New TB candidate vaccine looks good in animals; human trials ahead
New TB candidate vaccine looks good in animals; human trials ahead
Firm used human donor panel to screen antigens
In the urgent race to find a better TB vaccine, one of the most promising candidates on the horizon might be ready to start trials in humans as soon as the end of next year, say scientists at Corixa Corp., a biotech firm in Seattle.
So far, the vaccine has protected mice and guinea pigs against TB at least as well as BCG. In human trials, there’s reason to think it may work even better, say some who have seen it in action.
Developing the vaccine, at least on paper, has been a fairly straightforward process, says Steve Reed, PhD, executive vice president and chief scientific officer of Corixa. "It has taken us five years, $12 million, and about 50 human donors," he says, referring to the people with positive tuberculin skin tests whose T-cells helped the company find the key pieces of its product.
Reed’s creation is a type of subunit vaccine, meaning it is constructed of small pieces of the mycobacterium instead of being a killed or weakened version of the whole bug. In this instance, the units consist of three antigens, which Corixa has fused into a single molecule.
From 4,000 down to 100
Researchers used high through-put screening techniques to sift through all 4,000 proteins in the TB genome. Then, in an unusual departure from the way most vaccines are developed, they tested 100 of the best proteins on blood samples taken from the panel of donors. "That’s what made the real difference," Reed adds. "Most people work with mice; we work with humans."
The donor panel, whose members include foreign-born residents of the Seattle area, all have positive tuberculin skin tests but no signs of active disease, suggesting that their immune systems, having been sensitized to TB, are now coping successfully to contain the infection.
Working with white blood cells and macrophages from donated blood samples, Corixa scientists tested almost 100 antigens to see which caused the most proliferation of T-cells and production of gamma interferon in the most people. Those are two key responses in the type of cell-mediated immunity a TB vaccine must induce in order to succeed.
Because none of the antigens drew strong responses from every single donor, researchers decided to make a "cocktail" of the most promising proteins by joining them into a single molecule, Reed says.
The decision to make a fusion molecule was based strictly on bottom-line considerations, he adds. "We knew no manufacturer would be interested in making a vaccine composed of three different proteins, so from the start we had planned to go with a fusion," he explains.
The fusion also seems to elicit a stronger T-cell response than a simple mix of the three proteins. "It could be that you get a more coordinated response by getting [the T-cells] to work on the same molecule, instead of confusing them by throwing three different proteins at them," he speculates.
A lot to like
The man who’s been putting Corixa’s candidate vaccine through its paces in the animal laboratory agrees there’s plenty to like about it. "Their fusion molecule is one of the best we’ve seen," says Ian Orme, PhD, the affable Brit who heads of the mycobacteria research laboratories at the department of microbiology at Colorado State University in Ft. Collins. "For one thing, the fusion of the three peptides is sexy: You get this big protein that the macrophage has to spend some time chewing up, so that it gets presented quite well. That’s probably more immunogenic."
Then there’s the matter of adjuvants, Orme adds. "An adjuvant? That’s just a delivery vehicle, a sort of depot," he explains. "That is, if you just stick a solution of proteins into an animal, it disappears all over the place straightaway. But if you put it into something that traps it in one place, it appears that the macrophages see a sufficient concentration of antigens to push an immune response forward."
Plus, the Corixa adjuvant pushes forward just the right kind of response, Orme adds. "Most of the off-the-shelf adjuvants make a Th2 response," he explains. "You know, the kind that says, OK, boys, let’s go off and make antibody. And of course, antibody is totally useless, since the TB bugs are inside the macrophage where the antibody can’t get at them. What you need, naturally, is a T-cell population that’s a Th1 response, so the T-cells see the antigen and make gamma interferon, which activates the macrophage, which makes the proton pumps, which kill the TB."
Orme pauses. "Much trickier to find an adjuvant like that, of course. But in my opinion, Corixa’s got one of the best."
Better than BCG isn’t saying that much
Even though the vaccine looks good in animals, the way it stacks up against BCG is almost beside the point, to Orme’s way of thinking. In mice subjected to a TB aerosol challenge, the Corixa protein protects nearly as well as BCG and results, he says, in "a log less of bug load," compared with a log and a half reduction with BCG, Orme says. "Hard to do much better than that," he adds.
As for guinea pigs, BCG-vaccinated animals typically survive between 60 and 120 weeks before succumbing to necrosis in their lungs. By comparison, after some 70 weeks, animals vaccinated with the Corixa protein still appear to be healthy, "although we don’t know that for sure," Orme cautions, "since we haven’t chopped them up yet."
Still, he continues, comparisons between BCG and subunit vaccines can only go so far, BCG being the flawed vaccine that it is. "As you know, BCG is a living organism, with all these built-in adjuvants and proteins and various other things that may switch on a whole variety of things, some of which may be detrimental," he points out.
If only because the Corixa model is a tidy subunit package instead of the whole messy model, it may work in a more straightforward fashion, Orme says, by switching on "just the important things."
Reed emphatically agrees. "When we were weeding through those 100 genes, taking out the bad ones was just as important as selecting what was good," he says. "TB has lots of ways to confuse the immune system in the wrong direction, and we took all those parts out."
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