Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Success and failure of vaccines against renin–angiotensin system components

Nature Reviews Cardiology volume 6, pages 639–647 (2009)Cite this article

Abstract

Therapeutic vaccination pre-dated modern drugs as a possible strategy for treating hypertension. This approach is now being rediscovered, through use of modified angiotensins as immunogens together with carriers and adjuvants. Effective blockade of the renin–angiotensin system (RAS) with treatment twice a year might suit patients who dislike taking drugs on a daily basis and would also be an attractive option for those who have blood pressures in the prehypertensive range, if it can prevent hypertension itself from developing. Proof of concept with a vaccine whose efficacy is easy to measure will encourage development of further vaccines directed against targets such as aldosterone or other pathways where alternative treatments are scarce or absent. Two angiotensin-based vaccines are currently in development: PMD3117 comprises modified angiotensin I coupled to keyhole limpet hemocyanin, and Cyt006–AngQb is a conjugate of angiotensin II linked to virus particles. Early phase II studies in patients with hypertension demonstrated some efficacy, but the vaccines are not as effective as existing inhibitors of the RAS. Large studies now in progress will establish whether further modification of the immunogen or adjuvant is required to boost antibody titers.

Key Points

  • The renin–angiotensin system offers a number of targets for immunization, of which angiotensins I or II seem to be the most promising

  • Swapping life-long daily drug therapy for occasional injections could be undermined because most patients require a drug to eliminate excess sodium in addition to renin–angiotensin system blockers

  • Vaccines currently in development are less effective than oral inhibitors of the renin–angiotensin system, but might provide a model for vaccination against other targets that have few alternative therapies

  • For many patients, current treatment of hypertension starts too late to reverse long-term risks of complications completely

  • Vaccination might be more attractive for prevention than treatment of hypertension

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The RAS.
Figure 2: Comparison of RAS immune blockade with RAS receptor blockade.
Figure 3: Effects of the PMD3117 vaccine in patients with hypertension.
Figure 4: Structure of the Cyt006–AngQb vaccine.
Figure 5: Effect of Cyt006–AngQb on blood pressure and antibody titers in spontaneously hypertensive rats.
Figure 6: Profile of antibody titers in patients immunized with 100 µg Cyt006–AngQb, 300 µg Cyt006–AngQb, or placebo.

Similar content being viewed by others

References

  1. Turnbull, F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 362, 1527–1535 (2003).

    Article  CAS  Google Scholar 

  2. Turnbull, F. et al. Blood pressure-dependent and independent effects of agents that inhibit the renin–angiotensin system. J. Hypertens. 25, 951–958 (2007).

    Article  CAS  Google Scholar 

  3. Lewington, S., Clarke, R., Qizilbash, N., Peto, R. & Collins, R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360, 1903–1913 (2002).

    Article  Google Scholar 

  4. Kearney, P. M. et al. Global burden of hypertension: analysis of worldwide data. Lancet 365, 217–223 (2005).

    Article  Google Scholar 

  5. Lopez, A. D., Mathers, C. D., Ezzati, M., Jamison, D. T. & Murray, C. J. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367, 1747–1757 (2006).

    Article  Google Scholar 

  6. Messerli, F. H., Williams, B. & Ritz, E. Essential hypertension. Lancet 370, 591–603 (2007).

    Article  CAS  Google Scholar 

  7. Falaschetti, E., Chaudhury, M., Mindell, J. & Poulter, N. Continued improvement in hypertension management in England: results from the Health Survey for England 2006. Hypertension 53, 480–486 (2009).

    Article  CAS  Google Scholar 

  8. Rutherford, J. C., Taylor, W. L., Stowasser, M. & Gordon, R. D. Success of surgery for primary aldosteronism judged by residual autonomous aldosterone production. World J. Surg. 22, 1243–1245 (1998).

    Article  CAS  Google Scholar 

  9. Mancia, G. & Grassi, G. Systolic and diastolic blood pressure control in antihypertensive drug trials. J. Hypertens. 20, 1461–1464 (2002).

    Article  CAS  Google Scholar 

  10. Chapman, N. et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension (2007).

  11. Perreault, S. et al. Persistence with treatment in newly treated middle-aged patients with essential hypertension. Ann. Pharmacother. 39, 1401–1408 (2005).

    Article  CAS  Google Scholar 

  12. Brown, M. J. Renin: friend or foe? Heart 93, 1026–1033 (2007).

    Article  CAS  Google Scholar 

  13. Brown, M. J. et al. Better blood pressure control: how to combine drugs. J. Human Hypertens. 17, 81–86 (2003).

    Article  CAS  Google Scholar 

  14. Baigent, C. et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet 366, 1267–1278 (2005).

    Article  CAS  Google Scholar 

  15. Turnbull, F. et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch. Intern. Med. 165, 1410–1419 (2005).

    Article  Google Scholar 

  16. Hansson, L. & Zanchetti, A. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 351, 1755–1762 (1998).

    Article  CAS  Google Scholar 

  17. Staessen, J. A., Wang, J.-G. & Thijs, L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J. Hypertens. 21, 1055–1076 (2003).

    Article  CAS  Google Scholar 

  18. Yusuf, S. et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N. Engl. J. Med. 358, 1547–1559 (2008)

    Article  CAS  Google Scholar 

  19. Julius, S. et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 363, 2022–2031 (2004).

    Article  CAS  Google Scholar 

  20. [No authors listed]. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 288, 2981–2997 (2002).

  21. Yusuf, S. et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 372, 1174–1183 (2008).

    Article  CAS  Google Scholar 

  22. Dahlof, B. et al. The Losartan Intervention For. Endpoint Reduction in Hypertension Study. Lancet 359, 995–1003 (2002).

    Article  CAS  Google Scholar 

  23. Dahlof, B. et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 366, 895–906 (2005).

    Article  Google Scholar 

  24. ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 283, 1967–1975 (2000).

  25. Jamerson, K. et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N. Engl. J. Med. 359, 2417–2428 (2008).

    Article  CAS  Google Scholar 

  26. A Systolic Blood Pressure Intervention Trial (SPRINT) Clinical Center Networks, [online]. (2008).

  27. Harrap, S. B., Van der Merwe, W. M., Griffin, S. A., Macpherson, F. & Lever, A. F. Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term. Hypertension 16, 603–614 (1990).

    Article  CAS  Google Scholar 

  28. Wu, J. N. & Berecek, K. H. Prevention of genetic hypertension by early treatment of spontaneously hypertensive rats with the angiotensin converting enzyme inhibitor captopril. Hypertension 22, 139–146 (1993).

    Article  CAS  Google Scholar 

  29. Labat, C. et al. Effects of valsartan on mechanical properties of the carotid artery in spontaneously hypertensive rats under high-salt diet. Hypertension 38, 439–443 (2001).

    Article  CAS  Google Scholar 

  30. Frohlich, E. D. The salt conundrum: a hypothesis. Hypertension 50, 161–166 (2007).

    Article  CAS  Google Scholar 

  31. Brown, M. J. Aliskiren. Circulation 118, 773–784 (2008).

    Article  CAS  Google Scholar 

  32. Juillerat, L. et al. Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension 16, 564–572 (1990).

    Article  CAS  Google Scholar 

  33. Belz, G. G., Butzer, R., Kober, S., Mang, C. & Mutschler, E. Time course and extent of angiotensin II antagonism after irbesartan, losartan, and valsartan in humans assessed by angiotensin II dose response and radioligand receptor assay[ast]. Clin. Pharmacol. Ther. 66, 367–373 (1999).

    Article  CAS  Google Scholar 

  34. Mazzolai, L. et al. Angiotensin II receptor blockade in normotensive subjects: a direct comparison of three AT1 receptor antagonists. Hypertension 33, 850–855 (1999).

    Article  Google Scholar 

  35. Calhoun, D. A., Nishizaka, M. K., Zaman, M. A., Thakkar, R. B. & Weissmann, P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 40, 892–896 (2002).

    Article  CAS  Google Scholar 

  36. Goldblatt, H., Haas, E. & Lamfrom, H. Antirenin in man and animals. Tr. Ass. Am. Phys. 64, 122–127 (1951).

    CAS  Google Scholar 

  37. Michel, J. B. et al. Immunologic approaches to blockade of the renin-angiotensin system: a review. Am. Heart J. 117, 756–767 (1989).

    Article  CAS  Google Scholar 

  38. Michel, J. B. et al. Physiological and immunopathological consequences of active immunization of spontaneously hypertensive and normotensive rats against murine renin. Circulation 81, 1899–1910 (1990).

    Article  CAS  Google Scholar 

  39. Michel, J. B. Renin-angiotensin vaccine: old story, new project 'efficacy versus safety'. Clin. Sci. 107, 145–147 (2004).

    Article  CAS  Google Scholar 

  40. Michel, J. B. et al. Active immunization against renin in normotensive marmoset. Proc. Natl Acad. Sci. USA 84, 4346–4350 (1987).

    Article  CAS  Google Scholar 

  41. Gardes, J., Bouhnik, J., Clauser, E., Corvol, P. & Menard, J. Role of angiotensinogen in blood pressure homeostasis. Hypertension 4, 185–189 (1982).

    Article  CAS  Google Scholar 

  42. Conroy, J. M. et al. Pulmonary angiotensin-converting enzyme. Interspecies homology and inhibition by heterologous antibody in vivo. J. Biol. Chem. 251, 4828–4832 (1976).

    CAS  PubMed  Google Scholar 

  43. Thurston, H. & Swales, J. D. Comparison of angiotensin II antagonist and antiserum infusion with nephrectomy in the rat with two-kidney Goldblatt hypertension. Circ. Res. 35, 325–329 (1974).

    Article  CAS  Google Scholar 

  44. Oster, P., Bauknecht, H. & Hackenthal, E. Active and passive immunization against angiotensin II in the rat and rabbit. Evidence for a normal regulation of the renin-angiotensin system. Circ. Res. 37, 607–614 (1975).

    Article  CAS  Google Scholar 

  45. Brunner, H. R., Kirshman, J. D., Sealey, J. E. & Laragh, J. H. Hypertension of renal origin: evidence for two different mechanisms. Science 174, 1344–1346 (1971).

    Article  CAS  Google Scholar 

  46. Christlieb, A. R., Biber, T. U. & Hickler, R. B. Studies on the role of angiotensin in experimental renovascular hypertension: an immunologic approach. J. Clin. Invest. 48, 1506–1518 (1969).

    Article  CAS  Google Scholar 

  47. Gardiner, S. M. et al. Active immunization with angiotensin I peptide analogue vaccines selectively reduces the pressor effects of exogenous angiotensin I in conscious rats. Br. J. Pharmacol. 129, 1178–1182 (2000).

    Article  CAS  Google Scholar 

  48. Downham, M. R. et al. Evaluation of two carrier protein-angiotensin I conjugate vaccines to assess their future potential to control high blood pressure (hypertension) in man. Br. J. Clin. Pharmacol. 56, 505–512 (2003).

    Article  CAS  Google Scholar 

  49. Brown, M. J. et al. Randomized double-blind placebo-controlled study of an angiotensin immunotherapeutic vaccine (PMD3117) in hypertensive subjects. Clin. Sci. 107, 167–173 (2004).

    Article  CAS  Google Scholar 

  50. Lechner, F. et al. Virus-like particles as a modular system for novel vaccines. Intervirology 45, 212–217 (2002).

    Article  Google Scholar 

  51. Kundig, T. M. et al. Der p 1 peptide on virus-like particles is safe and highly immunogenic in healthy adults. J. Allergy Clin. Immunol. 117, 1470–1476 (2006).

    Article  Google Scholar 

  52. Jennings, G. T. & Bachmann, M. F. The coming of age of virus-like particle vaccines. Biol. Chem. 389, 521–536 (2008).

    Article  CAS  Google Scholar 

  53. Ambuhl, P. M. et al. A vaccine for hypertension based on virus-like particles: preclinical efficacy and phase I safety and immunogenicity. J. Hypertens. 25, 63–72 (2007).

    Article  Google Scholar 

  54. Tissot, A. C. et al. Effect of immunisation against angiotensin II with CYT006–AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study. Lancet 371, 821–827 (2008).

    Article  CAS  Google Scholar 

  55. Biotechnology reports biochemical findings from phase IIa study with hypertension vaccine Cyt006–AngQb Medical News Today [online], (2009).

Download references

Author information

Authors and Affiliations

  1. Clinical Pharmacology Unit, University of Cambridge, Cambridge, UK

    Morris J. Brown

Authors
  1. Morris J. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Morris J. Brown.

Ethics declarations

Competing interests

The author is a consultant for GlaxoSmithKline Bio.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brown, M. Success and failure of vaccines against renin–angiotensin system components. Nat Rev Cardiol 6, 639–647 (2009). https://doi.org/10.1038/nrcardio.2009.156

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2009.156

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing