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For the first time in 80 years, two new TB vaccines are about to enter human trials. The American-made candidate, which uses a form of BCG engineered to produce extra quantities of a king-sized protein to spark cellular immunity, is being developed by the Rockville, MD-based Sequella Tuberculosis Foundation and is due to begin Phase I trials this summer. Across the Atlantic, the British contender also uses BCG, but only to "prime" the immune system before "boosting" it with a second vaccine consisting of attenuated smallpox that has been genetically tweaked to make it produce the same big protein. Developers of the British two-step vaccine are recruiting human subjects for an early-stage trial in England.
The fact that both vaccine candidates use BCG is probably more than just coincidence, say TB experts. But what’s really important is not whether the old TB vaccine proves the key to a better one, but rather that the first round of vaccine candidates has finally graduated from preclinical development.
"This is what we hope will be the first of many TB vaccine candidates," says Larry Geiter, PhD, MPH, consultant for the Sequella Tuberculosis Foundation. "We have three more vaccine candidates on the runway, and we hope to have our second in trials by the end of the year. We also hope to keep putting one or two into the development process every year." Among Sequella’s other starters are a TB auxotroph, designed to shut down after an initial period of replication, and a DNA vaccine that incorporates a heat-shock protein. If all goes well, Sequella will conduct early trials in partnership with the National Institutes of Health, he adds.
Geiter’s counterpart in England likewise hails the new phase. "In the TB vaccine world, this is something we’ve not seen since BCG," says Helen McShane, MD, a Wellcome Clinical Scientist Fellow at the Nuffield Department of Clinical Medicine at Oxford University. "Now the task is to begin looking at all the promising candidates and see which works best."
How BCG — long spurned by American TB controllers for the way it muddles the skin test — wound up with starring roles in each of the new contenders makes for an interesting tale. On this side of the ocean, the story started years ago, in the laboratory of Marcus Horwitz, PhD, a professor in the department of microbiology, immunology, and molecular genetics at the University of California in Los Angeles (UCLA).
Horwitz was tinkering with subunit vaccines, built not from live or killed forms of an entire microorganism but from small, protein-based pieces of TB. Presented alone, the protein pieces got little immune response. They performed much better when teamed with an adjuvant, a substance designed to perk up immune response. But despite the high hopes Horwitz’s subunit approach generated in the TB vaccine community, it ultimately failed to deliver the requisite immune-system punch.
At length, Horwitz decided to try live vectors as delivery systems, settling after some experimentation on BCG. Its advantages were numerous: As a live organism, it could replicate inside the host, ensuring that whatever freight it carried would get good play. At the same time, it was widely used (except, of course, in the United States) and commonly believed to be safe.
For the cargo for his new vector, Horwitz decided to use the "B" version of Antigen 85, a complex of three look-alike proteins (dubbed A, B, and C) that are manufactured in lavish abundance by TB microbes. Again, Horwitz had compelling reasons for his choice. At a whopping 30 kd in size, Antigen 85 is an 800-pound gorilla among proteins. Plus, because it’s a key ingredient in the construction of cell walls, TB bugs churn out loads of the stuff. Horwitz (as well as many other TB researchers) came to believe that something so big and so abundant must be capable of getting the full attention of the immune system.
Teaming the big protein with the old TB vaccine made sense for other reasons, too. For one thing, regular BCG already secretes Antigen 85, and in such a way that the BCG version is tailored almost exactly the same as the version designed by M. tuberculosis. Altering BCG to make it churn out even more Antigen 85, it follows, ought to induce a brisk immune response, resulting in a rich store of memory T-cells ready for battle against actual TB bugs. So far, data from Horwitz’s animal studies show that’s what is happening.
When trials begin next summer, Sequella will pit the Horwitz version of BCG against regular BCG. Investigators will also compare the effects of BCG given at birth alone with BCG given at birth and then followed by a dose of Horwitz-styled BCG administered during early adolescence.
Back in England, BCG’s path to center stage occurred via events that are slightly less convoluted. There, researchers headed by Professor Adrian V.S. Hill, chief of Oxford’s Cellular Immunology and Vaccine Development Group, had noticed that smallpox viruses are able to boost previously primed immune responses. "We don’t know what it is about pox viruses that make them good at this, but we know they do it. We’ve seen this in work from other fields, including malaria and HIV vaccine research," says McShane. That work has already entered Phase I trials, she adds.
Even though the malaria and HIV work had harnessed the pox viruses to DNA vaccines to effect the one-two punch, McShane and Hill decided to team a pox vaccine with BCG. For one thing, they reasoned, BCG is not likely to disappear soon from global TB control practices, McShane says. "Most people agree that although BCG is far from adequate, it does afford limited protection, especially to children, so we’re a long way from stopping BCG immunization," she says. That made the old vaccine a logical platform from which to try launching a better one.
To direct the boosting to its proper target, McShane engineered her attenuated smallpox virus to secrete Antigen 85. So far, animal data (including results from tests in mice, guinea pigs, and primates) say the two-step strategy gives protection either equal to or better than BCG, depending mostly on what McShane says is the timing of the two vaccine doses.
BCG, named for French researchers Albert Calmette and Camille Guerin, was first used in 1921; since then, over three billion doses have been administered worldwide. Only modestly (and inconsistently) effective, BCG works best at protecting infants and young children from disseminated, often deadly forms of the TB.
From a vaccine developer’s point of view, using BCG makes sense in many ways, says Ann Ginsberg, MD, PhD, chief of the Respiratory Diseases Branch at the National Institutes of Health in Bethesda, MD. Since the vaccine does give limited protection, investigators doing human trials could hardly withhold it in countries where it’s already given. "Since any new strategy must work against a background of BCG vaccination, taking advantage of BCG’s good properties makes some sense," she explains. In other words, big-scale human trials in the developing world are pretty much stuck with BCG, so why not make the best of it?
Possibly, adds Geiter, American bias against BCG has actually kept researchers from taking what in retrospect seems a perfectly reasonable step. "This is purely my personal belief, but I sometimes think the TB community may have shot itself in the foot a bit here," he says. Just look at the omnipresent lists describing what a new TB vaccine should look like, he says. "Everyone has one of these laundry lists of essential vaccine qualities tucked away in a file cabinet. The problem may be the way the lists all equate essential qualities — like safe’ and effective’ — with qualities that maybe would be nice, but which are hardly essential, like doesn’t mess up the skin test."
Maybe, he adds, if those lists had read a bit differently and researchers had been thinking a bit more openly, today’s two new candidates would have emerged even sooner.