Hypertension, also termed high blood pressure, is a medical condition where the blood pressure is chronically elevated. Although symptomless in nature and in itself rarely an acute problem, persistent hypertension is one of the most important preventable causes of premature death worldwide and contributes to around half of all cardiovascular diseases. It is one of the major risk factors for stroke, myocardial infarction, heart failure, and vascular disease, and is a leading cause of chronic renal failure.
In hypertensionsystemic arterial blood pressure is elevated and it is the opposite of hypotension. Hypertension is classified as either primary (essential) hypertension or secondary hypertension; about 90–95% of cases are termed primary hypertension, which refers to high blood pressure for which no medical cause has been found (1).The remaining 5– 10% of cases (Secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart, or endocrine system. Persistent hypertension is one of the risk factors for stroke, myocardial infarction, heart failure and arterial aneurysm, and is a leading cause of chronic kidney failure. Moderate elevation of arterial blood pressure leads to shortened life expectancy. Dietary and lifestyle changes can improve blood pressure control and decrease the risk of associated health complications, although drug treatment may prove necessary in patients for whom lifestyle changes prove ineffective or insufficient. The development of a vaccine for the treatment of hypertension is now of similar importance as hypertension is one of the major causes of disease of the cardiovascular system and thus one of the most frequent causes of disease-induced deaths worldwide (1).
The World Health Organization attributes hypertension, or high blood pressure, as the leading cause of cardiovascular mortality. The World Hypertension League (WHL), an umbrella organization of 85 national hypertension societies and leagues, recognized that more than 50% of the hypertensive population worldwide is unaware of their condition (2). To address this problem, the WHL initiated a global awareness campaign on hypertension in 2005 and dedicated May 17 of each year as World Hypertension Day (WHD). Over the past three years, more national societies have been engaging in WHD and have been innovative in their activities to get the message to the public. In 2007, there was record participation from 47 member countries of the WHL. During the week of WHD, all these countries – in partnership with their local governments, professional societies, nongovernmental organizations and private industries – promoted hypertension awareness among the public through several media and public rallies. Using mass media such as Internet and television, the message reached more than 250 million people. As the momentum picks up year after year, the WHL is confident that almost all the estimated 1.5 billion people affected by elevated blood pressure can be reached (3).
Genetic predisposition and lifestyle habits such as inadequate physical activity, high fat diet, and high salt intake promote high blood pressure. Up to 30% of adults in most countries suffer from hypertension. Despite effective and relatively inexpensive treatment available, less than one out of four hypertensive individuals have their blood pressure controlled successfully (4). This poor overall treatment success is mainly attributed to the symptomless nature of hypertension and the necessity for long-term treatment with currently available medications that require at least once daily self administration.
Ambulatory blood pressure, blood pressure measured by numerous readings over a 24-hour period or longer, provides accurate and reliable information about a person’s blood pressure.
Angiotensin II, a small peptide which is part of the renin-angiotensin system (RAS). It induces narrowing of blood vessels and other effects to raise blood pressure. Diastolic blood pressure is the lowest pressure within the arterial blood stream occurring with each heart beat. Systolic blood pressure is the highest pressure within the arterial blood stream occurring with each heart beat (4).
The 2007 United States Preventive Services Task Force (USPSTF) guidelines on screening for high blood pressure recommended screening every two years for persons with systolic and diastolic pressures below 120 mmHg and 80 mmHg, respectively, and yearly for persons with a systolic pressure of 120 – 139 mmHg or a diastolic pressure of 80 – 89 mmHg (1). Hypertension can be classified according to its primary or secondary causes. The majority of patients (90%) suffer from primary hypertension, which many experts now believe is a multi-factorial disease. These factors include increased salt intake, reduced nephron mass, abnormal renin-angiotensin system, increased sympathetic tone and endothelial dysfunction. In contrast, secondary hypertension is associated with a single definable physiological dysfunction (primary kidney disease, renovascular disease, endocrine abnormality, sleep apnea, or coarctation of the aorta) and, thus, definitive treatment options may exist (1). Despite remarkable advances in new medications, the prevalence of hypertension continues to rise. From 1994 to 2004, increased public awareness of hypertension led to an increase in earlier diagnosis and treatment success. Unfortunately, approximately 30% of adults are believed to be unaware of their hypertension status, while 60% of individuals with hypertension are receiving the appropriate treatments and only 35% of patients have their blood pressure adequately controlled to less than 140/90 mmHg (from National Health and Nutrition Examination Survey (NHANES) data 1999 to 2004). The principal reasons associated with these dismal numbers are inadequate access and low compliance with treatments. One investigation reported that 11% of their patient cohort was non-compliant in adhering to an anti-hypertensive medication for more than 2 weeks (1). Therefore, improving patients’ compliance should be a primary goal for any new antihypertensive agents.
A hypertension vaccine could be an important alternative to conventional drug therapy because of patients’ inconsistent drug intake – if further research supports results from a small study testing the safety and tolerability of a vaccine. Juerg Nussberger, M.D., professor of medicine at the University Hospital of the Canton of Vaud, in Lausanne, Switzerland, and lead author of the study reported at the American Heart Association’s Scientific Sessions 2007 said that despite the fact that effective drugs are available, only about one out of four people has their blood pressure successfully controlled. Many patients are apparently unable or unwilling to take pills every day for the rest of their lives. If it could be added or substituted a vaccine that would need to be given just every few months, better control of high blood pressure could be achieved (5).
Vaccine against hypertension is an innovative treatment, injected every 4 – 6 months, to combat non-compliance. The pathogenesis of hypertension is multifactorial. Renin-angiotensin system (RAS) is important system in the body that regulates blood pressure. The most common cause is disruption of the Renin–angiotensin—aldosterone system (RAAS) and the first vaccine study was carried out against renin. While the vaccine reduced blood pressure in animal models, it also caused autoimmune disease. In the last decade, vaccines against angiotensin I, angiotensin II, and angiotensin II-type 1 receptors have demonstrated acceptable safety profiles in animal and human studies. Reduction in blood pressure can be achieved by inducing immunity against targets in the RAAS. The target antigen and selection of adjuvant are crucial factors determining effectiveness and safety of the vaccine. CYT006-AngQb (angiotensin II vaccine) reduced blood pressure in humans but the results were not reproducible with more frequent dosing. Vaccines for hypertension are still in the early phase. They hope for an effective vaccine for hypertension in the years to come (6).
The vaccine targets angiotensin II, a molecule that constricts blood vessels and raises blood pressure. Angiotensin II is already the indirect target of several blood pressure medications. Angiotensin-converting enzyme (ACE) inhibitors (such as benazapril and enalapril) reduce the production of angiotensin II in the blood by slowing its conversion from angiotensin I. Angiotensin receptor blockers (ARBs, such as candesartan and losartan) prevent angiotensin II from acting on these receptors, thus preventing constriction of the blood vessels. Martin Bachmann, Ph.D., senior co-author of the study and chief scientific officer at Cytos Biotechnology AG in Zurich, companies that create vaccines to treat and prevent chronic diseases, said that instead, they take non-infectious particles with a virus shape and chemically couple them with angiotensin II so the body begins to vigorously attack angiotensin II. To assess the antibody response and identify an effective dose of the vaccine (CYT006-AngQb), 72 patients with mild-tomoderate high blood pressure were injected with either 100 or 300 micrograms (ug) of the vaccine or a placebo. The patients included 65 men and seven women, average age 51.5 years old. After injections at zero, four and 12 weeks from the start of the study, patients who received the vaccine had a strong antibody response against angiotensin II, which was significantly higher in those receiving the higher dose. Blood pressure changes were evaluated at week 14. Compared with patients who received a placebo, those who were injected with 300ug of vaccine significantly reduced their daytime systolic blood pressure (the top number of a blood pressure reading, measuring pressure as the heart constricts) by 5.6 millimeters of mercury (mm Hg) and their diastolic blood pressure (the bottom number of a blood pressure reading, measuring pressure as the heart rests between beats) by 2.8 mm Hg. Their vaccine had the most striking effect early in the morning, the most dangerous time to have high blood pressure because it raises the risk of heart attack and stroke, (5).
Unlike vaccines generated against bacteria and viruses, a specific target antigen, anti-hypertension vaccine is complicated by the multi-factorial etiology of hypertension. The renin–angiotensin–aldosterone system (RAAS) is probably the most important regulator of systemic blood pressure and believed to be a major factor in hypertension onset. The RAAS cascade begins with the biosynthesis of the glycoprotein enzyme, renin, in the juxtaglomerular cells of the renal afferent arterioles. Renin cleaves angiotensinogen to form the decapeptide angiotensin-I (AngI). AngI is then further cleaved by angiotensin converting enzyme (ACE), a dipeptidyl carboxypeptidase, to produce an octapeptide, angiotensin- II (AngII). AngII can then bind to angiotensin type 1 (AT-1) receptors and type 2 (AT-2) receptors to initiate a myriad of downstream signalling pathways. The effects of the AT-1 receptor include vasoconstriction, aldosterone synthesis and secretion, increased vasopressin secretion, cardiac hypertrophy, augmentation of peripheral noradrenergic activity, vascular smooth muscle cell proliferation, decreased renal blood flow, renal renin inhibition and renal tubular sodium reuptake. AT-2 receptors are more abundant in the fetus and neonate, suggesting a role in embryonic development and a possible vasodilatation effect. ACE inhibitors (captopril, enalapril, benazepril, ramipril and trandolapril), AngII receptor blockers (irbesartan, candesartan, valsartan and losartan) and direct renin inhibitors (aliskiren) have all successfully been used to reduce high blood pressure (6).
Both ACE inhibitors and AngII receptor blockers have been on the market for many years, and there is evidence to support their benefits beyond blood pressure control. In particular, such agents have been demonstrated to improve the ejection fraction in patients with congestive heart failure, to reduce the levels of urine protein in diabetic patients and prevent recurrent strokes. Vaccines targeting renin, AngI, AngII and AT-1 receptors are currently under development, only two of which are inhuman clinical trial phase, PMD3117 (AngI vaccine) and CYT006-AngQb (AngII vaccine). Not all primary hypertension is expected to respond well to RAAS blockage therapy. Low-renin-level hypertension, a sub-group of primary hypertension, comprises nearly 25% of all primary hypertension cases and is found more frequently in blacks and in the elderly. The etiology of increased blood pressure in this group is probably due to a salt-sensitive phenotype. Interestingly, Aliskiren (a direct renin inhibitor) failed to lower blood pressure in patients who have low renin levels (1).
While only 35% of patients are able to achieve adequate control of their blood pressure levels through traditional therapeutic interventions, this proportion can be improved by the use of a long-acting (4 – 6 months) medication. The current renin vaccine is limited by the fact that it can induce autoimmune deposits. . Vaccines against angiotensin I, angiotensin II and angiotensin II type 1 receptor have shown promising results and good short-term safety profiles.
Two main obstacles towards development of novel hypertension vaccinations are:
(1) A need to prove superiority to the current oral RAAS blockade agents.
(2) A need to demonstrate the long-term safety profile (6).
Several classes of medications, collectively referred to as antihypertensive drugs, are currently available for treating hypertension. Reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. The aim of treatment should be reduce blood pressure to <140/90 mmHg for most individuals, and lower for individuals with diabetes or kidney disease (some medical professionals recommend keeping levels below 120/80 mmHg). If the blood pressure goal is not met, a change in treatment should be made as therapeutic inertia is a clear impediment to blood pressure control. Comorbidity also plays a role in determining target blood pressure, with lower BP targets applying to patients with end-organ damage or proteinuria. The first line antihypertensive supported by the best evidence is a low dose thiazides diuretic. Often multiple medications in combined are needed to achieve the goal blood pressure. Commonly used prescription drugs include: ACE inhibitors, alpha blockers, angiotensin II receptor antagonists, beta blockers, calcium channel blockers, diuretics (e.g. hydrochlorothiazide), direct renin inhibitors. Some examples of common combined prescription drug treatments include: A fixed combination of an ACE inhibitor and a calcium channel blocker. One example of this is the combination of perindopril and amlodipine, the efficacy of which has been demonstrated in individuals with glucose intolerance or metabolic syndrome (1).
ffiris pharmaasia is starting a development program for vaccination against hypertension. The vaccine will be based on the company’s own Affitome technology. However, for the first time it is now being used against a human hormone. The reason for this announcement is the approval of significant development funds by the Austrian Research Promotion Agency, FFG. The vaccine is targeting angiotensin II. CSO Dr Frank Mattner states that although chronic hypertension can be treated with drugs, the patient has to be precisely attuned to them and must then take medication constantly which often doesn’t work out. Their vaccine is intended to lower the burden of strictly following this medication dictate, thereby contributing to ensuring lasting success. Taking into account the long term aspect of hypertension leads to the often fatal sequelae such as heart diseases, stroke and kidney problems in the long term, sustainability is key for treatment’s success.
The idea of intervening in the body hormone regulation of blood pressure by means of a vaccine arose in recent years. Dr Walter Schmidt, CEO of Affiris explains that in order to develop a vaccine that can reduce hypertension, it must be able to trigger a highly specific immune response. The blood pressuring – increasing angiotensin II and the blood pressure reducing angiotensin 1-7 differ by only one amino acid, while the remainder of the structure is identical. Their Afitome technology allows us to adjust the immune response such that only angiotensin II is addressed.
Cytos Biotechnology Ltd (SIX:CYTN) Schlieren (Zurich), Switzerland gave an update on the development of its hypertension vaccine CYT006-AngQb. In a first phase IIa study the vaccine was safe, well tolerated and efficacious in lowering the mean ambulatory blood pressure by -9/-4 mmHg (systolic/diastolic) vs. placebo. The immune system generates over time antibody responses of increased affinities by selectively expanding those B-cells which get best access to the antigen through binding via surface bound high affinity antibodies. Those B-cell clones that bind the antigens best are selectively expanded at the expense of those clones that bind them weakly. If too much antigen is delivered too quickly, predominantly weakly binding antibodies may be expanded at the expense of those binding well. This could have happened in their studies second and third. The conclusions drawn from the results of the three studies are that the altered treatment regimen of studies second and third reproducibly lead to qualitatively different antibody responses with a significantly lower affinity than the conventional treatment regimen of study first. Furthermore, antibody affinity, which is of critical importance in cases where small target molecules like angiotensin II (8 aminoacids) are to be neutralized, can potentially be controlled by adjusting like the timing of booster injections. Cytos Biotechnology has therefore decided to continue its R&D program in hypertension. About the hypertension vaccine CYT006-AngQb CYT006-AngQb is a therapeutic vaccine in development for the treatment of hypertension. It is designed to instruct the patient’s immune system to produce an antibody response against angiotensin II. Angiotensin II is a small peptide in the body and part of the rennin angiotensin system (RAS), which is an important regulator of blood pressure. Angiotensin II causes blood vessels to narrow, resulting in increased blood pressure. In a phase IIa study with hypertensive patients, vaccination with CYT006-AngQb has been shown to significantly reduce the mean ambulatory daytime blood pressure by induction of antibodies that bind angiotensin II (The Lancet 2008, 371:821). A particularly strong blood pressure reduction has been observed in the early morning hours – a crucial time of day when adverse cardiovascular events are more likely to occur than during other times of the day. CYT006-AngQb is a first-in-class product candidate in this important indication and represents a completely novel approach to hypertension treatment. Treatment with CYT006-AngQb should allow for convenient dosing schedules and a smooth control of blood pressure due to a sustained antibody response induced by vaccination (4)
Medicine is changing. The revolution in medicine has fundamentally altered our notions of disease etiology and classification, and promises novel therapeutic interventions. Several classes of medications, collectively referred to as antihypertensive drugs, are currently available for treating hypertension. The creation of a vaccine against hypertension promises to eliminate the problems associated with conventional pharmacological agents, including noncompliance with daily dosing schedules, undesirable side effects and drug-drug interactions, and irregular, short-acting and ineffective diurnal blood pressure control.
Chockalingam. The Canadian Journal of Cardiology. 23 (7): 517–519 (2007)
Chockalingam. The Canadian Journal of Cardiology. 24 (6): 441-444 (2008)
Thong Huy Do, et al. Expert Opin. Biol. Ther. 10(7):1077-1087 (2010)
I was born in Kolkata, Qualified Ph.D on 1989 from Calcutta University (Spl. Endocrinology), acquired research experience of more than 22 years with publications of around 29 papers in various national / international journals , acquired teaching experience of more than 15 years, acquired experience of writing biology text book under ISC course which is currently under Cambridge press (Kolkata) for publication. Awarded Sangit Prabhakar and Prayag Sangit Samiti in Indian Classical music. Awarded certificate of appreciation – Celebrations of the centenary of Ramkrishna Mission & of Swamy Vivekananda’s historic return from west in 1897 as well as of 66th foundation day of the pratisthan. Ramakrishna Mission Seva Pratisthan (Kol-India), expressed its participation of my contribution to the success of the seminar in 1997.