Promising results from a phase 2 study of a vaccine for hypertension

March 15, 2008 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Few medicines in the past decades have been more successful than angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). As primary care providers are increasingly mindful of microalbuminuria and cardiovascular risk, more and more hypertensive patients are managed on ACE inhibitor / ARB combinations. And with the recent approval of Aliskerin, we have yet another tool to interrupt the – some would say - vestigial renin-angiotensin-aldosterone axis. Researchers at Cytos Biotechnology are asking whether we should use our immune system to rid us of the whole mess.

Results from a Phase 2 study of an anti-hypertension vaccine against angiotensin II were published in the journal Lancet. The vaccine, called AngQb, comprises angiotensin II linked to a virus-like particle, administered with aluminum hydroxide as an adjuvant.

It is a difficult task to design a vaccine for the purpose of breaking self-tolerance. Especially in an out-bred population – overcoming the immune safeguards against autoimmunity can be a challenge. The whole field of cancer immunology has been working for years on this problem. Presumably, T cells with antigen receptor specificity for antiogensin II should largely be deleted in the thymus. And then there are peripheral tolerance mechanisms such as regulatory T cells. Finally, if an antigen such as angiotensin II is presented to T cells without a second signal to indicate inflammation or “danger”, the result is T cell anergy, or antigen-unresponsiveness. The AngQb vaccine is uses the virus-like moiety to ensure that antigen presentation occurs in the setting of such a second signal.

Forty-eight patients with mild-moderate hypertension were randomized to receive placebo, 100 mcg vaccine or 300 mcg vaccine (administered at 0, 4, and 12 weeks). The purpose of the Phase II study was to evaluate the safety and tolerability of the vaccine, with a secondary purpose to look for vaccine efficacy. They found that there were very few adverse events associated with vaccine administration, in essence the same number of events as seen in the placebo arms. Anti-angiotensin II antibody titers rose and peaked at 6-8 weeks after the start of the vaccination schedule, as expected. Titers were highest in the 300 mcg arm, with a antibody half-life of near 17 weeks. Patients underwent 24-hours ambulatory blood pressure monitoring during the study. Such a small study is underpowered to see a statistically significant difference in blood pressure – anti-hypertensive medicines are approved on a surprisingly small blood pressure benefit. The researchers did note, however, a statistically significant benefit of the 300 mcg vaccine in preventing the early morning rise in blood pressure. These results will have to be confirmed by larger studies.

The idea of a hypertension vaccine is very innovative. Adherence to medication schedules is one of the largest obstacles to treating hypertension, and a vaccine would largely solve this problem. There are a few concerns with this approach, however. Patients are often taken off ACE inhibitors and ARBs when they are dehydrated, hypotensive, sustain kidney injury, have electrolyte abnormalities, or need to receive intravenous contrast. The reversal of the vaccine effects would be much more difficult if not impossible. The vaccination itself might have many limitations. Correlations between antibody titers and antibody blocking ability are sometimes poor – creation of good blocking antibodies is difficult in the controlled laboratory setting, let alone in a large out-bred patient cohort. The possibility exists for significant genetic variation in benefit from the vaccine. And of course there is the possibility that creation of antibodies against a self-protein could have unintended consequences, ranging from immune complex diseases to frank autoimmunity. Rare, unexpected consequences are only appreciated when large numbers of patients have been studied.