Schlieren, Switzerland - Circulating antibodies against angiotensin II has been shown to be a safe and well-tolerated approach to controlling blood-pressure levels in patients with mild to moderate hypertension, a new study has shown [1]. Although the vaccine is still in its exploratory stages, investigators showed that immunization against angiotensin II reduced ambulatory blood pressure during the daytime, especially in the morning.

First presented at the American Heart Association 2007 Scientific Sessions and now published in the March 8, 2008 issue of the Lancet, the placebo-controlled, dose-comparison trial explored the safety and tolerability of CYT006-AngQb (Cytos Biotechnology AG, Switzerland), a viruslike particle-based conjugate vaccine that targets angiotensin II.

"The basic issue is that people aren't very compliant with their medication," senior investigator Dr Martin Bachmann (Cytos Biotechnology AG, Switzerland) told heartwire. "Between 50% and 80% of people who should take their medication don't, even though they know they are hypertensive. A vaccine is a long-lasting immune response that can provide protection, so we thought if we immunized somebody against angiotensin II and neutralized the molecule, we might have to immunize only every six months or so and eliminate the need to take daily pills."

The purpose of the study was to investigate the safety and tolerability of CYT006-AngQb. Investigators enrolled 72 patients with mild to moderate hypertension, defined as a systolic pressure of 140 to 179 mm Hg and a diastolic pressure of 90 to 109 mm Hg, and followed them for four months. Patients were given 100 µg or 300 µg of the antigen or placebo at time zero, then at one month and three months. End points were safety and tolerability, with an "exploratory" look at efficacy with ambulatory BP measurements.

At the highest dose tested, investigators report that immunization with AngQb "raised a sufficiently high level of antibodies to significantly decrease blood pressure." By week 14, there was a mean ambulatory daytime blood pressure decrease of 9.0 mm Hg from baseline among those treated with the 300-µg injection. "The drop in blood pressure was especially pronounced in the early morning, when the renin-angiotensin-aldosterone system is most active and when most cardiovascular events occur," report investigators.

In terms of adverse events, the researchers, led by Dr Alain Tissot, also an employee of Cytos Biotechnology AG, say that most side effects were mild, transient reactions at the injection site. Three patients treated with 100 µg reported flulike symptoms, as did seven in the 300-µg group. No serious adverse events were related to treatment.

Asked about the safety of active immunization that blocks angiotensin for extended periods of time, Bachmann said the response is reversible and that the body has built-in mechanisms for overcoming the antibody if needed.

"On the one hand, it's not permanent," said Bachmann. "It has a half-life of about four months, which is, of course, much longer than any drug on the market. But it's not possible for an antibody to completely block angiotensin. There is always equilibrium between bound and free angiotensin, and if there is a need for angiotensin II based on some sort of physiological response, there will be some increase in free angiotensin II. In other words, the system still works."

Dr Franz Messerli (St Luke's Roosevelt Medical Center, New York), who was not affiliated with the study, raised some doubts, however. "There is no question that this is an intriguing new approach to antihypertensive therapy, and the data are very provocative," he said. "But there are also some concerns. Angiotensin II is the most powerful vasoconstrictor known, and not all angiotensin II is actually harmful. It has a physiologic role in the body for preventing blood pressure from falling in certain situations, such as dehydration or trauma."

Where we see the best potential for the vaccine is in patients with mild tomoderate hypertension, where one mechanism to block hypertension might be sufficient.

Messerli told heartwire that the safety issue with a vaccine that blocks angiotensin for months at a time must be looked at very carefully. Moreover, he is not convinced that patients will want to be vaccinated against angiotensin II, especially since the alternative is to take a drug daily without any side effects.

Drs Ola Samuelsson and Hans Herlitz (Sahlgrenska University Hospital, Göteborg, Sweden), who wrote an editorial to accompany the paper, point out that treatment of hypertension is based on lifestyle interventions and drug therapy, both of which require patient adherence [2].

"Poor compliance is common for both approaches and is the main reason for inadequate blood-pressure control," they write. "If vaccination against high blood pressure were safe and effective in the long run, it might solve many problems of noncompliance."

Like Messerli, Samuelsson and Herlitz question whether it will be safe to inhibit the actions of circulating angiotensin II for several months without being able to quickly reverse inhibition. Another safety issue is whether booster doses of an endogenous peptide like AngQb cause autoimmune disease, as was shown in a recent vaccination study in patients with Alzheimer's disease.

Asked where the company sees the vaccine being used, Bachmann told heartwire: "Patients above a certain threshold won't be able to control their blood pressure with just the vaccine. What we can say is that patients might end up taking just one pill, instead of two, which does help with compliance. But where we see the best potential for the vaccine is in patients with mild to moderate hypertension, where one mechanism to block hypertension might be sufficient."