The hope for this line of investigation is that immunization against the renin angiotensin system might obviate the need for lifelong oral therapy, Brown told the meeting here. There is an old literature investigating this possibility, but most of these studies used passive immunization. "We think this may be the first study of active vaccination against angiotensin," he noted.

The experimental vaccine, dubbed PMD3117, is a 12-amino-acid analog of angiotensin-1, linked to keyhole limpet hemocyanin and adsorbed onto aluminum hydroxide. Previous studies with this vaccine, developed by Protherics Molecular Design Ltd, Manchester, UK, have shown that in animals, it produced an antibody response that effectively blocked the effects of angiotensin. In spontaneously hypertensive rats, blood pressure of immunized animals was lower than controls for the period of monitoring, and a study in human subjects showed two doses of the vaccine were well tolerated and produced an antibody response.

In the present study, the researchers used a crossover design in 24 treated hypertensive patients. Each subject had been shown to be responsive to an ACE inhibitor and angiotensin blocker. For two weeks before the study, subjects stopped their antihypertensive medication. The rise in blood pressure was recorded using 24-hour ambulatory monitoring; patients with a rise in BP of at least 8 mm Hg systolic were eligible for randomization. Patients then went back on their usual medications and were randomized to receive one of two vaccine dosing regimenseither three or four injections of 100-mg peptide equivalent of PMD3117or to a control group receiving only the aluminum hydroxide.

After seven weeks, their normal medications were once more withdrawn for two weeks, and 24-hour ambulatory BP monitoring was again performed to see whether, with the antibodies on board, the natural rise in BP might be affected.

Brown reported that all patients showed a rise in IgG antibodies to angiotensin, although there was, as expected, a great deal of variability between subjects. There was a trend to higher antibody titers with four injections vs three, but this was "not remotely significant," he said. Median titers were 6739 with the three-dose and 11548 with the four-dose regimen by day 64.

Median half-life of the antibody titers was 85 days (95% CI 44 to 155 days). "Of course, that's very encouraging because if this approach were to be used it might be necessary to vaccinate only two or three times a year," Brown noted.

However, there was no significant difference in blood pressure between the groups during the two off-drug periods before and after vaccination. "The crossover of the study, which should have been sensitive to even a small effect of keeping the blood pressure down [with the vaccine], was performed and shows a very similar rise in BP on the two occasions," he said. While not significantly different from the control group, the rise in BP was 7.5 mm Hg lower in the four-dose group compared with the three-dose group (p<0.01). The inference is that, at least at these titers, BP is not affected, he said.

Again, though, the biochemical markers did show some hint of effect, with a twofold increase in plasma renin and a 60% to 70% reduction in aldosterone in those receiving the active vaccine. No changes in these markers were seen in the control group.

The vaccines were well tolerated, he added. Transient local swelling and itching occurred after some of the final active injections, and one patient in each group withdrew.

Brown noted that it is possible that higher antibody titers may be needed to see an effect on BP. "We have to be very cautious about arguing from titer to effect, and this is known in vaccines of all sorts, but the sense from previous studies and from maybe looking at the effect on infused angiotensin is that you'd want at least twice the antibody titer on average and that the peak responses we saw in this study would need to be more like average responses," he told heartwire.

In an interview, Brown speculated about the potential uses of a vaccine of this kind.

"I think myself that if the vaccine is eventually successfuland that's going to depend on reformulation, probably with a different adjuvantits long-term role would not so much be in the bread-and-butter patients who are currently well-controlled on an ACE inhibitor."

He feels that the vaccine may be an option, for example, for younger hypertensives or those who are still only at risk for high blood pressure. "Especially now with JNC 7 [new US hypertension guidelines] telling us that maybe we should be thinking of treating much sooner, at an age or stage where you wouldn't want to have people on lifelong drug treatment, that people might be prepared to be vaccinated at an early stage, and that may be what we need to stop people from ever developing hypertension."

Another potential use for an antiangiotensin vaccine would be in heart failure, where ACE inhibition has been shown to be life saving. "There's still a very low take-up of these drugs in other indications, particularly heart failure, whereas if you gave people a vaccine then you wouldn't have to worry about adding another drug."

Finally, Brown said, "thinking a bit more laterally," one of most important developments of late has been the completion of mapping of the human genome, with "30000 molecules that the Genome Project tells us are potential drug targets." Many of these may also potentially be used to raise an antibody response, an alternative to medication that "might be very attractive."