A personal ad seeking the perfect vaccine might read: "Must confer strong immunity, quickly, with a single dose and minimal side effects. Should offer lasting protection, preferably for a lifetime." Unfortunately, few vaccines would measure up. Many of them require multiple doses to get the immune system's attention or periodic booster shots to refresh its memory. Others may elicit a partial immune response but fail to activate T cells, the powerful search-and-destroy soldiers of the immune system.

Hence vaccine designers' fascination with one of the oldest vaccines around. The yellow fever shot has been fulfilling the perfect vaccine wish list since the 1930s, when it was first created at what is today the Rockefeller University. "It is perhaps the safest and most effective vaccine ever developed," according to Raul Andino of the University of California, San Francisco, one of several researchers hoping to transfer its successful traits to modern vaccines against other problematic pathogens.

Andino and the others are working to piggyback the immune-stimulating features of various vaccines onto the yellow fever shot. The scientists hope that by riding yellow fever's coattails, those vaccines will provoke a more potent and lasting immunity than they are able to muster on their own. "I think using a tried-and-true vaccine such as yellow fever will be very successful. I really like the idea," says immunology specialist Peter Palese of the Mount Sinai School of Medicine.

Based on a strain called YF17D, the yellow fever vaccine is a live but weakened form of the wild virus. Charles M. Rice, head of the Laboratory of Virology and Infectious Disease at Rockefeller, has shown in mice that a component of malaria vaccine inserted into YF17D elicited malaria-targeted T cells and gave the mice long-lasting protection against the infection. In similar experiments with mice and monkeys, Andino has used YF17D to deliver HIV antigens--immune-provoking bits of viral protein. The chimeric YF17D/HIV vaccine prompted a 1,000-fold higher T cell response than the same HIV proteins delivered with different vectors. Andino has also caused melanoma tumors in mice to regress with a YF17D vaccine carrying a tumor-specific antigen.

Chimeric YF17D vaccines developed by Acambis, a biotech firm in Cambridge, Mass., are already showing promise in early human trials, but they are all combinations of yellow fever and its close relatives in the so-called flavivirus family, including the dengue, Japanese encephalitis and West Nile viruses. Making chimeras containing proteins from unrelated pathogens is trickier. The main challenge is to insert the foreign protein into the yellow fever virus without disabling the vaccine. For that, it helps to know how the yellow fever vaccine stimulates such potent immunity to begin with, which has been a long-standing mystery.

The answer may lie with dendritic cells, immune system sentinels whose normal job is to digest sick cells infected by pathogens. The dendritic cells then alert immune warrior cells to the presence of an intruder by presenting them with its distinctive antigens. Rice recently showed that YF17D directly infects dendritic cells. A few other viruses, including HIV, herpes simplex and measles, infect them as well, but they either kill or incapacitate the cells. He found that YF17D lets them live and continue to fulfill their antigen-presenting function.

Something about being infected themselves might give extra urgency to the dendritic cells' communication with the other immune cells, Rice speculates. Or it could be just that the vaccine strain "is in the optimal antigen-presenting cells to begin with," he says, thereby accounting for the powerful immune response. Either way, the findings suggest a possible vaccine-design tip from nature.

"We know that dendritic cells are a crucial and central mechanism for making long-lasting immunity," Palese says. "It's a must." As researchers continue exploring ways to make yellow fever vaccine protect against other pathogens, it seems that the 70-year-old perfect vaccine still has some tricks to teach the scientists as well.