To the editor:

We would like to respond to the safety concerns raised in one of your news articles about Cytos Biotechnology's vaccine candidate for high blood pressure.

The article “Blood pressure vaccine shot down by safety concerns” (Nat. Med. 11, 1262; 2005) raises two questions about the vaccine's safety. The first, by Jean-Baptiste Michel, suggests that “targeting angiotensin in the tissues would inevitably trigger an autoimmune reaction.” In his experiments, Michel immunized animals against renin, a 340–amino acid protein present at high concentrations in the kidney. That vaccine resulted in a decrease in blood pressure but induced autoimmune disease in the kidney. Conversely, when Michel vaccinated animals against angiotensin I, there were no side effects, but there was also no decrease in blood pressure (Arch. Mal. Coeur. Vass. 82, 1323–1328; 1989).

The disease in renin-immunized rats and marmosets was primarily characterized by immunoglobulin deposits, which colocalized with renin and stained positive for complement factors. The researchers attributed these results to immune-complex disease, where polyclonal renin-specific antibodies cross-link the multiepitopic renin, forming immune complexes that deposit in the kidney and cause inflammation and disease.

In contrast, we do not expect such autoimmune disease to result from Cytos' hypertension vaccine. Our vaccine targets angiotensin II. Unlike renin, angiotensin II is an eight–amino acid, short-lived molecule, the size of which virtually precludes two antibodies binding to it and forming an immune complex. As in Michel's work, we showed that in preclinical experiments in rats, the vaccine generates high titers of angiotensin-specific antibody. Our vaccine, however, also succeeded in decreasing blood pressure. Most important, extensive histology and toxicology studies have so far showed no signs of immune-complex disease. A phase 1 trial in healthy human volunteers has shown reversible antibody responses, no safety concerns, no elevation of immune complexes in the sera and no clinical chemistry indicative of kidney disease.

Walinjom Muna raised the second question: “what are the long-term consequences of permanent receptor blockade in humans or closely related species?” Blocking the action of angiotensin in the long term with inhibitors of angiotensin-converting enzyme and angiotensin receptor blockers has proven effective and safe in millions of individuals. Blocking angiotensin with a vaccine is expected to be similarly effective and might also improve patient compliance. The experience gained so far shows the antibody response to be reversible, although long-term effects remain to be tested.

The development of Cytos' hypertension vaccine, currently in ongoing combined phase 1/2 trials, has required review by experts, ethics committees and regulatory authorities. Although the vaccine's long-term safety can only be ultimately determined by widespread clinical testing and postmarket evaluation, we reasonably expect it to be safe.