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Jacobs and Sweeney weren’t trying to build a better vaccine when they began their work; they were investigating a set of genes, called esx-3, found in all mycobacteria (the group to which the TB bug belongs). The idea was to explore the function of esx-3 by deleting it from the bacteria and observing the effects of the deletion. Ideally, they’d have done the work in M. tuberculosis. But esx-3 is so essential to M. tuberculosis the bacteria would have died without it, rendering the deletion experiment meaningless.
So the researchers devised a clever workaround using a different bacterium, M. smegmatis (Msmeg for short), which can tolerate the deletion. First, they infected mice with lethal doses of Msmeg, some with esx-3 intact and others with esx-3 deleted. The Msmeg with intact esx-3 rapidly killed the mice, but those bacteria lacking esx-3 caused no harm, apparently because the modified bugs were done in by the mouse immune system. The conclusion: esx-3 plays a key role in protecting mycobacteria from immune killing.
But no one cares much about Msmeg. Jacobs wanted to know if the findings apply to M. tuberculosis. So his group inserted esx-3 genes from M. tuberculosis into the modified strain of Msmeg, which they called IKE, for immune killing evasion. This experiment resulted in a new strain they dubbed IKEPLUS. The team expected this trick to reverse the effects of the deletion and restore the bacterium’s ability to evade immune killing, thus demonstrating that esx-3 from M. tuberculosis performs the same function as esx-3 from Msmeg.
Instead, the IKEPLUS strain, with its intact esx-3 from M. tuberculosis, was just as susceptible to the mouse immune response as was IKE, which lacked esx-3. The experiment was a flop. In fact, IKEPLUS not only succumbed, it induced an unusually strong mouse immune response, a particular type known as Th1 immunity (the mode of defense the body uses against organisms such as viruses and bacteria that invade cells).
Puzzling over that immune response, Sweeney and Jacobs had an epiphany. If IKEPLUS could elicit Th1 immunity without harming the mice, they reasoned, it might be an ideal vaccine delivery vehicle. To test that possibility, they immunized mice with IKEPLUS and challenged them with massive, intravenous doses of M. tuberculosis. Not only did IKEPLUS protect mice from TB better than the current TB vaccine, it cleared the bacteria from the livers of five immunized mice, which went on to survive more than 200 days after exposure to TB.
“IKEPLUS opens up a new paradigm for vaccinology,” Jacobs says. In particular, it suggests the possibility of creating a “multivalent” vaccine containing a cocktail of immune-stimulating substances that could be administered to newborns, as is the current TB vaccine, thus offering protection from some of the deadliest diseases.
“As a parent, when I read stories about the catastrophic threats polio and smallpox have posed to children, I fully understand what a profound impact infant vaccines have made,” Jacobs says. “Clearly, a focus on development of new vaccines to target TB, malaria, and HIV should be of the highest priority. I believe IKEPLUS can help contribute to this effort.”