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February 26, 2020

What is a Level 4 Biosafety Laboratory?

A Global Response to Coronavirus.

corona-virus-signs

In a headline image a floodlit cruise ship sits somberly in dock. In the foreground, buses ferrying passengers across the tarmac vanish into the dark Yokohama night. Flashing lights cast a red glow onto the metal fences separating the liner from the port, illuminating the quiet drama playing out under sodium lights. Absent from the restricted area are the disembarking passengers, uniformed emergency personnel, or masked stevedores – the anonymity of government-mandated quarantine is enforced. While on board, quarantined passengers are eating breakfast, lunch and dinner curtesy of Chef José Andrés’ nonprofit World Central Kitchen.

The vessel pictured is the coronavirus-stricken cruise liner the Diamond Princess which, to date, has dispatched a total of 454 cases of infection to the Japanese mainland.

Of these, 328 American passengers – 14 of whom have tested positive for the virus – have been transferred to the US where they will spend two weeks quarantined at Travis Air Force Base in Fairfield, CA or Lackland Air Force Base in San Antonio, TX. The 14-day quarantine covers the maximum incubation period for the virus and American authorities are following plans in line with those of other affected countries such as Australia, New Zealand, Russia, and of course the country of origin, China.

The eerie scene of the sequestered vessel is replicated in Cambodia where a second cruise liner, the Westerdam, turned away from Japan, Thailand, the Philippines, Guam, and Taiwan, remains at the port of Sihanoukville.

Initially considered to be virus-free, the Westerdam operated by Holland America Line, has caused a scramble by authorities to locate those who may have had contact with passengers prematurely permitted to disembark. According to Time magazine, an elderly couple who left the ship along with hundreds of others was detained at Kuala Lumpur airport where the 83-year old woman tested positive for the virus. Her 85-year old husband repeatedly tested negative. The cruise line maintains that ‘all passengers and crew were screened for illnesses and had their temperatures taken, and upon disembarkation the passengers underwent an additional health screening and were required to fill in a written health questionnaire.’(1)

All of which might seem to be adequate in terms of safety were it not for the fact that the novel coronavirus has an incubation period that could, in some cases, extend to 24 days. In an article published by China Daily, ‘[t]he median incubation period is three days, lower than the estimated 5.2 days, according to research conducted by Zhong Nanshan, a prominent scientist who is leading a government-appointed panel of experts helping control the coronavirus outbreak. [But] Guan Weijie, a member of the research team, told Red Star News on Monday that the coronavirus [has also] incubated for 24 days.’(2)

Indeed, a cause for concern. According to an update in The Washington Post on February 17, 2020, the number of ‘confirmed infections in China now exceeds 70,000, with the death toll rising to 1,770, the overwhelming majority of both in Hubei province.’(3) Of course, statistics on the number of people affected change almost hourly and given that a vaccine is not yet on the horizon, the situation in global terms is sobering.

But how did the epidemic begin?

What is a novel coronavirus and why is this one considered such a threat? Thought to have originated in a seafood market in Wuhan in the Hubei province of China, the virus – dubbed 2019-nCoV – is a member of a virus family that affects the mammalian respiratory system. With four different ranks – aka genera – its victims are overwhelmingly non-human animals, although the first two ranks – alpha and beta – also affect humans. According to Medical News Today, the most common vector of coronavirus communication is the bat – via secondary routes of transmission such as civet cats and camels. And although person-to-person exposure is increasingly significant, ‘[r]esearchers are still studying the exact parameters of human-to-human transmission.’(4) To date, 2019-nCoV has been fatal only to those with existing health complications and to seniors. Related to both Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), symptoms of 2019-nCoV are akin to those of viral pneumonia, including the presence of fever, coughing, and respiratory distress. However, some of those infected are asymptomatic and current screening procedures at international ports of entry rely upon recording passengers’ body temperature and travel itinerary – a seemingly insubstantial response to a looming global threat.

And indeed it is unsatisfactory. According to Richard Sugrue, an associate professor at Singapore’s Nanyang Technological University, ‘the only real way to confirm an 2019-nCoV infection is diagnostic testing like polymerase chain reaction (PCR) tests or electron microscopy, which may take several hours to complete and would be infeasible in a scenario like an international airport, where tens of thousands of people pass through every day.’(5) If you think that TSA lines are bad now, a whole new world of pain may be just around the corner…

With that said, thus far the world’s focus has been upon those directly impacted by the disease: cruise ship passengers and crew, other travelers, shoppers at the epicentral seafood market, and an estimated 760 million ordinary people in China who are now subject to ‘one of the biggest social control campaigns in history.’(6) In addition to residential lockdowns, roadblocks, rewards to informants, and the rejection of outsiders, China is also implementing high-tech measures to contain the outbreak. In a New York Times article, Raymond Zhong and Paul Mozur note that at a ‘high-speed rail station in the eastern city of Yiwu this past week, workers in hazmat suits demanded that passengers send the text messages that show their location data before being allowed to leave.’(7) Moreover, ‘Yunnan Province wants all public places to display QR codes that people must scan with their phones whenever they enter or exit.’(8)

But these are not the only people touched by the coronavirus outbreak.

Twenty miles from the seafood market sits a boxy building of concrete and glass. Unassuming from the outside, it is the Wuhan National Biosafety Laboratory and is Asia’s first level-four biosafety laboratory (BSL-4). BSL-4 facilities, of which there are currently only 54 worldwide, ‘investigate the most dangerous pathogens and have the maximum biocontainment levels. Microbes contained in BSL-4 laboratories pose a significant risk for transmission and are frequently fatal; most have no reliable cure. BSL-4 laboratories provide a safe environment in which laboratory staff can work with and study these highly pathogenic microbes.’(9) Housed at the Wuhan Institute of Virology, the facility was designed for ‘fulminant disease pathogens such as Cellular Level Biosafety Level 4 Laboratory, emerging disease research facility and fulminant disease pathogen storage facility (that is, BSL-4, BSL-3 and BSL-2, ordinary laboratory, animal feeding room and relevant supporting facilities), which [form a] complete emerging disease research unit.’(10) And the specified mission of the unit is to ‘research two or three types of fulminant infectious disease pathogens and develop the corresponding vaccines. […] By doing this, at the outbreak of a new infectious disease, active and scientific prevention and control measures can be taken, forming a new normal state for dealing with emerging disease and biological defense in the future.’(11)

‘At the outbreak of a new infectious disease’ – an interesting coincidence that this facility is located in such close proximity to the first appearance of 2019-nCoV.

We’re sure this is just a fluke. And what does this particular BSL-4 look like? Housed on four floors, the laboratory boasts its own power generation capability, life support system, and sewage treatment operations on the first floor, with the third floor designated as the blast air and ventilation infrastructure, and the fourth floor as the locus of the HVAC equipment. Using a double-layer sewer pipe collection system, waste water from a chemical shower through which personnel pass on their way out of the laboratory and other toxic liquid waste is heat treated to temperatures as high as 135℃ as a  disinfectant.

But as exciting as the waste water treatment facilities may be, the real interest is generated elsewhere. Pressing an elevator’s ‘Floor 2’ button brings you to where the actual science is conducted, with assessments on infection pathology and drug efficacy carried out in three cellular level laboratories, two animal laboratories, a dissecting room, and a preservation room for bacteria and viruses. The walls of this ‘core experiment zone’ are fabricated from laser-welded stainless steel and researchers work in a controlled environment of ‘a directional negative pressure system and double-layer filtering system to ensure that the air in the laboratory can be exhausted only after being filtered with a high efficiency particulate air HEPA filter with organized negative pressure control technology.’(12)

Search online for ‘Wuhan National Biosafety Laboratory’ and you’ll find a number of images and videos showing personnel in extremely advanced personal protection equipment (PPE).

With airtight, positive pressure suits and chemical grade Hypalon gloves that attach to ports in non-opening view windows, the researchers are also dependent on air hoses for life support while in the lab. But it is a different safeguard that is arguably the most effective personal protection for those working within the walls of the Wuhan premises. Since the operation exists to provide ‘safe and secure platforms which integrate reliable containment, well-trained personnel, and specific biosafety manuals and practices to protect researchers from being infected while manipulating microbial pathogens and prevent pathogens from being released into the outside environment,’ education is key.(13) All operators must be at least Level-3 certified in order to access this completely isolated environment that is ‘constructed to handle dangerous and exotic biological agents that are likely to cause serious or lethal human disease with high individual and community risks, for which there are no preventative or therapeutic interventions usually available.’(14) For employees, continual training is given both in pre-assessment and on the job. According to Emerging Infectious Diseases, a publication of the Centers for Disease Control and Prevention (CDC), the biosafety level 4 laboratory user instruction in China involves not only practice in a mock-up of a laboratory, complete with bioseal doors, air connection ports, biosafety cabinets, autoclave, pressure sensors, and chemical showers, but also on-going theoretical and practical training within the actual workspace. The hands-on practicum involves staff members expanding their familiarity with ‘features, such as airtight doors, dedicated airflow supply and exhaust systems, autoclave, chemical shower, negative-pressure environment, personal protective equipment, standard operating procedures, and safety procedures, including alarms and emergency operations.’(15)

And these SOPs and GLP requirements form the cornerstone of institutional safety. GLPs? That’s Good Laboratory Practices – which are, of course, different from the Good Manufacturing Practices (GMPs) we have described elsewhere.

Although both sets of regulations can pertain to laboratories, they serve two distinctly different purposes. According to Microchem Laboratory, GLPs are ‘designed to protect scientific data integrity, and to provide […] a clear and auditable record of open-ended research studies.’(16) In essence, the GLPs ensure quality and integrity of research studies into product safety whereas GMPs target that of individual batches of medical products manufactured in accordance with processes including SOPs and Hazard Analysis and Critical Control Points protocols (HACCP). For a complete breakdown of the differences between the two sets of regulations, it is well worth checking out Microchem’s analysis here.

So, with all of this in mind and given a snapshot of the level of facility dedicated to defeating the virus, what does the future hold for the containment of 2019-nCoV?

According to David Weiner, EVP and Director of the Vaccine & Immunotherapy Center at the Wistar Institute in Philadelphia, the key to stopping the virus in its tracks lies in engineering a DNA vaccine. Weiner and his team are transforming RNA snippets of the coronavirus’ genetic code into DNA and, in an article published by NPR, Weiner explains how the snippets ‘will then be injected into someone’s skin, where they will be taken up by skin cells. The skin cells will then turn those DNA sequences into proteins identical to the ones a virus would produce, and those will be what “teaches” the immune system to recognize the new virus.’(17) Furthermore, using gene snippets will dramatically shorten the time spent in R&D as Weiner’s past success at rapid vaccine development demonstrates. After an outbreak of the coronavirus that causes MERS, the Philadelphia team was able ‘able to design and develop and move into the clinic in 11 months.’(18) That’s impressively speedy.

And we can only hope that it will be sufficiently rapid to stop the outbreak as soon as possible. With a current fatality rate of 2.4%, 2019-nCoV is a viral variant that affects a greater number of individuals but claims fewer lives than another coronavirus, MERS (34.4% fatality rate).(19) This is, of course, encouraging news. Moreover, given its similarity to SARS, drugs and pre-clinical vaccines already developed are looking promising as a hypothetical starting point in thwarting 2019-nCoV, according to an analysis published in Business Insider.

However, it may well be that 2019-nCoV is a variant that – in effect – never actually disappears. Writing in Business Insider last week, Aylin Woodward suggested three possible scenarios for the future of the virus: a protective vaccine is manufactured; 2019-nCoV joins the ranks of endemic coronaviruses and becomes seasonal; public health interventions force containment and the virus ‘plays itself out.’(20) In effect, although pharmaceutical companies may be hedging their bets on scenario #1, this last hypothetical could stop the disease in its tracks before a vaccine can even be brought to market. But, like the all-important precautions taken by institutions such as the Wuhan National Biosafety Laboratory, the critical component in bringing scenario #3 to fruition is the adoption of measures to protect ourselves and our communities. And in this regard, the defeat of  2019-nCoV is uncomplicated – we simply need to understand prevention through pro-active education.

With a travel ban now in place, what are your fears regarding 2019-nCoV? We’d love to know if you have been impacted by recent developments – please drop us a note in the comments.

References:

  1. https://time.com/5785109/coronavirus-confirmed-westerdam-cruise-ship/
  2. https://www.chinadaily.com.cn/a/202002/10/WS5e41162aa310128217276612.html
  3. https://www.washingtonpost.com/world/asia_pacific/fourteen-american-cruise-passengers-with-coronavirus-among-328-evacuated-to-the-us/2020/02/17/1ac9be48-4f70-11ea-bf44-f5043eb3918a_story.html
  4. https://www.medicalnewstoday.com/articles/novel-coronavirus-your-questions-answered#3.-How-is-the-virus-transmitted?
  5. https://time.com/5772134/coronavirus-mild-symptoms/
  6. https://www.nytimes.com/2020/02/15/business/china-coronavirus-lockdown.html
  7. ibid
  8. ibid
  9. https://wwwnc.cdc.gov/eid/article/25/5/18-0220_article
  10. http://lssf.cas.cn/en/facilities-view.jsp?id=ff8080814ff56599014ff59e677e003d
  11. ibid
  12. ibid
  13. https://www.sciencedirect.com/science/article/pii/S2588933819300391
  14. ibid
  15. https://wwwnc.cdc.gov/eid/article/25/5/18-0220_article
  16. https://microchemlab.com/information/what-difference-between-glp-and-gmp-laboratory-testing-regulations
  17. https://www.npr.org/sections/health-shots/2020/02/12/804628081/timetable-for-a-vaccine-against-the-new-coronavirus-maybe-this-fall
  18. ibid
  19. https://www.businessinsider.com/wuhan-coronavirus-genome-close-to-sars-originated-in-bats-2020-2
  20. https://www.businessinsider.com/wuhan-coronavirus-mild-pandemic-how-it-could-end-2020-2
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