NEW YORK (GenomeWeb) – A team of Canadian researchers has been awarded C$7.3 million ($5.2 million) to support the development of vaccines for bovine tuberculosis and Johne's disease in cattle.
Backed by Genome British Columbia, Genome Canada, and other funding agencies, the team, which includes investigators from the University of British Columbia and the University of Saskatchewan, will employ reverse vaccinology coupled with high-throughput genomics to deliver the new vaccines to an animal health company for commercialization within four years.
Unlike the trial-and-error approach of traditional vaccinology, reverse vaccinology examines the genomic sequences of the infective organisms in an animal model and predicts the antigens that would raise immunity by looking for any protein that is secreted on the surface of the bacteria.
"The genomic method is to clone everything that could possibly be useful in parallel, express it in parallel, and test it in parallel," said Bob Hancock, a professor of microbiology and immunology at UBC and one of the lead investigators on the project.
"It's all high-throughput biology," Hancock told GenomeWeb. "It allows us to take away the guesswork. Every single possible protective antigen will be revealed, which will be every possible component of the two vaccines," he said. "We will then use the best components in a combination as our final vaccines."
There is a need for the vaccines. According to Genome Canada, Johne's disease and bovine tuberculosis cause losses of more than $86 million and $10 million, respectively, in Canada. According to the US National Institute for Animal Agriculture, Johne's disease, an often fatal infection of the small intestine, results in losses of $250 million in the American dairy cattle industry, where the typical remedy is to slaughter the herd containing infected animals. Estimates for the annual losses caused by these diseases to the worldwide cattle industry number in the billions.
Despite this impact, Hancock said that the new project is "unusual," both for its use of reverse vaccinology to develop vaccines for livestock, as well for its sizable funding amount.
Reverse vaccinology "has not been used much in animal health in the past," Hancock acknowledged, noting that the team's methodology, which relies heavily on next-generation sequencing, is viewed as being too costly.
"It is quite expensive and in animal health the margins are quite low and they don't like expensive technologies," Hancock said. "The investment of a large amount of money into this kind of vaccine development is quite unusual in the animal health area," he said.
At the same time, it seems that the animal health market has few options. Andrew Potter, director and CEO of the Vaccine and Infectious Disease Organization (VIDO) at the University of Saskatchewan, said that recent efforts to produce vaccines for these diseases using traditional approaches have failed, opening up the opportunity for reverse vaccinology to prove itself.
"If you look at mycobacterial vaccines, whether it's in human or bovine tuberculosis or Johne's, we have spent billions of dollars on research and have nothing," said Potter, who is the other lead investigator on the project. "That speaks volumes about the traditional approaches to vaccine development," he said, "so we are saying that for a few million we can answer the question."
Hancock and Potter have been collaborating for 25 years, and have already initiated work on the project. Prior to receiving the new award, they were able to establish proof of principle by predicting all of the potential protective antigens of Johne's disease, after they cloned about 100 genes in parallel, injected them into cattle, and identified three that showed that they would be protective.
With the new funding, the team will continue its work by predicting the potential antigens of the two diseases, synthesizing the genes massively in parallel, and testing them in cattle at VIDO.
"We would like to get more information about the immune response and the proteins that are expressed," said Hancock. He said that by working with VIDO the team will be able to use cattle directly as a test organism, as opposed to an intermediate model, such as mouse, and will also be able to perform multiple, non-lethal vaccine experiments in a single model to enable them to see if their antigens are being expressed. He noted that VIDO is also one of the few centers worldwide capable of conducting experiments in large animals using bovine tuberculosis, which is also infectious in humans.
While VIDO will oversee these animal experiments, Hancock's lab will conduct RNA sequencing of the resulting tissue samples, allowing them to not only determine antigen expression but to also look at host response.
"We want to predict the immune responses relevant to the infection, but also start to know a fair bit about the actual way the host responds to the different proteins and overall to the organism, and none of this is that well known for these organisms," Hancock said.
"Once we start infecting animals, or, for that matter, vaccinating animals, we will be sampling tissue all the time that can be sent to UBC for analysis," said Potter. "We will have a tissue bank as we move through this that can be analyzed at any time."
As vaccine development progresses, the team also plans to design companion diagnostics that will allow end users to quickly discriminate between animals that are vaccinated and animals that are infected.
"We don't want a regulatory authority to say that an animal has an infection when they are actually vaccinated because that would precipitate again slaughter," said Hancock. He speculated that these companion tests would likely be enzyme-linked immunosorbent assays, which are already widely used in the livestock industry.
"Because we are identifying a lot of antigens, we will have antigens that reflect host immune responses, and we are going to specifically test for those and [other] antigens that we won't include likely in our vaccine," Hancock said of the companion test development process. "The idea is to come up with a series of antigens that reflect an infection and another series of antibodies that only measure the response to our vaccines."
Ultimately, the team hopes to partner with an animal health company to commercialize the tests once they are developed by the end of this decade. Potter said that a global market exists for both, particularly bovine tuberculosis, and that they will need to partner with a global player to reach cattle industries worldwide.
"We will go with a company that can get this technology advanced the fastest and the broadest," said Potter. He noted that VIDO has nearly 40 years experience in commercializing vaccines.
To do that, though, the research team will also need to accumulate data to support the efficacy of the vaccines before they are introduced commercially, another goal of the four-year project
"To us as scientists it seems self evident that vaccination is better than killing," said Potter, "but we need to get data to back that up and we need to get data to suggest that international trade will be enhanced by doing this."