Bringing pandemic vaccine to flu clinics first requires animal, human testing

TORONTO - If you went by statements from the pharmaceutical industry, you might be tempted to think it was nearly time to roll up your sleeve for a swine flu shot.

In the so-called race to produce pandemic vaccine, several companies have declared themselves frontrunners, suggesting their products are on the verge of being ready.

But are they on the verge of being ready for use? Maybe not just yet.

"I've seen a couple of press releases ... saying `By early summer we're going to have something.' They may have something off the production line," Halifax vaccinologist Dr. Scott Halperin says with a chuckle.

Making vaccine and convincing regulatory agencies that the stuff is safe to inject into humans are separate matters. That is always the case but is especially true when the vaccine in question is to protect against swine flu.

The last time mass vaccination against a swine flu virus was undertaken, a spike in cases of Guillain Barre syndrome among those vaccinated led U.S. authorities to abandon the program.

It is still not known why that 1976 vaccine seemed to trigger an elevated number of cases of the paralyzing condition. (The syndrome, which is linked to several natural infections and to some vaccines, generally reverses itself over time.)

That incident casts a long shadow over discussions about a 2009 swine flu vaccine.

"Yes, it does," Halperin says. "Certainly it makes people plan to monitor very carefully with the new vaccine."

There are lots of questions regulators like Health Canada or the U.S. Food and Drug Administration will want answered before they give the go-ahead to pandemic H1N1 vaccines. And the clinical trials needed to get those answers take time.

"We can't hasten the time frame that you need to do clinical trials to get the fundamental, basic information that you generally need," says Dr. Tony Fauci, head of the U.S. National Institute for Allergy and Infectious Diseases.

NIAID is one of the U.S. National Institutes of Health. It will be working with the FDA and with U.S. licensed flu vaccine manufacturers to determine research needs for the new vaccine. The aim is to fill data gaps individual companies won't or can't undertake to plug.

Those include looking at vaccine safety in potentially more vulnerable groups like infants, people who are immunocompromised and pregnant women.

Another question NIAID may try to answer is whether it would be possible to compress the interval between two swine flu shots, if, as suspected, two shots are needed.

Companies will likely test a regime that would see two shots given with a 21- or 28-day interval. But if the pandemic starts to worsen and it appears waiting so long would be unwise, could the same effect be achieved with two shots given closer together? Companies probably won't do that research, but NIAID could, Fauci says.

The types of studies companies will need to do are the ones that answer the core questions about a vaccine. Is it safe to use in humans? Does it elicit an immune response - rising levels of antibodies - that would suggest it will be protective? What sized dose, and how many doses, does it take to do so?

Getting those answers means weeks of work by individual companies. They'll start by injecting their products first into animals, then into small numbers of human volunteers to determine that the vaccines are safe.

Once that is clear, larger trials will be needed to determine how large a dose people need to get a good immune response. That could take a couple of months, says an expert who has done many trials on flu vaccine.

"No matter how quickly you enrol the subjects in the study, even if everybody was enrolled on the same day, it's still going to take time to get the study done and get the data," says Dr. John Treanor, who teaches at the University of Rochester in northern New York.

That work should answer the question of whether people might get enough protection from a single shot or whether, because this is a new virus for our immune systems, two shots will be required. Experts hope for the former, but suspect the latter.

The industry has years of experience making flu shots and there is a high degree of confidence a successful swine flu vaccine can be made. But each flu virus has its own quirks and no one knows yet how well this new one will do at eliciting an immune response in people.

"Until they actually get it and start putting it into some animals and humans, they're not going to know for sure," says Halperin, a professor at Dalhousie University and principal investigator of the newly formed Public Health Agency of Canada/Canadian Institutes of Health Research Influenza Research Network.

Because seasonal flu shots have to be updated on a regular basis, regulatory agencies have a sort of fast-track process in place for these vaccines.

As long as nothing about the production of the vaccine changes, vaccine against a new strain or subtype of flu virus can be switched in under an existing licence with minimal additional information required.

That may not be the case here, however.

Some manufacturers - including GlaxoSmithKline, which has Canada's pandemic vaccine contract - have indicated they want to use adjuvants in their vaccines. Adjuvants are boosting chemicals that allow smaller doses to be used, which would speed up the time it takes to make enough vaccine for a country.

But there are no existing flu vaccines in Canada that contain adjuvants, so adding one could require an entirely new licence - and substantially more safety data based on clinical trials.

It is believed Canada will purchase adjuvanted vaccine. But what testing it will require to assure itself of the product's safety isn't currently known.