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“It’s a bit like, what would this approach take to be acceptable to people?” says Alan Daugherty, who directs the Cardiovascular Research Center at the University of Kentucky in Lexington. “In the real world, an ACE inhibitor has unequivocally been shown to reduce many types of [hypertensive] disease. So why would anyone switch to something new when it hasn’t got as much safety data and there’s no obvious distinction in terms of its therapeutic effect?”

Safety firstDesigned to assess mechanism and safety, both phase 2 trials were promising. No significant safety issues arose—the most common adverse event was local injection site reactions. The immunization schedules revealed high and long-lasting antibody titers. However, only the Cytos study found significant effects on blood pressure itself, giving them the early lead in the

race to market.On the one hand,

Protherics’ angio-tensin I vaccine not only was found safe, but also effectively stimulated antibody production and had some effects on the renin-angiotensin system consistent with a reduction in circulating angio-tensin II (that is, renin levels increased, which occurs when the negative feedback normally exerted by angiotensin II is removed). But the problem was blood pressure didn’t come down. “The conclu-sion was that the

antibody titer wasn’t high enough,” says Morris Brown, professor of clinical pharmacology at the University of Cambridge, who helped Protherics design the trial.

In contrast, Cytos’ angiotensin II vaccine had effects on both renin and blood pressure con-sistent with a reduction in angiotensin II. The blood pressure effect occurred in early morn-ing, when the normal diurnal pattern shows a relatively steep rise in blood pressure.

The observation that the Cytos vaccine blocked this morning rise in blood pres-sure was a surprise, but a welcome one, says Martin Bachmann, chief scientific officer at Cytos “because most strokes and heart attacks happen early in the morning.” Skeptics note,

inhibitors and angiotensin receptor blockers (ARBs). ACE cleaves a couple of amino acids off the prehormone angiotensin I to make its active counterpart, the 8-amino-acid-long peptide angiotensin II; ACE inhibitors block this conversion. Angiotensin II acts directly on vascular smooth muscle to induce constriction, and it stimulates aldosterone release, which in turn stimulates thirst and salt appetite. All these actions and the result-ing increased blood pressure are medi-ated through cell sur-face receptors, which can be blocked with ARBs. Like small-molecule drugs, vac-cine therapies have also targeted the syn-thesis and action of angiotensin II.

The Protherics vaccine comprises an angiotensin I pep-tide analog originally formulated with the adjuvant keyhole lim-pet hemocyanin and generates antibodies against angiotensin I. In contrast, Cytos’ vaccine immunizes against active angio-tensin II and is based on Qβ virus-like par-ticles to which angiotensin II antigen has been chemically cross-linked.

Clinical trials of both hypertension vaccines demonstrated effects on measures of the renin-angiotensin system, if not always the therapeu-tic bottom line: blood pressure itself. With one important exception—20 years ago, a renin vac-cine caused kidney failure in experimental ani-mals—no major safety problems have emerged in preclinical testing or in the nearly 100 sub-jects in the phase 2 trials. And yet, many in the biomedical community remain skeptical that vaccines will offer any practical advantage over the well-stocked medicine cabinet that already exists for the management of hypertension.

A race is underway between two companies, Cytos Biotechnology of Zurich and Protherics of London, to develop novel vaccines for high blood pressure by inducing antibody responses against endogenous hormones of the renin-angiotensin system. Cytos hit pay dirt first, announcing positive results last March from a phase 2 clinical trial. This result caught the eye of the pharmaceutical giant Pfizer of New York, which entered into a partnership with Cytos that will put CHF 10 ($8.5) million into the biotech company’s coffers and may yield up to CHF 140 ($118.5) million in future payments1.

But vaccines controlling hypertension differ from other therapeutic vaccines—such as those aimed at cancer, allergy, drug addiction or auto-immune disease—in that they target the con-stituents of a normally functioning hormonal pathway, rather than host cell components gone awry (Box 1). And although maintain-ing a constant low blood pressure by means of a vaccine is attractive from the aspect of compli-ance, which can be poor among hypertensive patients, some critics of the approach wonder whether blunting normal adaptive responses to environmental changes, like insult or injury, could spell trouble for vaccine recipients. Can a shot do the job, and allow the hypertension pills to be taken off the shelf?

Heart disease vaccinesThe market for antihypertensive agents is huge and the competition is stiff. At least 43 million adults in the US and fully two-thirds of people over age 60 have hypertension2. Physicians can choose from a host of antihypertensive agents, some of which have been used for decades. New small-molecule inhibitors are being devel-oped as well; Basel-based Novartis received approval for Tekturna (aliskiren), a direct renin inhibitor, just last year. Aldosterone synthesis inhibitors and epoxide hydrolase inhibitors, which target two enzymes downstream from the renin-angiotensin pathway, are also in the pharmaceutical industry’s pipeline.

Most antihypertensive drugs target the renin-angiotensin system and fall in two drug classes: angiotensin-converting enzyme (ACE)

Hypertension’s shot in the armTwo small companies developing therapeutic vaccines against hypertension are blazing a trail for immune treatments that address diseases of lifestyle with massive markets. But doubts linger over the safety of eliciting an immune response to normal body constituents. Jill U. Adams investigates.

Daily dosing of anti-hypertensive drugs may someday be replaced by vaccines.

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disease in hypertension at Vanderbilt University School of Medicine in Nashville, Tennessee.

Daugherty says the general concept is appealing. “Clearly drug [levels] go through huge peaks and valleys,” he says, whereas the vaccine should provide consistent and lasting protection. “I see that as one of the major ben-efits of this type of approach.”

The biggest hurdle for vaccine therapies will be proving that they are superior to stan-dard therapies. It’s one thing to show effec-tiveness against placebo, quite another to go head to head with an inhibitor or a blocker. Cambridge’s Morris Brown cites the new-est antihypertensive drug on the market, Novartis’ Tekturna. “In its phase 3 program, it was required to be compared directly against an ACE inhibitor and an ARB, so people could get a feel for if it was at least as good as or bet-ter,” he says. “I would expect the same for the vaccine. It’s what I would want to know.”

Some people question whether tissue-level effects undermine the efficacy of angiotensin vaccines. Angiotensinogen is secreted from the liver, and kidney-derived renin clips the pro-tein to make angiotensin I. ACE is prevalent in endothelial tissues such as the lung. But this route around the viscera is not the only path-way. “More and more it’s getting recognized that a lot of these components can be generated in different parts of the body,” says Daugherty, citing recent evidence of renin in bone mar-row–derived cells, and of macrophages gen-erating angiotensin by themselves, implying that they have all the components of the system within. “In other words, we don’t quite know whether a lot of the peptide production that we have is via systemic levels or whether it’s just generated locally,” he says.

If angiotensin circulating in the bloodstream is responsible for maintaining high blood pres-sure, “then a vaccine should be able to wipe that out easily,” says Daugherty. On the other hand, if tissue systems contribute to the over-all effect, then these local sites may turn out to be vaccines’ Achilles’ heel because antibod-ies wouldn’t be expected to penetrate tissues as well as small-molecule drugs. This might explain why there is circulating antibody after vaccination, but no effect on blood pressure.

Even if further clinical trials prove that neutralizing angiotensin I or II in the blood-stream is sufficient to control high blood pressure, no one knows whether the vaccine will protect against other disease-promoting effects of the renin-angiotensin system. “The real question is for tissue remodeling—the so-called blood pressure–independent effects of angiotensin II,” says Vanderbilt’s Nancy Brown. Angiotensin promotes hypertrophy in the heart and hardening of the arteries, and

tests, generated tenfold higher antibody titers, according to company literature. Protherics scientists targeted angiotensin I based on preclinical data. In their hands, an anti-angiotensin I vaccine induced better immune response and blood pressure control than an anti-angiotensin II vaccine in rats.

So why does one vaccine work and the other not? Daugherty says, “It’s probably a function of just the affinity of the antibodies. I think those arguments could be spun both ways, why it’s better to target angiotensin I or angiotensin II.”

A better mousetrapExecutives at Cytos and Protherics believe that their products will prove effective once formu-lations and dosing schemes are optimized and will subsequently find a market share. They point to the high proportion of patients—up to two-thirds—whose hypertension is not well controlled by current medications3. They high-light the problem of treatment compliance in hypertension, which has no symptoms to speak of beyond the readings on a blood pressure cuff. “Most people don’t like to be reminded every morning that they have some sort of disease,” says Cytos’ Bachmann. Other factors that derail adherence to treatment include side effects, the necessity of taking more than one drug and their cost4.

With more consistent control, the thinking goes, the better the cardiovascular outcomes for patients with hypertension. Even for those who are diligent in taking their medication, blood levels of drugs undergo daily cycles. “The ratio-nale for designing these [vaccines] is that you can have long-term efficacy without daily dos-ing,” says Nancy Brown, who studies vascular

however, that such an effect does not occur with the long-acting angiotensin receptor blockers. Furthermore, differences among placebo groups were similar to the largest effect on blood pres-sure by high-dose vaccine—about 6 mm Hg—which raises the possibility that chance played into the positive findings. Bachmann is the first to say more work needs to be done. “We would like to increase the overall efficacy of the vaccine, and then we’ll need to have phase 3 studies with a couple thousand people.”

Representatives of both companies believe the differences between their vaccines are significant. “We use the same basic trick with [all] our vaccines,” Bachmann says, by making antigens look like viruses. The trick is taking advantage of an immune system predisposed to recognize highly repetitive surfaces. “We take the antigen and couple it onto virus-like par-ticles. The immune system takes it for a virus and makes a very strong response against it.” In addition to targeting high blood pressure, Cytos is also working on vaccines for Alzheimer’s dis-ease and smoking cessation (Box 1).

As for the choice of target, Bachmann points out that angiotensin II circulates longer, mak-ing it a better choice for neutralization with antibodies. “Frankly, I’m not sure we’ve got great data on what angiotensin I and angio-tensin II levels are anywhere. If you look in the literature, both human and animal data, you’ll find an incredible quagmire of different levels,” says University of Kentucky’s Daugherty.

Since their 2004 study, Protherics has reformulated its vaccine so that the angio-tensin I analog is now linked to a proprietary adjuvant called CoVaccine HT (Protheric’s US patent 7,378,489B1 mentions tetanus toxoid as an adjuvant), which in preclinical

Box 1 Nicotine addiction: up in smoke

with more than one billion smokers and nearly five million deaths each year related to tobacco around the globe, smoking is a chronic condition with poor long-term health outcomes. Presently, success rates for smokers trying to quit are abysmal: <5% according to the us surgeon General. three companies are busy developing vaccines for smoking addiction: nabi Biopharmaceuticals of rockville, Maryland; Hamilton, Bermuda–based Celtic Pharma; and Cytos. nabi’s vaccine has been fast-tracked by the us food and Drug administration and recently received funding for phase 3 trials from the national Institute on Drug abuse. Celtic anticipates seeking a partner once their phase 2 results are made public. novartis is the development partner for the Cytos product.

a vaccine against nicotine induces antibodies that bind plasma-borne nicotine molecules before the drug reaches neural receptors. By greatly reducing or eliminating the nicotine that reaches the brain, the vaccines, together with counseling and behavior modification, may better help people quit smoking. But an incomplete reduction of the drug could have the opposite effect: if some nicotine reaches the brain, then smokers might try to compensate by smoking more cigarettes.

the early phase trials feature endpoints measuring abstinence for up to 12 months. the results show good antibody titers, tolerance and safety6. small therapeutic effects have been reported, too, particularly in patients with the highest antibody titers.

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Michel’s biggest concern is that, in the haste to get to clinical studies, effects of these thera-pies on the immune system have not been well characterized. “There is a big difference between a small peptide as an antigen and a big protein as an antigen,” he says, referring to the fact that short peptides like the angiotensins are too small to induce an immune response without being linked to a carrier protein. “We don’t know what is the respective role of the [carrier] protein and the peptide. This is a dif-ficult point,” says Michel, who would like to see comprehensive preclinical data showing the immune response to the carrier protein versus that of the peptide, as well as a more complete characterization of the pattern of immunity with regard to B cells versus T cells.

Although skeptics and detractors remain, the vaccine developers see sunny skies in terms of selling their product—whether the ‘buyer’ is a major pharmaceutical company to partner with for large-scale clinical trials, healthcare provid-ers or patients. Sally Waterman, the director of R&D for Protherics, recounts the huge inter-est generated by a story in the UK’s Daily Mail newspaper about hypertension vaccines. “We were bombarded with e-mails and requests. So I think people are desperately looking for some-thing which is less onerous than tablets.” Cytos found their first buyer in Pfizer. Protherics hopes the sale will bring their suitor calling, too.

Jill U. Adams, Albany, New York

1. anonymous. Nat. Rev. Drug Discov. 7, 794 (2008).2. Ostchega, Y. et al. J. Am. Geriatr. Soc. 55, 1056–1065

(2007).3. Chobanian, a.V. et al. J. Am. Med. Assoc. 289, 2560–

2572 (2003).4. Munger, M.a., Van tassell, B.w. & Lafleur, J.

MedGenMed. 19, 58 (2007).5. Michel, J.B. et al. Circulation 81, 1899–1910

(1990).6. Cornuz, J. et al. PLoS ONE 3, e2547 (2008).

vaccine—the angiotensins are smaller than renin, less likely to have multiple epitopes, which contribute to immune complex forma-tion—but found that no matter how good his antibody response was, blood pressure was not reliably affected. He remains today a voice of caution and perhaps the most vocal critic of the current efforts. Stephen Grimes, a principal scientist at Mercia Pharma in Scarsdale, New York, who develops therapeutic vaccines for chronic diseases, such as asthma and diabetes, says “immune complexes are not a given.” And Bachmann says of the Cytos trial, “We specifi-cally looked for immune complexes and we found none. We have also done toxicology studies and studies in hypertensive rats.”

Larger clinical trials may well put specific fears to rest, but a certain wariness accompa-nies the debut of any new therapy in today’s regulatory and litigious climate. “We live in an environment where there’s increasing scru-tiny and concern about safety of drugs,” says Douglas Vaughan, who chairs the department of medicine at Northwestern University’s Feinberg School of Medicine in Chicago. “I think any kind of drug that works through a potentially different pathway, whose mecha-nism of action is completely different, is going to raise the level of watchfulness.”

Immune effects under a microscopeAdverse side effects have already stymied the therapeutic vaccine approach in other indi-cations. For example, a clinical trial for an amyloid-β vaccine in Alzheimer’s patients was halted in 2002 because of adverse effects. And vaccines targeting cholesteryl ester transfer protein (CETP) are fighting an image problem after Pfizer arrested a clinical trial with its new CETP inhibitor in 2006.

small-molecule inhibitors are known to be protective of these tissue-damaging effects.

Strengths as weaknessesThe very selling point of vaccine therapies is that the effects can last for months. But what if a situation arose where a rise in angiotensin was necessary to maintain health, such as suf-fering severe blood loss from a car accident? “That patient would need the renin-angio-tensin system to provide adequate blood flow to the kidney,” says Nancy Brown. “Those are the situations that I’m worried about.”

Vaccine proponents say a trauma victim would be hospitalized, where it’s easy to maintain blood pressure by infusing fluids. They also point out that antibodies neutral-ize only a proportion of circulating hor-mone and that increased hormone secretion prompted by volume changes could sur-mount the blockade. Brown counters with a scenario that might not include medical care—serious dehydration from a stomach bug. “We see patients all the time, who are on [antihypertensive] drugs, who come in with some reason for hypotension. It’s reversible if we stop an ACE inhibitor or an ARB,” she says. But it would be a much longer wait for a vaccine’s effect to wear off. “I would like to be able to see safety data with a vaccine out in real life for awhile,” she adds.

Another hurdle will be to overcome any squeamishness about vaccine therapies in general. Jean-Baptiste Michel, of INSERM and the Université Paris Diderot, developed a vaccine targeting renin 20 years ago. Preclinical studies in rodents and primates showed good efficacy on blood pressure, but immune com-plexes ended up destroying subjects’ kidneys5. Michel moved on to work on an angiotensin I

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