Vaccines are unarguably one of the greatest success stories in medical history, eliminating or largely curtailing numerous age-old scourges such as smallpox and polio. But researchers’ track record in coming up with effective vaccines for today’s major and emerging diseases is, by and large, dismal. A Yale University spinoff, Vaxinnate, hopes to use recent breakthroughs in basic immunology to re-invigorate vaccine development and create new vaccines for cancer, West Nile virus, and influenza.

In the last decade, immunologists have uncovered the biological mechanisms of a very different kind of immune reaction than the “adaptive” response they’ve long studied. This “innate” immune response kicks in within mere minutes of an infection. In contrast, the adaptive response, with its familiar antibodies, takes days to get up to fighting speed. An effective vaccine should elicit both types of responses, and researchers now understand that the vaccines of old – made with weakened live viruses – did just that. But to avoid the risks inherent in using live viruses, vaccine developers have turned to individual proteins as immune-system stimulators. Although they’re safer and can generally boost antibody production, these vaccines often fail to prod the innate immune system to action.

Armed with new knowledge of innate immunity, Vaxinnate is working on vaccines aimed at kick-starting both types of responses. The company’s approach is to fuse a protein that cranks up adaptive immunity with another that stimulates innate immunity. The result is a single entity that “would provide both signals that are necessary and sufficient to get an immune response to anything you want,” says Yale immunologist Ruslan Medzhitov, Vaxinnate’s scientific cofounder and one of the key discoverers of some of the biological underpinnings of innate immunity.

Fusing the two protein molecules “is a good idea,” says Alan Aderem, director of the Seattle, WA–based Institute for Systems Biology. Injecting the two together without fusing them runs the risk of turning on too many immune cells, says Bruce Beutler, a professor of immunology at the Scripps Research Institute in La Jolla, CA. This in turn could cause excessive inflammation and lead to side effects like fever, rash, and in the worst case, shock. The fused proteins, on the other hand, would activate only a subset of cells – those bearing receptors for both proteins – which in turn would call to action both the innate and adaptive immune branches.

Founded in 2001, Vaxinnate has raised almost $25 million in venture capital and is now in early-stage animal testing of vaccine candidates for West Nile virus and influenza, with a leukemia candidate soon to follow. The company faces stiff competition on all three fronts from other research groups and companies, several of which are using conventional single-protein approaches. A number of cancer vaccines, for instance – including ones for leukemia – are already in mid- to late-stage human trials. Vaxinnate’s goal is to begin human tests of whatever emerges as its leading candidate by 2006.

Technical hurdles also stand in the way. Even coupling the two proteins may not be enough to avoid side effects, says Beutler. That’s because the subset of cells that the fused proteins interact with might not be narrow enough to exclude all of the culprits in inflammation reactions. Vaxinnate likely “would have to use some other trick,” says Beutler, to further restrict the vaccine to just the right cells.

Even with such challenges, Vaxinnate is one of only a few companies striving to inject some of the new science of innate immunity into vaccine and drug development. Medzhitov hopes that at the very least, Vaxinnate will turn vaccine development – traditionally a trial-and-error process – into more of a science.