Medical Countermeasures for Biological Warfare

Dr. Jim Anderson manages the Biological Warfare Threat Medical Countermeasures project at the Deptartment of National Defence (DND). He recently sat down with FrontLine editor Chris MacLean to discuss the challenges and implications of the biological threat and related preparedness requirements. Even a vastly abridged version of his life’s work underscores his dedication in this field. After 22-plus years as a medical officer in the Canadian Armed Forces (CAF), he worked at Citizenship and Immigration before being chosen to direct the office of public health security at the Public Health Agency of Canada (PHAC). He then returned to the CAF as head of communicable (natural) disease control for another eight years before being tapped for this current (civilian) role of mitigating the effects related to biological warfare, in which he has been immersed since 2013.

The Biological Warfare Threat Medical Countermeasures project started in 2001 to address a capability gap in the ability to protect Canadian Forces personnel against biological warfare (BW) threat agents. The objective of the project is “to prevent soldiers, sailors, air personnel from becoming casualties to biological warfare agents,” which means they will be protected while responding to and protecting others from a biological warfare event.

Protecting the protectors from biological warfare clearly requires a multi-faceted approach: “We do that by assisting and developing, licensing, procuring, stockpiling medical countermeasures against those threats,” explains Dr. Anderson.

The scope of the project, he says, is to develop and/or procure counter measures that cover a range of prevention diagnosis and treatment to cover six threat agents – smallpox, the plague, botulism, anthrax, the filoviruses (Ebola and Marburg hemorrhagic fever), and ricin poisoning.

The challenge of any product development is that it is a long and expensive process. However, developing medical countermeasures is further complicated by the obvious fact that researchers cannot expose people to deadly viruses in order to confirm the effectiveness of treatments under development. To test their research then, scientists are forced to find other means. For this, the regulatory bodies of the U.S. Food and Drug Administration (FDA) and Health Canada have created a process that assesses how scientists use animal surrogates to predict effectiveness in humans. It adds significant time to the process, but is a critical requirement.

Once the effectiveness has been established, scientists must begin the standard three-phase human testing process in order “to understand how they affect the body and how the body affects them, how long they will last in the body, and what levels and doses are necessary to be effective,” explains Dr. Anderson.

Another challenge of developing bio-threat countermeasures for members of the Armed Forces relates to market share. “Canada’s armed forces are small, and our requirements are equally small, so many of the big pharmaceutical companies are hesitant to make the effort to license products here in Canada,” he notes.
 

One option is to collaborate with allies, and Canada is currently involved in joint projects with the U.S. and the UK to develop a plague vaccine. “We are considering an offer to jointly develop a vaccine against botulism with the U.S., but we can also work with manufacturers directly.”

Historically, almost all financial support of medical countermeasures development for biological threats came from medical researchers within the various militaries. However, the greatest urgencies were seen as naturally-occurring threats. Early in the 20th century, for example, concerned that their soldiers would be exposed to mosquito-borne yellow fever and malaria while serving in tropical countries, the French, British, and American militaries worked to develop countermeasures to threat diseases prevalent in those areas.

More recently, military leaders began to focus more on terrorism and the potential for biological warfare. According to Dr. Anderson, the U.S. Department of Health and Human Services has “probably spent close to $30 billion on medical countermeasure development and acquisition” since 2001.

Biological Weapons
The United Nations’ Biological Weapons Convention went into force in 1975, but, according to Anderson, it did not stop the Soviets from continuing an extensive biologic warfare program. In fact, medical researchers around the world also had smallpox in their freezers.

In 1979, the World Health Organization deemed that smallpox was irradiated, and it was agreed that everyone would destroy their stocks of that virus – except for two locations that would continue to hold that virus for research purposes. The Center for Disease Control in Atlanta and a government facility in Russia each have official stockpiles of the virus. Some scientists contend that these stockpiles should also be destroyed, but for now, every five years, the WHO reassesses the need to continue to maintain those stockpiles for research.
 

“It doesn’t mean there isn’t additional smallpox out there,” Anderson points out. “Two years ago, a US Food and Drug Administration lab was moving to a new facility and, as they were cleaning out, they pulled out vials of smallpox they didn’t even know they had.” In fact, two of the six vials found in a refrigerator contained live variola. These vials had reportedly been stored for 51 years and the discovery came as quite a surprise. This clearly points out how dangerous and sustainable the smallpox genome is.

According to Dr. Anderson, the Soviet Union had massive research facilities that employed thousands of highly trained, technical people in their bio-weapons program. “Where did they go after the Soviet collapse?” In terms of credible threat, it’s easy to imagine smallpox in the hands of an adversary. “It’s highly contagious person-to-person, it’s easy to spread, and it has a high mortality rate. Having countermeasures to prevent or mitigate the effects of an attack reduces our vulnerability and thus reduces our risk from a rogue state or group of individuals that want to use it.”

Both NATO and the WHO have written recent reports on the threat of synthesis of smallpox. This is considered a big threat by the medical countermeasures community.

The Storage Challenge
Stockpiling medicine can often be onerous, especially long-term storage needs, such as for medical counter-measure vaccines. The smallpox vaccine is a prime example. This liquid product must be stored at –80°C in order to gain the longest shelf life (9 years). Imagine how difficult it is to deploy such product to the field while maintaining such temperatures.

This problem also surfaced during the 2015 Ebola crisis, when the vaccine was developed at the lab in Winnipeg and tested in West Africa. This too had to be stored at between –60 and –80°C. “A great deal of effort went on behind the scenes to move that vaccine into West Africa at –80°,” notes Dr. Anderson.
 

Identifying the storage issue as a business obstruction, Bavarian Nordic began research into freeze-drying their third-generation smallpox vaccine. Results so far have been very promising, and will offer a very long shelf life when refrigerated at –20° (a temperature that greatly reduces the logistics burden).

Freeze-dried product is being seen more and more. Despite the U.S. having a strategic national stockpile of refrigerated anthrax vaccine, its Department of Health and Human Services decided to pursue a new generation of the vaccine, one that would continue to be used for pre-exposure and post-exposure emergency situations. A contract was awarded in October, and Dr Anderson tells FrontLine that the new vaccine can also be freeze-dried to extend its shelf life.

Partnering for Public Health
While DND’s stockpiles are earmarked for military personnel, it will be police, fire and emergency medical personnel who will be the first boots on the ground if any kind of incidents happens here at home. The Centre for Emergency Preparedness Response at PHAC holds that public health responsibility to plan for and prepare against all hazards.

In the current public health landscape, the threat of terrorism is a looming factor of public safety – biological warfare by state or non state actors is a concern for all.

In addition to partnerships with allied military organizations, the Canadian Forces’ Health Services Group also works with public health partners and sometimes directly with the manufacturers.

“A number of manufacturers are afraid of the administrative effort of coming to Canada, doing the work to submit their technical data to Health Canada.” Even though it may already be licensed in the U.S. and/or Europe, the paperwork can appear a daunting requirement for minimal return. “One of the things our project can do is assist those manufactures in understanding the requirements and the process to get those products assessed by Health Canada.” This, he says, gives Canadians the assurance that the product has been vigorously assessed by the country’s top medical regulators.

A new non-replicating smallpox vaccine – one of the first products to be licensed under Health Canada’s the new “Extraordinary Use” drug submission rules for dealing with biological threats – is a third-generation being vaccine being produced by Bavarian Nordic, an international biotechnology company based in Denmark.
 

“We were able to assist them in engaging the regulatory body here in Canada,” says Dr. Anderson. Bavarian Nordic eventually submitted its product and received regulatory approval in December 2013 that applies to federal, provincial and municipal governments. “A doctor can’t write a prescription but a federal agency, provincial agency or a municipal agency can, and so, we did the work to get that product licensed here in Canada and it’s now a product that any of the government health preparedness groups across the country can use.”

Dr Anderson was director of the Office of Public Health Security from 2003-2005, so he is able to confirm they do have a stockpile of first generation vaccines, and that they are procuring the Bavarian Nordic product as well.

Similarly, DND project is working with the manufacturer of a botulism anti-toxin (there are typically 10-12 food-borne cases of botulism in Canada every year). “We’ve assisted the manufacturer in the process of submitting their information to Health Canada, and we have a contract for supply of that antitoxin. We have a stockpile of unlicensed product and we hope to have regulatory approval by Health Canada in the next year so that we will then be able to purchase the licensed product.” The Public Health Agency of Canada has a central responsibility for stockpiling and preparing for emergencies, but provinces and territories also have a role. And so, the work being done at DND contributes to the general preparedness for the country.

Dr Anderson goes on to explain that the botulism anti-toxin in DND’s stockpile is the U.S.-approved product. “It’s the same manufacturing line, the same process of collecting the serum and producing the drug product, but the Food and Drug Act distinguishes between that which was produced and procured before approval and that which is produced after.

What happens to the unlicensed inventory after approval is granted? “We would quarantine that and keep it,” explains Dr. Anderson. “We would procure and stockpile the licensed product, and keep [the unlicensed product] until its shelf life expires, because if we were in the midst of an emergency and we used up our licensed product, and there was still a need to prevent people dying from botulism, then we would have an option to use that. We would not destroy product that still has a role in an emergency.”

This situation is similar to the current status of the third generation smallpox vaccine being produced by Bavarian Nordic.

“The Health Services Group has had a stockpile of what we call ‘first generation’ (a replicating version) smallpox vaccine for decades. It’s a very effective vaccine, it was used in the World Health Organization’s smallpox ratification program through the 60s and 70s, and smallpox, one of the greatest human disease threats in our history, was eradicated. There hasn’t been a case since the 70s.”

Despite being “eradicated”, smallpox is seen as a credible bio-terror threat because: (a) live virus still exist, creating potential of dispersal due to human error; and (b) it could be deliberately distributed by an adversary. For these reasons, the bio-protection community considers smallpox to be among the top threats, which is why, years ago, DND secured a large stockpile of the first-generation vaccine, which is still considered “as potent and effective as the day it was made in 1980.”

Potent and effective certainly, but how safe is it? “Certain individuals, people who have a weakened immune system, people who have certain skin disorders, are at high risk of severe adverse events,” admits Dr. Anderson. In fact, the U.S. Centers for Disease Control and Prevention recommends that, in a non-emergency situation, anyone who has at least three of the major risk factors for heart disease (high blood pressure, high cholesterol, diabetes, family history of heart disease before the age of 50, or current cigarette smoking) should not be given the original smallpox vaccine. According to the FDA warning, use of the first two generations of the vaccine in certain individuals “may result in severe disability, permanent neurological sequelae and/or death.” While this may sound extreme, we must remember that it was used at a time when there was no other option, and saved millions of lives during a dangerous time.
 

When it was determined that smallpox still presented a serious threat to mankind, scientists began looking to improve this time-tested vaccine in order to eliminate the safety issues.

After years of independent medical research and testing, a third generation product finally overcame all of the problems, and “is safe to use” even by those individuals who were contra-indicated for the previous vaccines, says Dr. Anderson. “So we assisted Bavarian Nordic in obtaining a Canadian license, we’ve purchased product that is now in our stockpile, and we have a plan to procure additional quantities to bring us to our full operational capability.”

Assisting in this whole process is the Deputy Project Manager on the Biological Warfare Threat Medical Countermeasures project. A former Canadian and UK navy officer and mine counter-warfare expert, Jim Hewitt’s career spans more than five decades and includes operational command with the Canadian Armed Forces as well as project management at DND. As a project management professional, he knows the department and understands the corporate submission process, which complements Dr Anderson’s technical background and assists manufacturers navigate the system.
 

The team also includes a project control and administration officer, Leasa Perrault-Kay, and a project coordinator, Sue Martin. Matrix support comes from the CF Health Services Group Regulatory Affairs section which provides expertise on the complex rules of regulatory submissions. “They help guide us […] so that when we get to the end of the line, we know that Health Canada requirements will be met. We engage during the development process so the work is done more efficiently. In that aspect then, they will liaise, on the technical side, with the regulatory advisers to those U.S. and UK development projects. They also know the process and requirements of Health Canada so that when, say, there is a manufacturer in the United States that is perhaps hesitant to make the effort to bring their product information to Health Canada for approval, we can give them a perspective on the administrative effort that is required, assist with the process and arranging the meetings and that has also worked well,” notes Anderson.

This important support comes from the Regulatory Affairs Section at DND’s Health Services Group. “Asma Syed works with the project on Anthrax and Filovirus countermeasures as well as Botulism anti-toxin; Tim Smith works on Plague and Botulism vaccines as well as Ricin countermeasures; and Jen Zhang works on smallpox. Before that process expertise was in place, you could have a defence scientist or a brilliant researcher working on developing a product without knowing the regulatory requirements to get it approved – a lot of time and effort can be wasted.”

It is important to remember that the Public Health Agency of Canada is no longer a branch of Health Canada; it became a separate agency in 2003. Minister of Health, Jane Philpott, heads both, however they have different mandates and each has its own Deputy Minister. Health Canada is responsible for regulatory assessment of drugs and vaccines in Canada, while the Public Health Agency’s Center for Emergency Preparedness is responsible for maintaining emergency stockpiles and can help manufacturers approach Health Canada, but they don’t influence Health Canada’s decisions.

Similarly, the efforts at DND also have no influence over Health Canada’s decisions. “They assess our products the same way as they assess any other product being submitted for licensing or approval in Canada. It is all governed by the Food and Drug Act.”

International Cooperation
It’s hard to believe that any official groups entrusted with safety and security have been able to successfully share information, but that’s exactly what Dr. Anderson asserts – that a global community of military, public health, and industry are working together to thwart and mitigate bio-terror. “We work very closely with manufacturers and PHAC; if they are meeting, they invite us, if we are meeting, we invite them.”

Canada participates in NATO’s chemical biological working groups to share relevant information with NATO countries such as France and Germany.

For decades now, a quadripartite group consisting of Canada, US, UK, and Australia, have had a memorandum of understanding on chem-bio defence. Initially established for defence, the public health organizations of all four countries were included after terrorism became a global concern.

Representatives from Canada’s Public Health Agency and National Defence; U.S. Health and Human Services and the Department of Defence; Public Health England and UK Defence; and Australia’s Public Health and Defence, meet face to face twice a year to discuss and share R&D information on everything from early to advanced development. “It’s a very effective mechanism to support all of our preparedness. We do that both nationally and internationally. We also benefit to an extraordinary amount through partnering with the U.S. Defence Department in joint development projects. We also work with U.S. Health and Human Services and benefit from their funding of manufacturers, whether it’s for smallpox therapeutics (treatment for those with the disease), for the botulism antitoxin, or anthrax vaccine antitoxins.”

These biannual meetings are important to coordinate efforts among the partners, break down silos and reduce risk. “Our quadripartite group works to coordinate among partners so at least we know what others are doing. There is a mechanism to identify what is promising and focus resources on that. Development risk can be phenomenal, it can take 10 to 15 years, or longer, to develop a product, and could cost over a billion dollars. It’s a time-consuming, risky, expensive process, and within the government, we are looking to ensure that we coordinate our efforts.”

Protecting the Protectors
Just as first responders must be protected so they can protect Canadians at home, DND knows that if the Government of Canada is going to send its military personnel into a risk area, it is important to have medical countermeasures that will provide them protection and allow them to continue to do their job effectively.

Our Spring edition will feature an interview with Jean-François Duperre, Executive Director at the PHAC Centre for Emergency Preparedness and Response. We will also include discussions with Provincial and Municipal leaders on the ethical question of duty to provide protection for first responders.

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Chris MacLean is the Editor of FrontLine Safety and Security magazine.