The Good, the Bad and the Ugly: a review of SARS Lab Escapes

Introduction

In 2003–04, in the wake of the SARS epidemics, there were multiple cases of laboratory acquired infection (LAI) with SARS in just a few months: first in a P3 in Singapore, then in a P3 lab that was part of a military P4 complex in Taipei, and last a protracted case in a P3 in Beijing. The ‘WHO SARS Risk Assessment and Preparedness Framework’ has a good summary of these lab accidents:

1. The Good: Singapore P3 — Sep 2003

In a few words: This first SARS LAI accident (in Singapore) exposed some serious structural biosafety issues but the investigation was very thorough and transparent, and even extended into a review of all BSL-3s in the city-state. The Singapore government used it as an opportunity to fundamentally redesign its biosafety approach, just at the time when more BSL-3s were due to come in line. We also note that the (strongly controlled) local media do not seem to have contributed any additional details to the story.

1.1 The Accident:

In September 2003, a 27-year-old student from the National University of Singapore (NUS) was found to be infected with the SARS virus due to improper experimental procedures. [s.1]

  • The first time, he went in with the technician, wearing only street clothes, and did not engage in any work.
  • The second time, staff of the EHI were meeting. Before going to that staff meeting, the virology technician had grown up a stock of the New York isolate and centrifuged the supernatant from infected cells. The technician had then placed the centrifuge tubes in the Class II biological safety cabinet for the student to ampoule as a seed stock for his research. Accordingly the student put on a gown and two sets of gloves before entering the laboratory alone, where he spent 20 minutes unsupervised, transferring the cell supernatant into pre-labelled cryovials under the Class II biosafety hood. [s.6]
  • The third time he re-entered the lab with the technician who was back from her meeting and transferred the cryovials to a –70°C freezer located in the BSL-2 facility, as no such freezer existed inside the BSL-3 laboratory, so that all frozen BSL-3 virus strains were effectively stored in the BSL-2 freezer.

1.2 The Investigation:

Analysis of the ampoules of seed West Nile virus that the student stored on that 23rd Aug showed that the vials contained SARS- CoV as well as West Nile virus. That SARS-CoV matched the SARS isolate that was handled at the EHI.
Poor record keeping made it difficult to ascertain if there was a live SARS virus in the BSL-3 laboratory on that exact 23rd Aug, but it was established that there was some there 2 days before. [s.8]
In other words there had been a SARS-contamination within the BSL-3.

1.3 Structural Issues:

At the invitation of the Singapore Ministry of Health, the investigation team went further than the EHI P3 lab and looked also at overall biosafety practices in other Singapore institutions. This was both a very courageous and very useful initiative, especially in view of the large number of new Singapore BSL-3 labs that were supposed to come in line soon at the time.

1.4 The Aftermath:

At the end of September, Lim Ruisheng, Minister of Environment of Singapore, apologised to the people of Singapore for the SARS infection incident in the laboratory of the Institute of Environmental Health. Lin Ruisheng said:

2. The Bad: Taiwan Military P4 — December 2003

In a few words: The second SARS LAI accident (Taiwan) was a less straightforward affair. First the human factor played a big role in delaying notification to the authorities. Then the accident had a large epidemic potential as it involved international air-travelling shortly after infection. Also, while the official reporting of the accident was generally transparent, a few aspects of the story remained somewhat opaque due to the military setting.
Taiwanese media, and interestingly also mainland China media, have contributed circumstantial details to the story. Generally, the reaction of the authority seems to have been earnest and constructive.

2. 1 The Accident:

Oddly most references to this lab accident simply fail to mention that it happened in a military P4 laboratory (likely built or equipped by France) utilising type III glove ported isolators [t.17]. These facts are particularly important and should be better publicised.

IPMR entrance
Example of a mobile Class III BSC (Biosafety Cabinet) — suitable for a BSL-4

2.2 Fear of Losing face and bringing shame:

Faced with the standard symptoms of SARS, Lieutenant-Colonel Chan was very aware that he may have caught SARS. However he decided to self-isolate at home, relying on his father to care for him, as he was unwilling to seek medical care because he dreaded bringing disgrace to himself and his institution.
His father eventually persuaded him [t.6] to seek medical attention by threatening to commit suicide. He checked into Taiwan Hoping Hospital only on Dec 16 by which time he had developed other SARS symptoms, such as a cough and signs of pneumonia. He was readily diagnosed as having SARS [t.16].

2.3 Reaction from the Authorities

A chest x-ray showed pneumonia in his right lung and polymerase chain reaction tests of throat and blood samples were positive for the SARS virus. The finding was further confirmed on multiple samples in two laboratories in Taipei.

Lieutenant Colonel Chan leaving hospital

2.4 WHO enquiry and international cooperation:

A WHO Team was invited to investigate the case. Anthony Della-Porta, who had earlier headed the WHO investigation of the SARS LAI assisted with the investigation.
As far as we can tell, the WHO investigation seems to have been rather comprehensive and transparent, finding and reporting quite a few failures, with the exact circumstances of the accident well delineated [t.13]. The international cooperation effort that followed seems to have been constructive and certainly helped rebuild trust in the Taiwanese capacity to manage their BSL3/4s:

2.5 Lessons to be learnt:

Henk Bekedam, the WHO representative in China, told reporters in Beijing that the case in Taiwan should alert scientists:

Post Scriptum (Jan 2022):

On the 24th Jan 22, Science magazine published an article about a recent Academic Sinica SARS-CoV-2 leak which revealed the true identity of Lieutenant Colonel (LTC) Chan.

LTC Chan / Jan Jia-Tsrong from his CV (left) and news reports at the time (right)

3. The Ugly: Beijing P3 — February to April 2004

In a few words: The third lab incident is a very unsatisfactory affair. It happened in the context of a rather toxic ivory-tower academic system leading to unchallenged bad practices. Very limited official information was released when it ever was; effectively the Chinese government, and consequently the investigation report, provided very little insights or simply did not discuss key issues.

3.1 Setting the wrong expectations:

Following the Singapore SARS lab accident it became clear that laboratories handling SARS may not be as safe as one could expect, especially in nations rushing to build more P3 labs. This raised the question of the safety of the laboratories handling SARS in China.

Article from the 19th Dec 2003

3.2 Flagship role of the CDC Institute of Virology:

The National Institute for Viral Disease Control and Prevention (NIVDC) in Beijing (病毒病预防控制所), in short the Institute of Virology, is part of the Chinese Center for Disease Control and Prevention (China CDC, 中国疾病预防控制中心 ).
The CDC itself had only been formed in early 2002 and had to immediately ride through the SARS epidemic. In June 2003, mainland China had no more new or active SARS cases and the SARS epidemic was officially declared as being over. The Institute of Virology was then designated by the Ministry of Health as one of the six storage units for the SARS virus. [b.1]

Main entrance of the Institute, 100 Yingxin Street — 2020
Side alleys — source: Baidu
5-storey building of the Institute where the leak happened, source: Baidu

3.3 An academic ego got hurt

The director of the Diarrhoea Virus Department was Academician Hong Tao (洪涛) of the Chinese Academy of Engineering. 72 y-old at the time and a highly respected virus expert, he was one of the main pioneers in the field of medical electron microscopy, the main founder of the virus morphology discipline in China, the discoverer of diarrhoea rotavirus (“洪氏腹泻” Hong’s Diarrhoea) which caused a acute diarrhoea outbreak in North China in 1983, the discoverer of the intracellular morphology of epidemic hemorrhagic fever virus, and one of the founders of the Chinese Society of Electron Microscopy which he used extensively in his virus morphology work. He also had extensively studied chlamydia. [b.11]

Academician Hong Tao, 72 at the time
  • Nanfang Hospital (Guangzhou) had found virus particles in lung tissue samples of SARS patients through electron microscopy as early as February 20, but their research was forced to stop after the “ban” issued at the meeting of the 17–18 March [b200]
  • Researchers from the Chinese Academy of Military Medical Sciences (Beijing) also discovered virus particles in samples on February 26, which were identified as a coronavirus after being reviewed by 6 virus morphologists. On March 21, the Military Medical College reported to the relevant departments the discovery of the coronavirus. However, the findings were not officially announced until April 9. [b200, b103]
Academician Zhong Nanshan, 66 at the time

3.4 Fighting back with more P3s doing SARS research

Prior to the SARS epidemic, in 2002 (as part of the important reforms of the CDC in January of that year), Hong Tao’s Virus Morphology and Viral Diarrhoea Laboratory (病毒形态学与腹泻病毒实验室) at the CDC Institute of Virology was divided into three laboratories, all under his control: the prion (which can cause mad cow disease) laboratory department, the viral diarrhoea laboratory and Hong Tao’s laboratory, designated as the Academician Laboratory (each of the 5 Academicians at the Institute traditionally have their own laboratory). [b.3, b.8]

3.5 Lab contamination — Feb 2004

Ren Xiaoli (任 小 莉, pseudonym) is a Virus Morphology doctoral student at the Institute of Virology in his last year before graduation. Under the guidance of Hong Tao (founder of the Chinese Virus Morphology discipline) and Wang Jianwei (王健伟), then director of the Viral Diarrhoea Department of the Institute of Virology, Ren Xiaoli and 21 doctoral and master students such as Yang (杨某) and Guo (郭某) joined the frontline of SARS scientific research. [b.3]

‘There are two more infected people’ — Caijing, May 2004 [b.1]

3.6 Community Transmission — Apr 2004

On March 7th Song (宋某 as given in the reports at the time), a 26 year-old graduate student of Anhui Medical University (安徽医科) started a short-term internship in the viral diarrhoea department of the Institute of Virology in Beijing, during which time she worked with adenovirus (腺病毒) and syncytial virus (合胞病毒). Her research has nothing to do with SARS. With her qualifications, she was not allowed to enter the P3 laboratory for SARS research and she always maintained that she never did. [b.1, b.4]

3.7 The Response of the Authorities

China officially reported Li SARS case on the 22nd April, then Song, Wei and Yang SARS cases on the 23nd April [b502, b504]. The institute was temporarily closed and quarantined on the 23rd April. [b1, b513]

Staff of the Chinese Center for Disease Control and Prevention closing the gate of the Institute of Virology, preparing for terminal disinfection , 100 Yingxin Street [b.3]
100 Yingxin Street, Source: WHO [t.21]

3.8 Summary of cases:

There were in total 11 cases over four generations. Note that the official report would only mention the 9 cases of the Song-contamination chain (April), ignoring the two February primary cases that are linked to the contamination of the diarrhoea lab and had been disclosed by Caijing since May. [b512, b513, b514]

Extract from Investigation Report — note that there were 2 additional Feb cases (11 in total) [b.57]

3.9 The Official Investigation

a. Brief role of the WHO and missing February cases

The WHO sent a team on the 26th April 2004 which included ‘experts in epidemiology, virology, infection control, and laboratory biosafety’ [b518].

Source: WHO [b520]

b. The Official Conclusions

The Ministry of Health would produce its investigation report on the 1st July 2004. There is no mention of the WHO at the time in the press reports. The WHO team had most likely long left the scene and its role in the investigation, whatever its extent, was not discussed.

Summary of the 9 cases starting from Song [b.7]
Official conclusions 2 Jul 2004, [b58]

Investigative journalists add important elements

Over about two months a few Chinese magazines and newspapers were able to add some crucial elements of this story (some acquired via insiders), such as the positive cases of Cui and Ren [b1] and the location of the fridge out of the P3 lab [b3[.

3.10 The omissions

Some international experts were disappointed that many details about the incident and the lab’s operating procedures remain very opaque or simply hidden.

a. No full report published

This was supposed to be a joint China-WHO investigation [b519].
However the WHO simply withdrew from the scene without trace. There was not even an update posted by the WHO after the 18th May and the WHO did not publish the official report produced by China.

b. February inspection of the Institute

On July 12th, 2004, shortly after the reorganisation meeting, according to media reports at the time, the Ministry of Health was rather sanguine about the SARS virus leak. And they had good reasons.

c. The cause of the contamination

Ren and Cui had tested positive for antigens back in May, as disclosed by Caijing [b1]. Judging from the few available extracts, the Ministry of Health report simply confirms the positive tests but never mentions the February context, nor does it include them in the official count of the cases (hence stopping at 9 and not 11).

3.11 The sanctions:

The Ministry of Health decided the following sanctions: [b4]

3.12 All is well that ends well:

In any case the sanctions seem to have been more on paper than anything else:

Wang Jianwei
Dong Xiaoping
Report of the WHO-China Joint Mission on Coronavirus Disease 2019–16–24 Feb 2020
Li Liming
Novel Coronavirus Wuhan Strain 01 (IVDC China’s CDC)

3.13 Déjà vu:

On the 5th August 2021 US Right To Know released some emails showing that some senior researcher got infected with SARS-CoV-2 at the very same Beijing Institute of Virology (NIVDC) in January or February 2020:

4. Conclusion: Lessons from SARS Lab-Escapes

4.1 Importance of people and processes:

All the three SARS lab-leaks that we looked at were the result of people either making mistakes or taking deliberate short-cuts, and were often made worse by bad processes that only surfaced after the investigation and were not questioned before — even when seemingly quite obvious to an external observer.

4.2 Importance of Laboratory location:

The location of major labs (P4s and top P3s), especially civilian ones, tend to be often in major cities — close to universities and related biological industries — and thus often in the middle of land and air transport hubs, including international transports.

Box: Can lab processes ever be fool-proof?

Formal processes school:
One standard reaction when faced with human errors and faulty processes is to try to redesign processes and reinforce training. While this answer has some value, experience would indicate that in a domain where the human factor is very important — such as in P3 lab — such an approach may never work perfectly.

  • Adding more rules for those handling pathogens won’t help if the people infected are usually not the ones handling the pathogens (i.e: indirect infections via contamination of the lab surfaces, via aerosols or via wastes).
  • Adding more federal and international regulations won’t help if the regulations aren’t consistently followed.
  • If there are still unrecognized technical flaws in the standards for biocontainment, how would we know until an incident made those flaws apparent?
  • Limiting the work on enhanced pathogens (reducing the R0)
  • Positioning labs in sparsely populated environments and far away from transport hubs
  • Possibly implement practical quarantines in labs

4.3 Importance of Institutional Factors:

The quality of the response to a Lab-Escape in a given country is largely framed by a few key institutional factors, as nicely demonstrated by the 2003–04 SARS lab-leaks:

  1. Government (central and local) transparency
  2. Central government willingness to learn from mistakes
  3. Free press that can contribute to transparency

In particular we note that:

  • The answer in Singapore was very strong on (1) and (2), much less on (3) where the press did not add any material knowledge.
  • The answer in Taiwan was very strong on (2), a bit less on (1) most likely due to the military setting (a P3 lab with a military P4 lab), and rather strong on (3) [interestingly mainland China media reports also added some important details].
  • The answer in Beijing was very poor on (1) and (2) but rather good on (3), as investigative journalism provided essential details without which we would have only the most limited understanding of the exact circumstances of the leaks, since neither the WHO or Beijing released any report.

4.4 Adapting Case Definitions to include potential Laboratory Exposure:

At the time of these SARS lab-escapes, the WHO and the US CDC used a definition for a ‘SARS suspected case’ that required that the case had one or more of the following exposures during the 10 days prior to onset of symptoms:

  1. close contact with a person who is a suspect or probable case of SARS;
  2. history of travel, to an area with recent local transmission of SARS;
  3. residing in an area with recent local transmission of SARS.

4.5 Managing the risk of a new biotechnology age:

We are at the cusp of a new biotechnology age. As with any new technology age, we see competition between nations driving developments and implementations that quite often are running ahead of a proper risk assessment.

References

For a quick approximate translation of pages in Chinese, please use the Google Translate extension with Chrome. It works rather well.

Introduction:

[i.1] WHO SARS Risk Assessment and Preparedness Framework, Oot 2004, www.who.int/csr/resources/publications/CDS_CSR_ARO_2004_2.pdf

Singapore:

[s.1] ‘Laboratory-Acquired Severe Acute Respiratory Syndrome’, NEJM, Apr 2004, //www.nejm.org/doi/full/10.1056/NEJMoa032565

Taiwan:

[t.1] IPMR and Taiwan bio-warfare capabilities: https://bit.ly/3ldKkaU

Beijing:

The main articles of investigative journalism are:

Official sources:

[b.9] People’s Daily Online and Jiangnan Time (20 Dec 2003), ‘The Nation’s emergency inventory of SARS laboratories’ : http://news.sina.com.cn/o/2003-12-20/10381388019s.shtml

Official conclusions:

[b51] Only extracts of the official ‘Analysis Report on the Epidemic Control of the ‘4.22’ SARS Epidemic in Beijing in 2004' (2004年北京‘4·22’SARS疫情流行控制情况分析报告) are known. The report misses the Ren and Cui cases from February. Note that the report title focuses on the April cases (‘4.22’), a possible odd justification for not mentioning the two primary February cases which explain the contamination of the lab.

Chinese Blog entries:

[b100] A good Chinese entry on SARS leaks: ‘Thinking: The SARS virus leak in 2004’ Automated Translation: https://bit.ly/36mIgal. Original ‘思考: 2004年SARS病毒泄露事故’, should come up as first link in this Sogou search: https://bit.ly/2IsWRsh

Additional Sources:

[b501] There are 4 Koch postulates in the original formulation, and 6 as modified by Rivers for viral diseases. See ‘Koch’s postulates fulfilled for SARS virus’ (May 2003) https://www.nature.com/articles/423240a

On the chlamydia controversy

[b200] For an excellent recap of the events: ‘SARS virus hits China’s scientific research system’, Jun 2006, https://news.sina.com.cn/c/2003-06-11/01461156694.shtml, also through http://blog.sina.com.cn/s/blog_8d622a9e0100xgqb.html

On nepotism:

[b301] Yi Ming, The problems of Chinese academia and their way out, Jul 2004 (亦明, 中国学术界的问题及其出路), http://bbs.tianya.cn/post-free-179032-1.shtml. Also https://drive.google.com/file/d/1XyWj30Pcpp3Ru1o5m1jML6L6wVWc5dmz/view?usp=sharing for translation and https://drive.google.com/file/d/1vQ-yGL47x6VOBLiWgee5zydfog1Hzv_h/view?usp=sharing for a copy of the original.

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Opinions, analyses and views expressed are purely mine and should not in any way be characterised as representing any institution.

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Gilles Demaneuf

Gilles Demaneuf

Opinions, analyses and views expressed are purely mine and should not in any way be characterised as representing any institution.