A Canadian lab’s Ebola experience

| January 5, 2015 | 0 Comments
A succession of scientists at the National Microbiology Lab in Winnipeg have been leaders in contributing to the fight against Ebola, including the development of new therapeutics.

A succession of scientists at the National Microbiology Lab in Winnipeg have been leaders in contributing to the fight against Ebola, including the development of new therapeutics.

An Ebola outbreak is currently raging in West Africa at a pace never seen in all past epidemics caused by Ebola virus. It is posing a severe challenge not only to the countries directly affected, where containment of the disease has not yet happened, but to countries worldwide, as concern mounts about the spread of the virus by travellers and health-care workers who have dealt with sick patients.
It is worth noting that Canada is playing an important role in the fight against Ebola. It is donating equipment and supplies, providing in-country diagnostic support and pioneering the development of therapeutics that show great promise in the fight against the Ebola virus.

Of more than 17,290 reported cases of Ebola, 10,825 were lab-confirmed and 6,128 people had died by press time in December. Actual numbers are much larger. Here, in the high-mortality Monrovia region of Liberia, people gather for assessment by health workers.

Of more than 17,290 reported cases of Ebola, 10,825 were lab-confirmed and 6,128 people had died by press time in December. Actual numbers are much larger. Here, in the high-mortality Monrovia region of Liberia, people gather for assessment by health workers.

What is Ebola?
Ebola is a serious viral disease first recognised in 1976. Prior to the ongoing epidemic in West Africa (Guinea, Sierra Leone and Liberia), it has caused smaller outbreaks in Central Africa. The initial symptoms of Ebola-infected individuals are not particularly specific — fever, headache, nausea and diarrhea — and are similar to symptoms of other disease-causing agents. The disease typically progresses to more characteristic symptoms, including vomiting blood, nose bleeds, bloody stool and bleeding from many different body sites. Bodily fluids contain high levels of virus and are extremely infectious.

The Ebola virus up close.

The Ebola virus up close.

Different strains of Ebola exist, with the Zaire strain causing the highest known fatality rate, up to 90 percent. It is this Zaire strain, or a close relative, that is causing the current outbreak in West Africa. Although most Ebola strains circulate only in Africa, there is one strain, called Reston, that is found in the Philippines. Fortunately, this strain does not appear to cause disease in humans.
The Ebola virus exists quietly in nature in a cycle that likely involves fruit bats. Every so often, it makes a leap into humans, possibly by human contact with the infected reservoir, or by hunting and butchering of infected wildlife, most notably great apes. Once the Ebola virus crosses over into humans, human-to-human transmission occurs by direct contact with live or deceased patients and their bodily fluids. Health-care workers and close family members are at particular risk of contracting the disease from these individuals.

UN health workers in Liberia do their part to contain the virus and help those afflicted.

UN health workers in Liberia do their part to contain the virus and help those afflicted.

Establishing a Winnipeg lab
In 1990, plans began to build a new state-of-the-art microbiology laboratory for what was then Health Canada (now the Public Health Agency of Canada) and to relocate the major component of laboratory testing from Ottawa to Winnipeg.  Program scientists met with the architects to plan the layout of the new laboratory.
One important question was whether to include what is now known as a Biosafety Level-4 (BSL-4) lab within the new complex. (Microbial agents are placed into four different biosafety levels — BSL — for work in a laboratory. The least dangerous, posing low individual and community risk, are categorised as BSL-1 agents and are unlikely to cause disease in healthy workers or animals. Agents at BSL-2 are of moderate individual risk and low community risk. Examples would be the bacterium that causes Lyme disease and dengue virus.

The International Committee of the Red Cross has also been working in Liberia.

The International Committee of the Red Cross has also been working in Liberia.

Then we have more dangerous agents — those categorised as BSL-3 and BSL-4 organisms — that require higher containment, more sophisticated engineering and more rigorous procedures. Agents at BSL-3 pose high individual risk, but low community risk as they do not spread by casual contact from one individual to another or are treatable by anti-microbial or anti-parasitic drugs.
The pinnacle of biocontainment is found in BSL-4 labs, which work with agents that are almost exclusively viruses, although certain multi-drug-resistant tuberculosis strains have been studied in BSL-4 labs, too. Most BSL-4 viruses are little known to the public — they cause such diseases as Argentinian hemorrhagic fever and Bolivian hemorrhagic fever — but some of the better known ones include Ebola, Lassa fever and smallpox.
The question of whether to have a BSL-4 lab in the Winnipeg facility was not as simple as it might seem. Construction of BSL-4 facilities, which require a box-within-a-box concept, requires special ventilation, sewage disposal and multiple backup systems. They are extremely costly not only to build, but also to maintain. However, after careful consideration and thanks to the leadership and vision of Dr. Joe Losos, director-general of the Laboratory Centre for Disease Control at that time, a BSL-4 laboratory was included in the plans.
That decision was made in light of the increasing importance of emerging diseases and the fact that Canada had to rely on the U.S. Center for Disease Control (CDC) whenever a suspected case of a Level-4 virus infection, such as Ebola or Lassa fever, was encountered in Canada.
Looking at all the events that have occurred since 1990, including multiple outbreaks of Ebola, the identification of new Level-4 viruses such as Nipah virus and the increased concern about bioterrorism, building a BSL-4 lab was a wise decision. The Winnipeg laboratory, now known as the National Microbiology Laboratory (NML), has contributed significantly in the battle against the Ebola virus.

A Level-4 lab in Winnipeg — early days
Construction of the NML occurred throughout the 1990s, culminating in the relocation of Ottawa staff to Winnipeg in 1998. This laboratory is renowned for its work in many areas of microbiology, including housing one of the few BSL-4  laboratories to be found worldwide. Level-4 laboratories are equipped to work with viruses, such as Ebola, which have high fatality rates with no licensed vaccines or treatments and would be a threat to the community if released from containment. Extreme precautions are taken in constructing and maintaining Level-4 laboratories. All staff are well trained and must follow rigorous protocols.
Extensive work went into the construction, certification and preparedness for Canada’s first Level-4 laboratory. A biosafety expert with experience in Level-4 laboratory work, Dr. Mike Kiley, was recruited to oversee construction and a blue ribbon panel of experts was consulted. Health Canada scientists joined a World Health Organization-led project in West Africa (Cote d’Ivoire) in 1996 and 1997, aimed at determining the natural reservoir of the Ebola virus, to give themselves  experience in working with a Level-4 virus and to help establish international credentials.
Following the opening of the laboratory in 1998, a lot of work went into proper certification of facilities and in June 2000, the first Level-4 virus strains arrived at the NML. All steps were taken in consultation with a community liaison committee and efforts were made to keep the public fully informed.

Canada’s contributions to the fight against the Ebola virus
The Canadian laboratory was able to recruit an exceptional scientist, Dr. Heinz Feldmann, from Marburg, Germany, as chief of the Special Pathogens (Level-4 lab) Program. His leadership was key to getting the scientific program off on a strong footing for the quality of the science and the diagnostic capability offered by NML. Soon after the program started, Dr. Frank Plummer, a renowned researcher in the field of HIV, became scientific director-general of the NML. Dr. Plummer provided excellent support for Level-4 activities, allowing the scientists freedom to develop their own scientific interests within the framework of their public health responsibilities and fully backing NML’s role as an active partner in responding to outbreaks of diseases such as Ebola. Dr. Feldmann left NML in 2008 for a job at the Rocky Mountain Lab in the United States and a Canadian scientist, Gary Kobinger, was recruited as chief of the program. Dr. Kobinger has not only maintained the lab’s high standards, he and his staff have been leaders in contributing to the fight against Ebola, including the continuing development of new therapeutics.

A mobile lab for outbreak responses
The NML looked to play a role in international outbreak responses and carved a special niche by developing a mobile lab capability that was immediately embraced by the WHO. The mobile lab, sometimes referred to as a lab-within-a-suitcase, was initially deployed in response to an Ebola outbreak around 2003.
The mobile laboratory provides a safe, rapid and flexible platform to offer effective diagnosis of the Ebola virus and other infectious agents, such as the protozoa that causes malaria or bacteria responsible for enteric diseases. A rapid diagnosis is critical to patient isolation and treatment as well as contact tracing in an attempt to stop further cases from occurring.
The mobile lab can be set up quickly and may be used in remote settings. Most testing is undertaken to determine the possible occurrence of pathogens in patient clinical samples by looking for the genetic material of the respective pathogen. This test is safe, as chemicals are added to the samples that will inactivate all pathogens that might be present. And it is rapid, providing test results in only a few hours.
The NML mobile lab has been deployed to investigate outbreaks of different diseases beyond Ebola, including SARS, Nipah, Rift Valley fever and Marburg, another filovirus (meaning threadlike in appearance) and, thus a distant relative of the filovirus known as the Ebola virus. At  press time, the lab was being used in Sierra Leone to help combat the current Ebola outbreak. Many other countries have followed the Canadian lead and have developed a mobile lab capability.

Possible therapeutics developed at NML
There are no vaccines currently licensed to combat Ebola although several candidate vaccines exist, including the promising VSV-EBOV, developed by the NML. Trials to document the Canadian vaccine’s safety and efficacy are under way and the government has donated 800 vials to the WHO for use under the challenging circumstances posed by the current West African Ebola outbreak.
The Canadian vaccine uses a strategy whereby an attenuated (weakened) recombinant virus, called vesicular stomatitis virus, which causes mild or no disease in humans, has a gene inserted that allows it to express (make) the Ebola virus glycoprotein. Antibodies are produced to this Ebola virus glycoprotein antigen and are presumed to neutralise the Ebola virus, hence stopping virus multiplication in the infected individual. To date, the vaccine has proven to be 100 percent protective in animals given one dose and challenged with live virus four weeks later. It has also shown promise in protecting some animals from disease if given after exposure to the Ebola virus. It was 33 percent effective 30 to 60 minutes after infection and zero percent effective after 24 hours.
This vaccine has been used once in humans under exceptional circumstances. In 2009, a German scientist had a possible needle stick exposure to the Ebola virus and a request was made for the Canadian vaccine. The vaccine was administered to this individual, who recovered fully, with no ill effects from the virus or vaccine. However, it is not clear whether she was, in fact, infected with the virus and conclusions cannot be drawn from just one event.

Monoclonal antibody therapeutics
A mixture of three monoclonal antibodies made against different components of the Ebola virus has been developed and tested by the NML in collaboration with American scientists. It is known as ZMapp and has been shown to completely protect rhesus macaque monkeys up to five days after infection with the Ebola virus. The antibodies in this mixture are designed to bind to the protein of the Ebola virus, neutralising the virus and preventing it from doing further damage to the infected host.
The ZMapp therapeutic has not been validated in humans to date, but it was used on compassionate grounds to treat a small number of Ebola patients during the ongoing outbreak. The current supply of ZMapp has been exhausted, but more is being produced. Mapp BioPharmaceuticals has licensed this drug and is conducting the next stages of research needed to seek regulatory approval. Plans are being made to scale up production. Accelerated trials have been set to determine the safety and efficacy of this treatment for humans.
It was my pleasure to direct the NML scientific program that deals with zoonotic diseases (such as Ebola, which are maintained in nature by animals, but transmissible to humans) from its planning inception in 1990 until my retirement in 2010. I have had the privilege of working with exceptional and dedicated individuals at all levels (scientific, technical and biosafety) who are too numerous to identify by name. Their contributions have helped make Canadians safer from the threat of communicable diseases, at home and when travelling abroad.

Dr. Harvey Artsob was founding director of the Zoonotic Diseases and Special Pathogens program at the National Microbiology Laboratory of the Public Health Agency of Canada in Winnipeg with a cross appointment as adjunct associate professor in the department of Medical Microbiology at the University of Manitoba.

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Dr. Harvey Artsob was founding director of the Zoonotic Diseases and Special Pathogens program at the National Microbiology Laboratory of the Public Health Agency of Canada in Winnipeg with a cross appointment as adjunct associate professor in the department of Medical Microbiology at the University of Manitoba.

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