significant platform for evaluating vaccines and drugs for the novel coronavirus.

Science and Technology Daily:As an institute that specializes in studying viruses, how has your previous experience into virus research helped in the fight against the COVID-19 outbreak?

Guan Wuxiang:The WIV began construction of the Wuhan National Biosafety Laboratory following the 2003 SARS epidemic. The Institute focuses on virus research, especially on highly pathogenic viruses. We have carried out basic research into and developed prevention and control technologies for a variety of viruses, which laid the foundation for coping with outbreaks of new infectious diseases.

In particular, the Institute's research team has been studying coronaviruses for over a decade. It is equipped with general nucleic acid testing techniques for coronaviruses, commonly used methods for detecting nucleic acid and antibodies of SARS-like coronaviruses, and virus isolation and cultivation methods. These all played an important role in the identification of pathogens during the early stage of the COVID-19 outbreak.

Science and Technology Daily:Considering the Institute's years of experiencein researching coronaviruses, is it possible to predict novel coronavirus outbreaks?

Guan Wuxiang:Since the SARS outbreak in 2003, China has improved its infectious disease surveillance system and further strengthened its infectious disease prevention and control capacity by means of special support projects for researching major infectious diseases. The existing system mainly focuseson the surveillance of and the early warning for infectious diseases. Currently, it is not possible to actively predict outbreaks.

Forecasting virus outbreaks and pandemics is a difficult task all across the world. Humans are not fullyaware of all the viruses that exist in nature and the patterns of their occurrence, development, spread and pathogenesis. To develop from the current level of passive warnings to the level of active forecasting, a group of diligent researchers are needed to continue basic research and technological development. Carrying out long-term monitoring and investigation of viruses found in wild animals is an important task in monitoring possible infectious diseases.

Well-organized research and development teams

Science and Technology Daily:At present, how many teams at the WIV are carrying out scientific research into COVID-19? What exactly are they doing?

Guan Wuxiang:According to the development of the epidemic and the tasks being undertaken, the Institute organized over 120 top researchers from different subfields into 12 scientific research teams. They are mainly responsible for carrying out pathogenic testing, virus monitoring, drug screening and other work. In addition, more than 40 people from six support teams were organized to provide assistance for the scientific research work. The national virus resource database is responsible for the collection and standardization of COVID-19 samples; the biosafety level 3 (BSL-3) laboratory and biosafety level 4 (BSL-4) laboratory are mainly responsible for the normal operation of the laboratories and the guarantee of the scientific researchers' safety. Meanwhile, the analysis and testing center and the experimental animal center are responsible for the analysis and testing of large instruments and the protection of the safety of laboratory animals, respectively.

Science and Technology Daily:What does a typical work day consist of for the scientific researchers?

Guan Wuxiang:Since the COVID-19 outbreak began, the researchers at the WIV have been fighting on the frontlines against the epidemic. They volunteered to forgo the Spring Festival holiday, overcame all kinds of personal difficulties, and devoted themselves to researching COVID-19.

The lab's researchers work shifts lasting around five to six hours, during which they are unable to eat, drink or use the toilet. Taking into account the time spent on preparation and data processing, they work an average of around 10 to 12 hours a day. In order to efficiently utilize the research machinery, multiple teams take turns to enter the BSL-3 labs in the Xiaohongshan and Zhengdian Scientific Park to carry out research. The team responsible for pathogen detection, which has a large number of samples to work on, is divided into two groups that take turns to work in the BSL-3 and BSL-2 labs.

Hearing that our COVID-19 pathogen detection team didn't have enough researchers to conduct detection of so many samples, many of the Institute's young peoplevolunteered to take part in pathogen testing.

BSL-4 Laboratory's contribution and achievements

Science and Technology Daily:Could you please highlight the major breakthroughs and progress made by the BSL-4 Laboratory in terms of scientific and research advancement?

Yuan Zhiming:The BSL-4 Laboratory is actually a subsidiary of the Wuhan National Biosafety Laboratory. In addition, there are also two BSL-3 Labs, numerous BSL-2 Labs affiliated to the WIV, several ordinary labs, as well as facilities and supporting equipment for animal testing. The aforementioned labs and institutes constitute a cluster platform to safeguard biosafety.

After receivingsamples ofathen-unidentified pneumonia virus and successfully isolating the new coronavirus pathogen, the Wuhan National Biosafety Laboratory then applied for a number of accreditations that later enabled it to cultivate COVID-19 pathogenic cells and test them on infected rodents and non-primate animals. In addition, the lab's scientific research ethics supervisory committee and its animal testing management body have guaranteed the welfare of all animals used in trials by managing, observing and checking the whole process before providing their approval.

Therefore, the Wuhan National Biosafety Laboratory has made overall progress in several areas, including purification of the proliferation of the COVID-19 virus, assessment into neutralizing antibody titers from the plasma of recovered patients, evaluation of the effects of disinfectants, assessment of the establishment of non-primate animals' experimental models and antibody medicines, development of inactivated vaccines, and trials on animal protection. So far, our achievements have encompassed the standardized techniques of virus proliferation and inactivation, the rollout of new disinfectants, the assessment of COVID-19's inactivation, the modeling of infections in rhesus monkeys and evaluations on candidate antiviral medicines and inactivated vaccines. The established model for animals has also provided a fundamental basis for evaluating other candidate antiviral medicines and vaccines.

Stringent protocols taken to avoid virus leaks

Science and Technology Daily:What preventive and protective measures do personnel take when both entering and exiting the BSL-4 Laboratory, where biological safety controls are among the strictest?

Yuan Zhiming:All those working in the BSL-4 Laboratory must undergo theoretical and practical training and pass evaluations for physical and psychological competences. Even if they pass those accreditation tests, they won’t be givenaccess until they receive permission from their directors.

Upon arrival at the entrance to the lab, researchers' basic physical conditions, such as blood pressure and body temperature, are checked to ensure they are within the appropriate ranges for working inside the lab. Throughout the entire process, only researchers endorsed with the requisite qualifications and accreditations can unlock the door leading to the lab's ring corridors. It is there that they will examine the operations of the lab, complete the entrance and exit form, and inform the monitoring center.

Following the first access, researchers will enter the first fitting room after unlatching a second door. Here, they change into disposable protective suits and check and put on the positive-pressure protective suit, before connecting it to a breathing supply hose. After these procedures are complete, they will pass through a decontamination shower room before arriving at the main laboratory room. In order to guarantee biosafety, there must be no fewer than two testing personnel working at the same time in the lab. Access is denied to anyone who wishes to enter the lab alone.

Researchers generally exit the laboratory via the same route they enter. Before they/researchers exit, chemical disinfection and water rinsing must be performed in the decontamination shower room, and the positive pressure protective suits must be thoroughly disinfected. After removing the inner protective suit, all personnel must shower and then put on their own clothes, exit the laboratory, and fill out the Laboratory Personnel Entry and Exit Registration Form. At this point, a lab shift is complete.

Inside the laboratory, all contact between researchers and the outside world is made through the monitoring center. In case of any abnormal situation, the researchers will first contact the center as soon as possible. When experiments are underway, the monitoring center will also be staffed with biological safety, biological security and equipment support personnel throughout to ensure that any potential emergencycan be properly handled.

Science and Technology Daily:In terms of preventing virus leaks from the laboratory, what special protective technologies and measures does the BSL-4 Laboratory utilize?

Yuan Zhiming:The core of the Wuhan BSL-4 Laboratory is surrounded by stainless-steel walls, forming a "box-within-a-box" structure. The core lab enclosure can ensure sufficient structural strength and tightness to form a static seal. The lab's dynamic seal uses negative pressure technology to ensure a strict and orderly pressure gradient between the functional areas, thereby effectively preventing any air contaminated by infectious pathogenic microorganisms from spreading to areas with low contamination probability and to the external environment.

Air emitted from the lab is filtered and discharged by two-stage high-efficiency filters to ensure the safety of the emissions. Waste water is discharged after high-temperature treatment in a sewage treatment system. Polluted waste in the lab is subjected to high-temperature and high-pressure treatment by double-door autoclaves, and then safely removed and delivered to a centralized medical waste disposal unit with corresponding qualifications for disposal. Whenever personnel pass through the entrance and exit channels, their positive pressure protective suits are chemically disinfected using the chemical showers to ensure the safety of the passageways. The above technical protection measures ensure that viruses inside the lab cannot escape.

The laboratory not only has high-standard biological safety facilities, but also a strict biological safety management system, including a series of procedural documents and standard operation manuals on scientific research programs, personnel, laboratory animals, waste disposal and infectious material management. These ensure that the lab runs safely and efficiently. The physical facilities of the laboratory are tested annually by a third-party organization, and its operations are subject to supervision and evaluation by the China National Accreditation Service for Conformity Assessment, as well as annual inspections by relevant national authorities.

Science and Technology Daily:Research into the COVID-19 virus will take a long time. What follow-up work will be done in the future?

Guan Wuxiang:The WIV will continue to face the urgent scientific and technological needs for rapid handling and emergency response. It will also carry out scientific research and make breakthroughs into the testing of pathogens, development of antiviral drugs and vaccines, evaluation of neutralizing antibody titers in recovering patients' plasma, and research animal models and pathogenic mechanisms.

Facing the long-term demand for the prevention and control of infectious diseases, the Institute will continue to conduct basic research and development into prevention and control technologies in the fields of biosecurity and public health. It will also provide scientific and technological support and decision-making consultation in order to safeguard biosecurity.

The article was published in Chinese on Science and Technology Daily and translated by Zhu Bochen, Wang Yiming, Wu Jin and Zhang Rui from China.org.cn.Youcanalsoreadthisarticleat：http://www.china.org.cn/china/2020-05/14/content_76044840.htm

Editor：余昊原