Here in Canada, cases of rabies infections in humans are fairly rare. When it does occur though, the consequences can be serious. Globally, rabies infection is still the cause of tens of thousands of deaths a year, particularly in Asia and Africa. According to the World Health Organization, approximately 40% of those bitten by suspect rabid animals are children under the age of 15. Although there are a number of rabies vaccines that are commercially available for the control of wildlife rabies infection, some vaccines distributed to wildlife don't effectively immunize all at-risk species—such as skunks, for example.
The NRC's Human Health Therapeutics Research Centre, as its name might imply, is generally focussed directly on human health. But when it comes to rabies, infection in a variety of animals—raccoons, skunks, coyotes, mongooses, bats, foxes, and even dogs—can eventually lead to infection in humans. What's more, the cell culture process used to produce vaccines for humans is essentially the same as that used for animal vaccines.
Since 2006, researchers at the NRC have been working with Guelph-based company Artemis Technologies Inc. (ATI), which produces a wildlife vaccine bait commercially known as ONRAB®. A vaccine bait consists of a small packet the size of a Loonie (the Canadian 1-dollar coin), coated with a mixture that is attractive to animals, consisting of vegetable shortening, wax and other scents and flavours. Inside these small packets is the vaccine itself—in scientific terms, an adenoviral vector that transports a rabies glycoprotein gene, AdRG1.3, which is produced using a mammalian cell culture process developed at the NRC.
In order to effectively immunize all at-risk species, the vaccine needs to be broadly distributed among wildlife populations. This is accomplished by dropping hundreds of thousands of doses by plane, ATV or by hand into forests and other wildlife areas.
In terms of the initial development of the vaccine, a viral construct was modified at McMaster University to produce AdRG1.3, a recombinant virus that expresses the rabies glycoprotein. The Ontario Ministry of Natural Resources and Forestry acquired the rights to use AdRG1.3 from Microbix Biosystems and then partnered with ATI to produce ONRAB®. However, in order for the vaccine to demonstrate effectiveness in wildlife field trials, as well as receive regulatory approval, the vaccine had to be produced at commercial scale. ATI needed specific expertise in cell culture scale-up and manufacturing facilities—an area in which the NRC excels—to produce large quantities for field trials.
On the surface, the prospect of scaling up vaccine production may seem very straightforward – just add more of each ingredient, right? Not exactly.
"There was a lot of technology involved in scaling this product up," says Alex Beath, President of ATI. "It's certainly not like making a pot of soup… it's a process that requires different growth additives, precise levels of reagents along with a specific media formulated by the NRC. Working with the NRC has been an excellent experience. They have been very flexible and have understood our needs. They were able to provide exactly the type of expertise that we needed."
All grown up: technology transfer for production
Since the beginning of the partnership, the NRC has produced close to 50,000 litres of the AdRG1.3 virus, which has been used by ATI to manufacture over 27 million vaccine baits to support vaccination campaigns across North America. In addition, the NRC has provided training to ATI staff members for the in-house scale-up of production. In turn, results from field vaccination campaigns in Ontario, Quebec, New Brunswick, and the United States have demonstrated that ONRAB® is one of the most effective commercially available vaccine baits on the market. ATI has been able to sell their baits at a very competitive price and, thanks to the NRC's expertise in optimizing production processes, product yields have gone up while costs have gone down. In short, all of the hard work has paid off for everyone involved.
Recently, the large-scale cell culture-based technology developed at the NRC was successfully transferred to ATI, which is now licenced to manufacture the ONRAB® vaccine up to the 300 litre scale at its own facilities in Guelph, Ontario.
"We're a very small company," says Alex Beath. "We have 12 employees. But we are now at the point where we are able to produce over 10 million vaccine baits a year. Without the help of the NRC, we never would have reached these quantities in such a short time."
It's a sentiment that's echoed by Chun Fang Shen, the NRC's project lead for the partnership: "With Artemis, we've been able to help a Canadian client from the beginning of their product development, providing support for process optimization, scale-up, manufacturing, and regulatory approval."
It'd be interesting to know if our furry forest friends are aware of the lengths we've gone to in order to help keep them healthy, happy, and free to roam another day…