Two centuries ago Edward Jenner administered the first scientifically developed vaccine, injecting fluid from a dairymaid’s skin lesion into an 8-year-old boy. The English physician knew that dairymaids who contracted cowpox, a comparatively mild skin disease, became immune to the much deadlier smallpox, which at the time killed 400,000 Europeans a year. Jenner hoped the fluid from the cowpox lesion would somehow inoculate the boy against the smallpox scourge. His hunch proved correct. Today vaccines (vaccinia is Latin for “cowpox”) of all forms save 3 million lives per year worldwide, and at a bargain price. A measles shot, for instance, costs less than a dollar per dose.
By training the human immune system to recognize and ward off dangerous pathogens, vaccines can protect against disease for decades, or even for a lifetime. Preventive vaccines work by introducing harmless microbial chemical markers, known as antigens, which resemble the markers on living microbes. The antigens train the immune system to recognize and destroy those microbes should they ever appear in the body. By injecting cowpox antigens into his patients’ bloodstream, for instance, Jenner primed their immune systems to attack the similar smallpox virus.
Today medical scientists are taking Jenner’s ideas in new directions. They are exploiting a growing understanding of the immune system to develop therapeutic vaccines: ones aimed not at preventing infection but at rooting out established disease or even changing how the body functions. In the spring of last year, the FDA approved Provenge, a vaccine that beats back prostate cancer and is the first of the new generation of therapeutic vaccines to go into widespread use. That may be the trickle before the flood. A 2010 survey by the market analysis firm BCC Research identified 113 therapeutic vaccines in development, many already in human trials.
The cancer shot With a near-endless supply of patients willing to undergo novel treatments, cancer researchers have been among the most aggressive in experimenting with therapeutic vaccination. “Cancer vaccines are the stalking horses for therapeutic vaccines,” says cancer immunologist Lloyd Old. Based at the Cancer Research Institute in New York, Old is the director of the Cancer Vaccine Collaborative, an international program dedicated to fighting cancer from the inside out.
Much of the Collaborative’s work is based on Old’s pioneering studies of the immune system over the last half-century. His research built on the insights of 19th-century surgeon and cancer researcher William Coley, who noticed that for then unknown reasons, postoperative cancer patients with severe bacterial infections often experienced complete remission. In 1891 Coley took the first steps toward cancer immunology when he began intentionally injecting late-stage bone cancer patients with Streptococcus bacteria, which cause strep throat. The injections shrank tumors, but the resulting infections killed two of his patients. He then tried injecting a combination of heat-killed bacteria, a mixture that became known as Coley’s toxin. Although it remained controversial, Coley’s cancer vaccine was widely used until radiation and chemotherapy became standard treatment in the 1940s.
By the time Old began his cancer research, in the 1950s, Coley’s toxin had been relegated to the American Cancer Society’s “black book” of suspected quackeries. “Coley’s vaccine was in such disrepute in large part because no one could explain how it worked,” Old says. Nevertheless, he became fascinated with Coley’s promising results, especially after hearing reports of mouse tumors shrinking after injections of zymosan, a yeast extract. Tumors in those animals continued to grow for close to two weeks after the injections but then started to disappear.
“Clearly the zymosan was not killing the tumors directly,” Old says. “Instead it affected the host in a way that triggered a tumor-clearing response.” He spent much of his career investigating ways the immune system can clear the body of cancer. In the process he identified one of the first recognized cytokines, or immune signaling molecules. Cytokines direct the biochemical conversation that immune cells use to coordinate their activities. Old’s insights suggested that Coley’s toxin worked because it tricked the body into releasing a flood of cytokines by exposing the immune system to what seemed like an enormous bacterial attack. The cytokines then directed an immune response to the bacteria, an onslaught that also killed cancer cells.
Many of the cancer vaccines in development today tap into our current understanding of how dozens of these cytokines help coordinate an effective cancer-clearing response. (The much-publicized HPV cancer vaccine works in a more traditional style: It primes the immune system to fight off human papillomavirus, which can cause cervical cancer.) To make the Provenge prostate cancer vaccine, biochemists at Seattle’s Dendreon Corporation extract a sample of a patient’s own immune cells and bathe them in a chemical soup of prostate cancer antigens that are chemically linked to a cytokine that screams, “Attack this!” The activated immune cells are then injected back into the patient’s body to spread the call to arms.
In the study of 512 prostate cancer patients that led to Provenge’s approval, one-third of the vaccinated patients remained alive after three years, compared with one-quarter of those who received a placebo shot, for an average life extension of four months. Old is hopeful the next wave of cancer vaccines can improve those numbers. The Cancer Vaccine Collaborative is working on treatments that target multiple cancer antigens, which should trigger a more aggressive immune response and increase the odds of defeating tumors.
Potential patients: 1.5 million Americans are diagnosed with cancer each year.
The diabetes shot
In cancer, the immune system is too indulgent of diseased cells within the body. In autoimmune disease, the opposite problem occurs: For reasons still unclear, cells of the immune system mistakenly turn against healthy tissues such as insulin-making pancreatic beta cells (causing juvenile diabetes) or the fatty sheaths that protect nerves (multiple sclerosis). The job of an autoimmune vaccine is to shut down these self-attacks. One promising approach boosts T-regulatory cells, or T regs, a recently discovered subgroup of the white blood cells known as T cells. At the University of Calgary’s Diabetes Research Centre in Alberta, immunologist Pere Santamaria is focusing on what he calls “weak” T regs, cells that seem to have only a very feeble antigen response.
“Most immunologists would tell you that these cells are garbage in the system,” Santamaria says. “But I don’t think anything in our bodies is junk.” He believes that weak T regs are designed to thwart budding autoimmune reactions before they become threatening. In essence, he says, weak T regs can mature into killer T cells that weed out other immune cells mounting attacks on healthy tissues.
To create a diabetes vaccine, Santamaria has attached a cocktail of antigens from pancreatic beta cells to synthetic iron oxide nanoparticles. This biosynthetic hybrid stimulates the development of weak T regs into killer T cells that destroy the immune cells directing the autoimmune attack. Santamaria’s team recently tested his vaccine in diabetes-prone mice. It restored normal blood sugar and insulin levels in animals that already had diabetes and prevented or slowed its onset in young mice that had not yet developed the disease. The team is now readying the vaccine for human trials and is designing related vaccines to treat other autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.
Potential patients: Three million Americans have type 1 diabetes; 400,000 have been diagnosed with multiple sclerosis.
The allergy shot
Allergies are the result of a milder type of internal combat in which the body turns against itself. Allergy treatments that involve repeated injections of minute amounts of allergens such as pollen, mites, and mold have been around for nearly a century. Until recently, scientists did not know how such shots worked, simply that they did—at least in a significant percentage of patients. But these allergy shots must be given at least once a week for months and then at least monthly for three to five years. They work best against mild respiratory allergies, such as hay fever, but generally can’t be used to counteract severe allergies to certain foods or drugs because of the danger of triggering anaphylaxis, a life-threatening immune reaction.
Many immunologists now believe this type of “desensitization” allergy therapy boosts levels of T-reg cells specific to the allergens in the shots. Thereafter, when the T regs encounter their associated allergens, they respond by secreting inflammation-calming cytokines. Equipped with this deeper understanding, researchers are trying to make allergy vaccines safer and more effective by designing them to micromanage the allergic immune response. One way to do that, Swiss immunologist Martin Bachmann has found, is to mimic a microbial infection. He has taken DNA from Mycobacterium tuberculosis and slipped it into synthetic protein capsules virtually identical to those produced by viruses. “The immune system immediately recognizes this pattern as a foreign invader,” Bachmann says. This spurs the immune system to create more cytokine-producing T regs and suppresses the body’s allergic response.
When injected into animals, Bachmann’s virus-bacteria hybrid induces a strong antibody response that his company, Cytos Biotechnology, is exploiting to design vaccines against two common inflammatory disorders. In 2009 Cytos reported the results of a placebo-controlled study with 299 patients allergic to dust mites. Each subject received six weekly injections with either a placebo or one of two doses of active vaccine. At the end of the trial, those who received the high-dose vaccine scored an average of 39 percent lower on symptoms and medication use than did those who got the dummy shots.
Bachmann has had similar success with an asthma vaccine that uses the same virus-bacteria combination. In clinical trials with moderately asthmatic patients who were on chronic steroid treatment, the vaccine has proved just as effective as steroids at keeping asthma at bay. Cytos plans on testing the vaccine in more expansive trials soon.
Potential patients: Up to 50 million people in the United States suffer from allergies.
The heart disease shot Some of the new therapeutic vaccines are actually designed to attack the body, albeit in a selective way. A new experimental heart-disease vaccine takes aim at unwanted biochemicals within the body, specifically low-density lipoprotein (LDL), better known as bad cholesterol. When large quantities of LDL cholesterol circulate through the bloodstream, it can be deposited on artery walls, leading to a buildup of plaque and triggering inflammation. Anti-cholesterol vaccines that encourage the immune system to attack LDL have been in the research pipeline for decades, but early attempts produced mixed results in animals.
Part of the problem may be that an overly aggressive immune attack on artery-clogging plaque can worsen the situation, says Prediman Shah, director of cardiology at Cedars-Sinai Medical Center in Los Angeles. In the early stages of cholesterol buildup, the immune system removes LDL from artery walls with a relatively gentle antibody-clearing response. But if the plaque buildup continues, the immune response may escalate into overaggressive inflammation that further damages the arteries and clogs them with bits of plaque and dead immune cells.
“The last thing we need from a vaccine is more inflammatory damage,” says Shah, who has been working with Swedish cell biologist Jan Nilsson on a vaccine that boosts the antibodies responsible for gentle plaque removal while damping vessel-damaging inflammation. They have found they can manipulate the desired immune response by varying which piece of the ldl molecule they include in their vaccine. They have also discovered the vaccine lowers blood pressure in mice and protects against the rupture of aneurysms.
Shah and his colleagues expect to complete their animal studies by the end of the year and then plan to ask the FDA for permission to launch human trials. “The challenge shouldn’t be underestimated,” he cautions. He points to the disastrous results of a small patient trial using an experimental Alzheimer’s vaccine, a related type of therapeutic vaccine. Like cardiovascular disease, Alzheimer’s involves the buildup of plaque, in this case tangled beta-amyloid proteins in the brain. In 1999 scientists published spectacular results from a study in which a vaccine cured the mouse equivalent of Alzheimer’s. The vaccine contained bits of beta-amyloid protein and directed an immune attack against them. When the vaccine was rushed into clinical trials, however, 18 of the 298 participating Alzheimer’s patients developed life- threatening brain inflammation. Twelve recovered fully, but six suffered permanent, disabling brain damage. Years later, autopsies showed that the vaccine had indeed cleared amyloid plaque from the volunteers’ brains, but the associated inflammation had killed tissue elsewhere in the brain.
Potential patients: Cardiovascular diseases kill more than 800,000 Americans a year.
The obesity shot
Vaccinating against one of the body’s own hormones seems counterintuitive, or even dangerous. But to ease the obesity epidemic, a vaccine that targets ghrelin—a gastrointestinal hormone that appears to stimulate appetite—could be well worth the risk. Here, too, the strategy is to micromanage how certain molecules behave in the body.
“When you diet, the body responds as if it were starving and produces ghrelin to slow down fat metabolism and stimulate eating,” explains Eric Zorrilla, a neuroscientist specializing in eating disorders at the Scripps Research Institute in La Jolla, California. Zorrilla’s experimental antiobesity vaccine consists of ghrelin molecules chemically linked to hemocyanin, a protein extracted from the keyhole limpet marine snail. Hemocyanin is known to provoke a powerful immune response in humans. In theory, the response to a vaccine combining ghrelin and hemocyanin should clear ghrelin from the bloodstream.
After trying several biochemical configurations, Zorrilla and colleague Kim Janda hit on one in 2006 that caused immunized mice to lose weight. There are potential dangers to immunizing against the body’s own chemicals, though. In particular, the researchers must ensure that their vaccine does not result in an autoimmune response to cells that produce ghrelin, which could trigger severe swelling and inflammation. “We didn’t see evidence of that in the animal studies, but it’s a concern,” Janda says. He and Zorrilla continue to refine the vaccine in preparation for human trials.
Potential patients: Nearly 75 million adults are classified as obese in the United States.
The addiction shot
Efforts to produce anti-addiction vaccines began in the 1970s, but those currently in clinical trials trace back to newer research from the mid-1990s, when Barbara Fox, then an immunologist at ImmuLogic Pharmaceutical Corporation, helped develop a cocaine vaccine. The hurdle, she explains, was to get the immune system to register and attack the small, relatively uncomplicated cocaine molecule rather than the complex biological proteins typically found on microbes.
“We had to couple the cocaine to a carrier protein,” Fox explains. “We needed a longer molecule that the immune system could recognize as foreign and dangerous.” Eventually Fox and her colleagues attached a cocaine molecule to one piece of the deadly toxin produced by cholera bacteria. “This molecule itself isn’t toxic,” Fox says. “But it’s the part that generates the strongest response from the immune system.”
In lab animals the vaccine prompted the immune system to produce antibodies custom-tailored to attach to cocaine molecules. Once bonded, the antibodies make the cocaine molecules too large to slip through the tight blood-brain barrier. As a result, the chemical cannot deliver its pleasurably addictive effects to the brain.
Fox’s vaccine has been sustained and improved by psychiatrist Thomas Kosten at Baylor College of Medicine in Houston. In 2009 Kosten reported the results of a clinical trial with 115 cocaine addicts, half of whom received the vaccine. The others received dummy shots. The vaccine produced a strong antibody response in 38 percent of those who received it. These patients were cocaine-free at 45 percent of their follow-up exams two to four months after receiving the vaccine.
What’s more, the urine tests used to verify abstinence revealed that several users had tried to thwart the vaccine by overdosing. “Some urine samples showed cocaine levels over a million,” measured in nanograms per milliliter, Kosten says. “I’ve never seen any living person with over 100,000.” Yet no one was dying of heart attack or stroke, as would be expected if a high level of cocaine reached the heart or brain. In fact, the participants reported that they were not feeling much of anything. The vaccine is currently in a national clinical trial expected to end within the year.
Kosten is also researching vaccines for methamphetamines and opiates, which are among several anti-addiction shots that have the keen interest of the National Institute on Drug Abuse, says NIDA director Nora Volkow, a research psychiatrist who has used brain imaging to investigate the addictive properties of drugs. NicVAX, an antismoking vaccine that recently received $10 million in funding from NIDA, is in large clinical trials under the auspices of its maker, Nabi Biopharmaceuticals. The vaccine generates antibodies to nicotine by linking the addictive molecule to an inactivated bacterial toxin. As with the cocaine vaccine, the resulting antibodies do not clear nicotine from the blood so much as stick to it, creating a chemical complex too large to migrate into the brain.
Volkow was initially skeptical about the possibility of a nicotine vaccine. “I thought people would simply overcompensate by smoking more cigarettes,” she says. But in a pilot study conducted on heavy smokers, 24 percent of those who received the NicVAX vaccine were smoke free for the last two months of the six-month study—double the quit rate of those who received placebo shots. Among those who developed antibodies to nicotine but were not able to abstain from smoking, the number of cigarettes they smoked dropped significantly.
It is too soon to know how long these vaccines will last and whether they will prevent addicts from switching to other drugs. But NIDA is embracing the approach and is now researching a vaccine against heroin, the use of which is a vector for HIV transmission in many countries. Volkow has moved past her doubts about addiction vaccines. “That was before I saw the results of early trials,” she says. “Now I see how vaccine technology can be used against a host of public health issues.”
Potential patients: 46 million Americans smoke cigarettes; an estimated 1.6 million used cocaine in 2009.
Jessica Snyder Sachs is the author of Good Germs, Bad Germs: Health and Survival in a Bacterial World.
