Vaccines Stage A Comeback

By Michael D. Lemonick and Alice Park

You seldom see them on the cover of Prevention Magazine, but vaccines are the great prevention success story of modern medicine. They are not perceived as new or sexy; they have been around since the days of George Washington, when Edward Jenner first scraped the scabs from milkmaids infected with cowpox to inoculate people against smallpox. By the end of the 20th century, vaccines had conquered many of man's most dreaded plagues, eliminating smallpox and all but wiping out mumps, measles, rubella, whooping cough, diphtheria and polio, at least in the developed world. Vaccines had done their work so well, in fact, that in the context of 21st century medicine, with its smart drugs and high-tech interventions, they seemed almost quaint and out of date, a kind of biomedical backwater.

That perception changed dramatically after Sept. 11 and the anthrax attacks. Suddenly, vaccines were back in the headlines. The U.S. government was scrambling to build up its supplies of smallpox inoculations, and an anthrax vaccine that had been stuck in a legal and scientific morass for years was thrust back on the fast track.

Yet defense against bioterrorism is only part of the vaccine renaissance. Over the past few years, dramatic advances in the fields of immunology, virology and genetics have jump-started this long-stalled field of medicine. All the easy things that vaccines can do had been done, and researchers were ready to move on to far tougher challenges--using vaccines to fight off cancer, for example, or attack the protein deposits that clog the brains of Alzheimer's patients or even as a potential treatment for heart disease. "We are in a new era of vaccine research," says Dr. Gary Nabel, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID). "It's an amazingly exciting time to be in this field."

An important trigger for this turnaround, surprisingly enough, was vaccine research's most notable failure. In the 1980s, as the AIDS epidemic began to spread, scientists tried to fight it as they had polio and chickenpox--by crippling the virus and using it to train a patient's immune system to ward off the real infection. Nobody really understood how the process worked at the molecular level, but until AIDS came along, that didn't matter much.

HIV, however, proved too sophisticated for such crude tactics. The virus managed to take advantage of loopholes that even experts hadn't expected, such as hiding within immune-system cells to avoid detection and mutating so rapidly that the body's defenses couldn't keep up. Immunologists' only hope of closing those loopholes was to delve more deeply into the exquisite complexity of the immune system in an effort to understand its secrets.

That effort has paid off. After more than a decade of research, scientists now know that the immune system doesn't simply flick on and off like a light switch. Instead, it responds to a bacterial, viral or parasitic invasion with a combination of defensive weapons matched precisely to the severity of the threat.

That kind of fine-tuning necessarily makes the immune system complicated--but to understand the vaccination revolution, you first have to understand the complications. The simplest immune reaction--triggered by a mosquito bite, for example, or an allergen--is inflammation. When the insect bites, the immune system uses cellular troops that have had no special training. Cells called leukocytes, neutrophils and mast cells routinely cruise the bloodstream sniffing for an unfamiliar chemical signature. If they find it, they signal for reinforcements that swarm to kill the invader--the equivalent of an infantry attack.

If the invading bugs are too powerful for this first line of defense, the immune system sends in a second wave of cells. These represent what is known as the innate immune system. Unlike the first wave of defenders, which are crude killing machines, these cells are preprogrammed with biochemical weapons that can target specific types of invaders, including common viruses like influenza and rhinovirus (which causes the common cold).

Even this two-stage counterattack isn't always sufficient, however. When that's the case, it's time for the heavy artillery--the even more specialized cells of the acquired immune response. These cells learn from experience. Once they have been exposed to a virus or bacterium, they will recognize it if it shows up a second time. That's why, for example, you can get chickenpox once but rarely twice.

That much was known decades ago; what drives vaccine researchers today is the effort to understand and manipulate this highly tuned system. The acquired immune response, for example, actually comes in two parts. The first involves antibodies, the molecules produced to match, like a key fitting into a lock, the multiple proteins that coat the surfaces of viruses and bacteria. The more keys on the immune cell's ring, the more likely that the cell can lock onto and destroy a pathogen.

Sometimes, though, the bugs use biochemical trickery to disguise themselves and evade antibodies. The acquired immune system's counterstrategy: so-called antigen-presenting cells, including dendritic cells that latch onto invading bugs and strip them of their chemical camouflage. Thus exposed, the pathogens are prepped for destruction by killer T cells, whose job is to engulf and destroy them. The killer Ts are meanwhile lured to the site of infection in the greatest possible numbers by signaling chemicals known as cytokines, released by the dendritic cells.

The whole process resembles a highly trained military force or, in Nabel's happier analogy, a musical collaboration. And while it works beautifully most of the time, the immune system needs extra help against some diseases. "You literally have an immunologic orchestra," Nabel says, "and if the different sections don't come in in the proper sequence or are not harmonized in the proper way, you may end up with a piece that you're not very happy with."

One way that can happen is if a bacterial or viral illness gets out of control before the immune system can respond. That's where vaccines come in. "What a vaccine does," says Nabel, "is alert these specialized cells that an incoming agent could be a problem, and allow the immune system to respond more quickly and effectively than if it had never seen the bug before." In effect, he says, "you move up the immunologic-response chain of events so the final, acquired response kicks in faster."

That hasn't worked so far for deadly diseases like tuberculosis, malaria or AIDS, in part because no model for natural immunity exists for any of them. Thus scientists cannot crib from nature for vaccines, as Jenner did for smallpox. But that is changing as researchers get a sense of how many instruments in the immune-system orchestra they have at their disposal, and how to get the best performance from them. With HIV, for example, the virus mutates too rapidly. No sooner has the acquired immune system learned to identify and lock in on it than HIV develops new antigens on its surface and turns invisible again.

But a recent strategy, shown effective for the first time at NIAID, may be able to thwart this evasive action. Known as "prime-boost," it gives the immune system a whiff of the virus' scent before hitting it with the actual vaccine. In Nabel's lab, that whiff consists of a snippet of DNA from HIV's outer coating--not enough to trigger a full immune response but, as his work was the first to show in animals, enough to put the system on alert. In the past this strategy hasn't worked in humans because our immune system, unlike those of other mammals, doesn't respond robustly enough to DNA alone. To amplify DNA's poor signal strength, Nabel's group sends in the "boost"--a crippled common-cold virus packed with a payload of viral antigens--a few days after priming, and the immune system goes into high gear. That's the theory, anyway.

It's too early to know whether this strategy will work against HIV, but it is already working against another deadly virus. Ebola, though it has claimed far fewer victims than HIV, has enormous potential for devastation. There is no cure or vaccine for it--but in a recent trial, Nabel's group has shown that DNA priming can protect monkeys from Ebola.

A patient-ready AIDS vaccine may not be available for human trials for another decade, but once it is, Nabel and others plan to use every trick they have learned to boost its effectiveness. They may, for example, mix cytokines with the vaccine, counting on these chemicals to rally extra killer T cells against the virus. They may give a small jolt of electricity along with the priming dose of viral DNA; that shock seems to enhance the DNA's ability to trigger a response. And they are even experimenting with firing the DNA directly into immune-system cells at high pressure with so-called gene guns to make sure the nucleic acids have maximum impact.

One of the inventors of the gene gun thinks that shooting viral DNA could someday replace traditional vaccines. Dr. Stephen Johnston, director of the Center for Biomedical Inventions at the University of Texas Southwestern Medical Center in Dallas, is using medicine's newfound skill at sequencing genomes to figure out precisely what genes express, or turn on, when a bug first enters a host's cells. Using microarrays, also known as "DNA chips," Johnston is working to identify those genes, then snip them from a pathogen's genome and use them, or the proteins they make, as vaccines to trigger an immune response.

A similar strategy could lead to vaccines against malaria and TB. But while conquering such hitherto vaccine-resistant diseases would be dramatic, it would be positively revolutionary to extend vaccines to illnesses that have seemed beyond their reach. One such candidate is heart disease--which may involve the immune system in ways nobody ever imagined just a few years ago. The buildup of fatty cholesterol deposits on artery walls may begin, it turns out, with an inflammation perhaps caused by bacteria. This immune response alters the arteries in ways that make them prone to cholesterol damage. A vaccine that could prevent the initial infection or tamp down the inflammatory response might, doctors believe, prevent the chain of events that leads to heart attacks from getting started in the first place.

Cancer would seem to be the last disease you could prevent or treat with a vaccine. After all, infection plays no role in cancer, except in a few rare types of malignancy. And a cancer cell, unlike an invading pathogen, isn't wholly foreign to the body. Nevertheless, researchers are learning that the immune system can even be trained to go after tumors. CanVaxin, for example, a vaccine for the deadly skin cancer melanoma, is made from cancer-cell lines taken from three different patients; among them, they express more than 20 disabled tumor antigens that the immune system can learn to recognize.

"What we've been able to show," says Dr. Guy Gammon, vice president of clinical development for CancerVax, the biotech company that makes the vaccine, "is that not only do a majority of patients make an immune response, but that those making a strong response survive longer."

Indeed, in early clinical trials on people whose tumors had been surgically removed, those receiving the vaccine lived on average twice as long as controls. To make the vaccine even more potent, company scientists are testing a version of CanVaxin enhanced with cytokines to help boost the response of patients with immune systems damaged by chemotherapy. In Canada a vaccine called Melacine, made by Corixa, is also fighting melanoma, shrinking tumors as effectively as chemotherapy but with fewer side effects. It is currently in trials in the U.S.

Researchers are heartened by their preliminary success with a more complicated regimen, in which inoculations are custom-made from--and for--each patient. Early in 2001, scientists from Stanford University reported some shrinkage of advanced colon or lung tumors in half of a dozen patients. The vaccines they used were made of dendritic cells harvested from the patients themselves and mixed with a protein found on colon and lung tumors. These were then put back into the patients. "Our hope is to make these vaccines more potent and to try them in earlier-stage disease, possibly even using them to prevent disease," says the lead researcher, Dr. Lawrence Fong.

And that's undoubtedly only the beginning. Just a decade ago, medical science despaired of ever finding vaccines that would be able to ward off illnesses like malaria and tuberculosis, which have plagued humanity for thousands of years, and AIDS, which looked as though it might turn out to be even deadlier than these ancient killers. The notion that this venerable disease-prevention strategy would prove effective against these and others seemed farfetched.

Now it's clear that the age of vaccines was proclaimed over much too soon. Some of the new inoculations now under development won't pan out, of course. But doctors have learned their lesson, and if history is any guide, it's a happy one: any statement about the limits of vaccinations has a good chance of being proved wrong--and sooner than anyone expects.