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Old vaccine retooled to overexpress large protein
A new TB vaccine candidate using a genetically modified version of the BCG vaccine has so far delivered promising results in guinea pigs challenged with TB, says its inventor, Marcus Horwitz, PhD, professor of medicine in the department of medicine and microbiology, immunology, and molecular genetics at the University of California in Los Angeles. The vaccine is expected to enter human safety trials within the year, he adds.
Horwitz says he modified the BCG vaccine to make it over-express one of the proteins secreted by the TB mycobacterium. That protein, Antigen 85-B, is used to build the bug’s cell wall. Because it is the most abundant protein, Antigen 85 seemed from the start a likely candidate for triggering an immune response, says Horwitz. Because it is secreted outside the mycobacterium, it is readily available to the immune system for recognition and processing.
"We’d already done some work that showed extracellular proteins are important immunoprotective molecules for intracellular parasites in general," say Horwitz. "In addition, we’d shown that purified extracellular proteins induced protection. We decided to focus on the 30 KD protein, the Antigen 85 protein, because it’s the most abundant secretory protein."
In fact, when Horwitz immunized guinea pigs using just the Antigen 85 protein in combination with an adjuvant, results were good, he says. The problem was that the immune response wasn’t as strong as he’d have liked.
Trial and error suggested that BCG might make a better delivery vehicle than the adjuvant. BCG met the qualifications on several counts, he explains: "We needed a host that wasn’t pathogenic, but that would reproduce readily," he says. In some respects, E. coli might have been a candidate, because it, too, produces the Antigen 85 protein, albeit in small quantities. M. smegmatis, on the other hand, secretes the protein abundantly, but doesn’t multiply readily in the host.
Perhaps BCG’s biggest plus is that it not only reproduces briskly, churning out sufficient quantities of Antigen 85 as it goes along, but also encodes the protein in its native form — that is, folded in the same way as if M. tuberculosis were making it, says Horwitz.
Once he’d settled on BCG as the host, experiments showed that Horwitz’s genetically tweaked version of the century-old vaccine gave a lot better protection than did ordinary BCG.
For now, Horwitz says he’s working on ways
to increase the potency of his candidate vaccine, perhaps by lengthening the interval between immunization and challenge. In a preliminary experiment when he did just that, the test animals did indeed show more protection, he says.