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Chronic Disease Vaccines Need Shot in The SPECIALSECTION obesity, smoking, and addictive drugs for the past 30 years. “In large part, society still views addiction or even obesity as a moral failure rather than a chronic disease.” It’s dif- fi cult to persuade drug companies and the general population to invest in treating some- thing they view as a failure of willpower with an intervention like a vaccine, Janda says. But he isn’t giving up and neither are oth- ers. “If you can fi nd a target that is the under- lying cause” of an illness, Janda says, “then you can develop a vaccine for its treatment.” There are now a number of vaccines in clini- cal trials for cancer, which is considered a chronic disease, Janda says, so why not ones for obesity, diabetes, and drug abuse? “We know why we failed previously and that there are clear pathways in front of us,” Chronic Disease Vaccines Need adds Martin Bachmann, an immunologist formerly with Cytos Biotechnology. He says Shot in the Arm that poor antibody responses and lack of specifi city—critical fl aws for a vaccine—are Whether vaccines to prevent obesity, asthma, smoking-related illnesses, and other problems that companies are now addressing chronic diseases will ever work remains an open question by using full-length proteins, rather than pep- on September 22, 2012 tides, and experimenting with viruslike par- IN JULY, GLOBAL HEADLINES PROCLAIMED 6% (18 of 298) of the clinical trial subjects ticles that yield a higher and more consistent that a “fl ab jab” was imminent, an obesity vac- receiving the AN1792 vaccine developed a antibody response. cine that would allow consumption of endless severe brain infl ammation. And Nabi Bio- fast and fatty foods without punishing weight pharmaceuticals’s nicotine vaccine, designed Mite-y vaccine gain. The proof: Mice that were injected with to suck the high out of smoking, failed in a Vaccines were originally developed to com- a vaccine targeting the hormone somatostatin Phase III trial last year. Switzerland-based bat microbial pathogens such as the small- gorged on a high-fat diet with signifi cantly Cytos Biotechnology also attempted vaccines pox virus and the tuberculosis bacterium; www.sciencemag.org less weight gain than those given a sham for smoking, as well as hypertension and type people are traditionally injected with live or injection. “Thousands of people contacted us 2 diabetes, and though its researchers made dead copies of a pathogenic microbe, or with volunteering for clinical trials. Everyone from progress, the company ran out of funding in its molecular components—a viral surface mothers wanting to lose baby fat to weight 2011 and abandoned most of those efforts. protein, for example—to rally the immune lifters in Germany,” says vaccinologist Keith Vaccine developers also face a “psychoso- system to produce antibodies or cells that Haffer of small, South Dakota–based Braasch cial” problem, says Kim Janda, a chemist at specifi cally target the invader for destruction. Biotech, who led the rodent study. the Scripps Research Institute in San Diego, Yet vaccines may be able to do more than With funding interest from several South California, who has worked on vaccines for prevent infections. Consider asthma, the target Downloaded from American companies, Braasch Biotech of one vaccine effort. Worldwide, does plan to begin human clinical trials of more than 300 million people suf- its somatostatin vaccine late in 2013. Hold fer from asthma, often sparked the extra cheese on that large sausage pizza, by a violent immune response to however. It’s diffi cult enough to develop and common environmental allergens. obtain approval for a traditional vaccine Current treatments include corti- against a bacterium or virus, let alone create costeroids, which reduce infl am- one that rouses the immune system to target mation but have side effects, and molecules that drive a chronic disease such as a procedure called desensitization obesity. Indeed, potential vaccines for hyper- in which asthma/allergy patients tension, asthma, Alzheimer’s disease, obesity, are given increasing doses of an and smoking (because it is a risk factor for allergen cocktail. But the success heart disease, cancer, stroke, and more) have of desensitization varies from per- all been hyped for their promise in recent son to person and occasionally years and then suffered high-profi le failures. causes a life-threatening reaction: In 2002, for example, a vaccine that raised anaphylaxis. antibodies to the β-amyloid protein that accu- Mite-y vaccine. Dust mites such as Dermatophagoides farinae A team led by Bruno Pitard at mulates in the brains of people with Alzheim- (pictured) are a trigger of allergies and asthma, prompting efforts the University of Nantes in France CREDITS (TOP TO BOTTOM): D. HURST/ALAMY; DENNIS KUNKEL MICROSCOPY, INC./VISUALS UNLIMITED, INC. UNLIMITED, INC./VISUALS MICROSCOPY, KUNKEL DENNIS HURST/ALAMY; D. BOTTOM): TO (TOP CREDITS er’s disease suffered a scary setback when to immunize people against one of their proteins. is now tackling asthma with a www.sciencemag.org SCIENCE VOL 337 21 SEPTEMBER 2012 1479 Published by AAAS DISEASE PREVENTION www.sciencemag.org/special/prevention variation on the traditional vaccine. Pitard’s searching for another use for Braasch Bio- enous hormone controlling appetite might strategy stems from the observation that 50% tech’s vaccine Somatovac, which they found cause anorexia or wasting away, for example. of Europeans with allergies harbor antibodies was a promising way to boost milk produc- Haffer isn’t the fi rst to dream of an obesity against the Der f 1 protein from Dermatopha- tion in cows and lean meat production in vaccine. Janda and others have targeted the goides farinae, one of the most common pigs without using bovine growth hormone appetite-stimulating hormone ghrelin in their dust mites in the United States and Europe. or antibiotics. He realized that Somatovac attempts to build an obesity vaccine. Back in But instead of immunizing with actual Der f might also promote leanness in humans and 2006, Janda made headlines similar to those 1 proteins from this mite, which can trigger therefore fi ght obesity. received by Haffer’s work when he and col- an allergic response in people with asthma, Haffer sent two different versions of the leagues reported that vaccinating adult male Pitard and his colleagues are test- rats with a segment of ghrelin protein, or the ing a vaccine composed of DNA full-length version, slowed weight gain and coding for the protein, with the idea fat buildup in the body but didn’t seem to that it would train the immune sys- affect appetite. Janda cautioned at the time tem to tolerate it. that the study rats dined on a mundane, low- When naked DNA is injected fat, low-energy chow. He couldn’t predict into the body, however, it is rap- from this study whether the vaccine would idly degraded before it can express prevent diet-induced obesity—the kind that the antigen it encodes. That prob- affl icts many people consuming a high-fat lem has frustrated many develop- Western diet—or trigger weight loss in ani- ing naked DNA vaccines, so Pitard mals that were already obese. is now treating his Der f 1 DNA Mariana Monteiro, an endocrinologist with so-called tetrafunctional block at the University of Porto in Portugal, pre- copolymers, which, as his team dis- sented more evidence at The Endocrine Soci- covered in 2009, encourage gene ety’s Annual Meeting in June 2011 that an on September 22, 2012 delivery into the skeletal mus- antighrelin vaccine could reduce appetite- cle, where the protein can then be promoting brain chemicals in mice. She manufactured. The team recently revealed that tethering ghrelin to a viral pro- immunized mice using this modi- tein could trigger enough antighrelin antibod- fi ed vaccine, and those mice had a Vaccine recipe. First produce a viruslike particle, then ies in the rodents to reduce eating, increase fi vefold reduction in their asthmatic chemically link multiple copies of an antigen, such as energy use, and reduce levels of neuropeptide reaction, Pitard says. Lung tissue nicotine. The result: a conjugate vaccine that triggers strong Y—a potent appetite stimulator. But there and bronchioles carried far fewer antibody production. was no overall weight loss at the end of the www.sciencemag.org infl ammatory cells and cytokines study. Monteiro wrote in October 2011 in than in asthmatic mice vaccinated with a pla- somatostatin vaccine to Jackson Laboratory Expert Review of Vaccines that the under- cebo. Despite that encouraging data, it will be in Bar Harbor, Maine, where researchers whelming impact on long-term food intake at least 5 years before a clinical trial of the there tested them on mice that had previously and body weight “might be due to activation asthma vaccine begins, Pitard predicts. bulked up from consuming a high-fat diet for of compensatory mechanisms.” Most candidate vaccines for chronic dis- 8 weeks. Neither vaccine made the already- Janda and his team have also explored pas- eases don’t target microbial molecules but plump rodents lose weight, but they gained sive immunization: injecting antighrelin anti- proteins made by the human body. Take the 10% less weight than control rodents, even bodies in mice. In a study published in Feb- Downloaded from strategy behind the original Alzheimer’s dis- though all the animals ate the same quan- ruary in Molecular Pharmaceutics, Janda’s ease vaccine, which sought to activate the tity of high-fat food during the 6-week study, team showed that a cocktail of three mono- immune system against β amyloid. Because Haffer reported in July in the Journal of clonal antibodies targeting ghrelin could of the dangerous brain infl ammation that fol- Animal Science and Biotechnology.
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