Current Pharmaceutical Design, 2012, 18, 1005-1010 1005

Vaccination Against High Blood Pressure

Duncan J. Campbell*

St. Vincent’s Institute of Medical Research and the Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy,
Victoria, Australia

Abstract: Despite the attractiveness of a vaccination strategy for the treatment of high blood pressure, and many decades of research, at-
tempts to translate this strategy to hypertension management have been unsuccessful. Immunization against components of the renin an-
giotensin system offers the prospect of improved long-term control of hypertension because efficacy does not require daily compliance
with oral medication. Moreover, such a strategy may provide therapeutic benefits beyond blood pressure control, such as improved pre-
vention and treatment of heart failure, and cardiovascular, cerebrovascular, and renal disease. However, despite these potential advan-
tages, there are a number of concerns about the safety and efficacy of this approach. Renin immunization demonstrated effective blood
pressure reduction in animal models of hypertension but was accompanied by autoimmune disease of the kidney. Moreover, there are
theoretical arguments that angiotensin immunization may have limited effectiveness and clinical studies confirmed these limitations.
Vaccination against the angiotensin II type 1 receptor is another possible approach but has yet to undergo clinical evaluation. Thus, the
role of vaccination against renin angiotensin system components in hypertension management remains to be established.

Keywords: Angiotensin I, angiotensin II, angiotensin II type 1 receptor, renin, immunization, angiotensin converting enzyme inhibitor, an-
giotensin receptor blocker.

1. HIGH BLOOD PRESSURE

2. RENIN VACCINATION
Hypertension is an increasingly important medical and public
health issue. Its prevalence increases with advancing age, and more Renin vaccination has been almost universally successful as a
than half of people aged 60 to 69 years and approximately three- strategy for reduction of blood pressure in renin-dependent animal
quarters of those aged 70 years and older are hypertensive [1-3]. models of hypertension [18] and in the spontaneously hypertensive
The World Health Organization reports that suboptimal blood pres- rat, a model that does not have elevated renin and angiotensin levels
sure (>115 mmHg systolic blood pressure) is the number one at- [24]. However, one consequence of renin immunization was auto-
tributable risk factor for death throughout the world, being respon- immune disease of the kidney, characterized by anti-renin antibody
sible for 62% of cerebrovascular disease and 49% of ischemic heart deposition in the juxtaglomerular apparatus and progressive intersti-
disease [4]. tial inflammatory injury of the kidney [19].
Inhibitors of the renin angiotensin system play an important 3. VACCINATION AGAINST ANGIOTENSIN PEPTIDES
role in hypertension therapy, particularly for patients with co-
morbidities such as heart failure, high coronary risk, post- In contrast to the hypotensive effects of renin vaccination, most
myocardial infarction, diabetes, and chronic kidney and cerebrovas- previous studies of angiotensin I and angiotensin II vaccination
cular disease [5-13]. Antihypertensive medications that target the failed to show a reduction in blood pressure in animal models, de-
renin angiotensin system include angiotensin converting enzyme spite effective blockade of the pressor responses to intravenous
(ACE) inhibitors which block ACE-mediated conversion of angio- administration of these peptides [17]. Angiotensin vaccination has
tensin I to angiotensin II, angiotensin II type 1 (AT1) receptor been revisited as a strategy for the treatment of hypertension in the
blockers (ARB) which prevent the action of angiotensin II on the hope that new conjugates of angiotensin I and angiotensin II will
AT1 receptor, and renin inhibitors. produce antibodies of sufficient titre and affinity to reduce blood
pressure in patients with hypertension [25-28]. However, as re-
There are many classes of anti-hypertensive therapy in addition viewed by several authors, the proof of concept for angiotensin
to inhibitors of the renin angiotensin system. Yet, despite the avail- vaccination remains to be established [21-23,29,30].
ability of these therapies, only half of people taking these medica-
tions achieve a blood pressure of less than 140/90
mmHg [2,14]. 3.1. Vaccination Against Angiotensin I
One of the major contributors to poor blood pressure control is lack In an attempt to block the renin-angiotensin system with anti-
of patient adherence to treatment [5]. About half of patients who bodies to angiotensin I, Downham et al. [25] coupled the amino-
were prescribed an antihypertensive drug stopped taking it within terminus of angiotensin I to either tetanus toxoid or keyhole limpet
one year [15,16]. There is, therefore, a need for alternative treat- hemocyanin and these conjugates were administered with either
ment strategies that ensure greater adherence to prescribed therapy diethylaminoethyl cellulose or aluminium hydroxide as adjuvant.
and achieve target blood pressure in a greater proportion of indi- Both tetanus toxoid and keyhole limpet hemocyanin conjugates
viduals. Vaccination against components of the renin angiotensin produced antibodies against angiotensin I in male Sprague Dawley
system may be one such strategy, and there have been multiple rats and reduced the pressor response to intravenous administration
attempts, over many decades, to treat hypertension using this strat- of angiotensin I but not to angiotensin II. However, only the key-
egy to inhibit the renin angiotensin system [17-22]. This review is hole limpet hemocyanin conjugate produced antibodies against
an update of my previous review of angiotensin vaccination [23]. angiotensin I in humans. Eight healthy male human volunteers were
immunized with two doses of 50
g conjugate and 8 were injected
with the aluminium hydroxide adjuvant as placebo. All immunized
volunteers produced antibodies to angiotensin I. However, in com-
*Address correspondence to this author at the St. Vincent's Institute of parison with placebo, immunization produced no statistically sig-
Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia;
Tel: 61 3 9288 2480; Fax: 61 3 9416 2676; Email: [email protected]
nificant change in the mean pressor response to intravenous angio-
tensin I administration, although a rightward shift of up to 2-fold in

1873-4286/12 $58.00+.00 © 2012 Bentham Science Publishers

1006 Current Pharmaceutical Design, 2012, Vol. 18, No. 7 Duncan J. Campbell

the angiotensin I dose-response was seen for the volunteer with the expressed in Escherichia coli, that spontaneously assemble into a
highest antibody titre [25]. capsid structure. By coupling the amino-terminus of angiotensin II,
This strategy of angiotensin I vaccination was further investi- the conjugate (CYT006-AngQb) elicited antibodies directed to
gated in a randomized double-blind placebo-controlled study of mainly angiotensin II and angiotensin III, with much lower binding
patients with essential hypertension [26]. Seventeen patients were to angiotensin I and to angiotensinogen.
administered 3 or 4 doses of 100
g angiotensin I-keyhole limpet When spontaneously hypertensive rats were immunized with
hemocyanin conjugate and 10 patients received injections of the 400
g conjugate on days 0, 14, and 28, high antibody titres were
aluminium hydroxide adjuvant as placebo. The primary objective evident on days 21 and 28, accompanied by a reduction in systolic
was to determine whether a sustained antibody titre to angiotensin I blood pressure on days 23 and 30, as assessed by tail cuff plethys-
could be achieved in hypertensive patients. Secondary objectives mography. When spontaneously hypertensive rats were immunized
were to assess the safety and tolerability of the vaccine, and the on days 1, 15, 29, and 43, and blood pressure monitored by teleme-
effects of the vaccine on renin and aldosterone levels and blood try, reduction in systolic blood pressure was first evident on days
pressure. All patients were receiving either ACE inhibitor or ARB 46-47, and then beyond day 57. However, although the reduction in
therapy, and their hypertension was confirmed to be responsive to blood pressure was statistically significant, the blood pressures of
this therapy by measuring the increase in blood pressure that oc- immunized spontaneously hypertensive rats remained above the
curred during a 2-week period of drug withdrawal. They then re- levels of normotensive rats and of spontaneously hypertensive rats
sumed drug therapy and commenced the immunization schedule. At administered the ACE inhibitor enalapril (10 mg/kg) by daily oral
day 50 of this schedule, after 3 or 4 doses of conjugate at 2- to 3- gavage. None of the rats administered CYT006-AngQb developed
week intervals, and 7 days after the last immunization, drug therapy renal pathology when examined 177 days after immunization. The
was withdrawn for a second 2 week period to assess whether im- immunization schedule elicited antibodies of high affinity, with a
munization affected the rise in blood pressure during drug with- dissociation constant (Kd) of ~2.6 nmol/L for angiotensin II, and
drawal, in comparison with the period of drug withdrawal before total binding of angiotensin II was ~300 nmol/L. Total angiotensin
vaccination. Three and four doses of conjugate produced similar II levels (antibody-bound and free) were increased 9-fold (to ~85
and sustained antibody titres and the immunization procedure was pmol/L), indicating occupancy of a very small proportion of anti-
well tolerated, apart from minor skin reactions at the site of immu- body binding sites (<0.03%) by angiotensin II [27].
nization. Angiotensin I antibody titres declined after the last immu- The angiotensin II conjugate was further assessed in hyperten-
nization with a median half-life of 85 days, although antibodies to sive patients in a multicenter, double-blind, randomized, placebo-
keyhole limpet hemocyanin had a much longer half-life. However, controlled phase IIa trial [28]. Seventy two patients with mild-to-
angiotensin I vaccination had no detectable effect on 24 hour ambu- moderate hypertension were withdrawn from antihypertensive ther-
latory blood pressure, either during drug therapy or 2 weeks after apy and randomly assigned to receive subcutaneous injections of
withdrawal of drug therapy [26]. There was, however, indirect evi- either 100
g CYT006AngQb (n=24), 300
g CYT006AngQb
dence of renin angiotensin system blockade by angiotensin I vacci- (n=24), or placebo (n=24) at weeks 0, 4, and 12. The placebo injec-
nation. Angiotensin I vaccination was associated with lower urinary tion was sodium phosphate buffer formulated with the adjuvant
aldosterone excretion during drug therapy. Moreover, renin levels aluminium hydroxide. The primary outcomes were safety and toler-
during withdrawal of drug therapy were higher in immunized pa- ability. Secondary outcomes were changes in renin levels and blood
tients. In addition, there was a statistically significant inverse corre- pressure. All patients receiving CYT006AngQb responded with
lation between the angiotensin I antibody titres and the fall in renin high IgG titres against angiotensin II. The peak titres after the third
levels during withdrawal of drug therapy, suggesting that higher injection were not higher than the peak titres after the second injec-
antibody titres prevented the fall in renin levels during drug with- tion, and the titres after the 100
g dose were ~80% of the titres
drawal by reducing the tonic angiotensin II-mediated negative after the 300
g dose. At week 14, which was 2 weeks after the
feedback inhibition of renin secretion. third immunization, angiotensin II antibodies of 7 high-antibody
Recently, Hong et al. described a new strategy by which spon- responders were of high affinity, with Kd of 1.4 nmol/L. The in-
taneously hypertensive rats were immunized with angiotensin I duced antibody response was reversible, with a half-life of about 4
modified at the C-terminus (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-Sar- months after the third injection.
Leu) to prevent metabolism and cleavage by ACE [31]. The peptide There was a 24% increase in plasma renin levels at week 14 of
was conjugated to bovine serum albumin via its amino-terminus the vaccination protocol in patients immunized with the 300
g, but
and 16-week old male spontaneously hypertensive rats were immu- not the 100
g, dose [28]. Angiotensin II immunization had no
nized at 4-week intervals for 4 immunizations. The first immuniza- effect on office blood pressure. The 100
g dose had no significant
tion was with complete Freund's adjuvant and subsequent immuni- effect on ambulatory blood pressure at week 14, whereas the 300
zations were with incomplete Freund's adjuvant. The immunized
g dose produced a placebo-corrected reduction in mean 24-hour
rats made antibodies that recognized both angiotensins I and II ambulatory blood pressure of 9/4 mmHg (p=0.015 for systolic
conjugated to bovine serum albumin. However, only a modest re- blood pressure and p=0.064 for diastolic blood pressure). Further
duction in blood pressure of approximately 16 mmHg was evident analysis of the 24-hour profile showed the 300
g dose had no ef-
at 16 weeks after the first immunization and the immunized rats fect on night-time blood pressure, and the hypotensive effect was
remained hypertensive. Of particular note, these authors reported mainly due to a reduction in the early-morning surge in blood pres-
renal vasculitis in two of 9 immunized rats examined 28 days after sure [28].
the last immunization, but in none of the 9 non-immunized control
rats [31]. In subsequent studies, more frequent immunizations and higher
doses of vaccine did not reduce blood pressure of patients with
3.2. Vaccination Against Angiotensin II mild-moderate hypertension, despite higher antibody titres, and the
absence of blood pressure reduction was attributed to lower anti-
In an attempt to block the renin-angiotensin system with antibodies
body affinities [32,33].
to angiotensin II, Ambühl et al. [27] conjugated amino-terminally
modified angiotensin II to a virus-like particle. Angiotensin II was When assessing the incidence of adverse events, it is notable
modified with amino acids Cys-Gly-Gly at its amino terminus to that the placebo injection did not contain the virus-like particle. All
permit directional conjugation to the virus-like particle, which was patients experienced adverse events, which were mild in most
derived from the RNA bacteriophage Qß and is a macromolecular cases, due to injection site erythema, induration, oedema, and pain.
assembly of multiple copies of the viral coat protein, recombinantly None of the recipients of placebo therapy withdrew from the study
Vaccination Against High Blood Pressure Current Pharmaceutical Design, 2012, Vol. 18, No. 7 1007

whereas 5 of 48 recipients of active therapy withdrew before study and triiodothyronine are unlikely to influence the normal supply of
end, two for unspecified reasons, one withdrew consent, one be- angiotensin II to its receptors in tissues [23].
cause of syncope after the first injection, and one was withdrawn These arguments against angiotensin II vaccination being able
because of vertigo (in the absence of orthostatic hypotension) and to influence free angiotensin II concentrations in tissue are sup-
unsatisfactory compliance with study rules. Moreover, of the 48 ported by the studies of Ambühl et al. [27]. They reported that
patients who received at least one dose of active therapy, 21% (3 of spontaneously hypertensive rats immunized with CYT006AngQb
24 receiving the 100
g dose and 7 of 24 receiving the 300
g produced antibodies with a dissociation constant (Kd) of ~2.6
dose) experienced symptoms compatible with a systemic reaction to nmol/L for angiotensin II and total binding of angiotensin II of
the vaccine, with influenza-like illness, rigors, raised body tempera- ~300 nmol/L, in association with a 9-fold increase in plasma levels
ture, or pyrexia, occurring within hours of dosing and resolving of total (bound plus free) angiotensin II. As noted by the authors
within 1-2 days after injection. Other adverse effects specific for the [27], by the law of mass action, this concentration of antibody was
active therapy included injection site pruritus and toothache. No predicted to bind 96–99% of angiotensin II in plasma and 85–97%
unintended abnormalities of the immune system were observed. of angiotensin II in tissues, assuming steady-state antibody levels in
the interstitial fluid are 3.5-fold lower than in plasma [35]. Thus,
3.3. Do Antibodies and Binding Proteins Necessarily Reduce
the 9-fold increase in total angiotensin II levels observed by Am-
Free Hormone Concentrations?
bühl et al. [27] may return free angiotensin II levels in interstitial
The angiotensin vaccination strategy to treat hypertension and fluid to the levels that existed before immunization.
other cardiovascular diseases is based on the premise that angio-
Nevertheless, although angiotensin vaccination may have little
tensin antibodies reduce free angiotensin II concentrations in the
effect on long-term blood pressure, it may buffer changes in blood
vicinity of angiotensin II receptors, and thereby reduce angiotensin
pressure. As previously discussed [23], an important role of binding
II receptor activity. We do not know whether angiotensin vaccina-
proteins is to buffer short-term changes in free hormone concentra-
tion had this effect in the studies reported so far. Angiotensin I for-
tion, such as those due to oscillations in hormone release. It is
mation and its conversion to angiotensin II occur primarily at tissue
therefore likely that angiotensin antibodies will similarly buffer
sites, in proximity to angiotensin II receptors [34], and there are
oscillations in free angiotensin concentrations. For example, buffer-
many challenges to the delivery of antibodies of sufficient titre and
ing the rise in free angiotensin concentrations may attenuate the
affinity to reduce free angiotensin II concentrations at these tissue
pressor response to intravenous administration of angiotensin.
sites. One challenge is that steady-state antibody levels in intersti-
Moreover, angiotensin II antibodies may buffer the increase in free
tial fluid are about one-third that of plasma levels [35].
angiotensin II concentrations on assuming the upright posture in the
The strategy to reduce free angiotensin peptide levels by angio- morning, thereby attenuating the early-morning surge in blood pres-
tensin vaccination is different from other vaccination strategies in sure, as observed by Tissot et al. [28]. Conversely, antibody-bound
one important aspect, in that the renin angiotensin system ensures a angiotensin will operate as a reservoir of angiotensin that may be
continuous supply of angiotensin peptides. A normal plasma renin released when free angiotensin concentrations fall. For example,
activity of 1.5 nmol angiotensin I/L per hour will produce 36 antibody-bound angiotensin II may buffer the fall in free angio-
nmol/L angiotensin I per day. Not all of this angiotensin I will be tensin II concentrations that accompany the recumbent posture
converted to angiotensin II, but angiotensin II production in vivo is when individuals go to bed, and thereby explain the failure of an-
probably much higher than this estimate because tissues, and not giotensin II immunization to reduce night-time blood pressure in
plasma, are the major sites of angiotensin I and II production [36]. the study of Tissot et al. [28].
Moreover, renin levels and angiotensin production may increase by
10- to 100-fold in response to ARB and renin inhibitor therapies 3.4. Renin Response to Angiotensin Vaccination
[37,38]. Whereas angiotensin peptides are normally rapidly cleared Renin secretion is subject to tonic negative feedback inhibition
with a half-life of less than 60 seconds [39], binding to antibodies by angiotensin II, and the reactive increase in renin levels in re-
protects them from clearance. Thus, the reactive renin response to sponse to inhibitors of the renin angiotensin system provides an
immunization against angiotensin, and the associated increase in indirect measure of inhibition of the system. In contrast to the
angiotensin peptide formation, may cause antibody binding sites to marked increase in renin levels produced by ACE inhibitor or ARB
be occupied by angiotensin, and thereby prevent reduction in free therapies [37,38], angiotensin immunization produced only a 24%
angiotensin concentrations [23]. increase in plasma renin levels at week 14 of the vaccination proto-
There are many examples of plasma binding proteins for circu- col in hypertensive patients [28], which suggests only a modest
lating hormones. These include binding proteins for thyroxine, reduction in free angiotensin II concentrations. Higher renin levels
cortisol, vitamin D, and sex steroids. For each hormone and its may have occurred during the earlier stages of the vaccination pro-
binding proteins, equilibrium exists between free and bound hor- tocol when net uptake of angiotensin II by antibody binding sites
mone. For example, thyroxine-binding globulin (TBG) binds thy- was occurring. Tissot et al. [28] speculated that the modest increase
roxine with a Kd of ~0.1 nmol/L and triiodothyronine with a Kd of in renin response to angiotensin vaccination was due to the slow
~1 nmol/L [40]; free thyroxine and triiodothyronine concentrations accumulation of angiotensin II antibodies, with a corresponding
are 10-25 pmol/L and 3-8 pmol/L, respectively [41]. Normal slow effect on free angiotensin II concentrations, in contrast to the
plasma TBG concentrations have a capacity to bind ~260 nmol/L abrupt effects of ACE inhibitor or ARB therapies. This speculation
thyroxine and are ~one third occupied by hormone [40]. Thus, the is based on the assumption that blockade of the renin angiotensin
nanomolar Kd of triiodothyronine for TBG is similar to, and the Kd system by angiotensin II vaccination was comparable to that pro-
of thyroxine is much lower than, the reported Kd of angiotensin II duced by ACE inhibitor and ARB therapies; however, this assump-
for its antibodies of ~1.4 nmol/L in the study of Tissot et al. [28]. tion is not supported by the much smaller reduction in blood pres-
Moreover, the plasma concentrations of thyroxine and triiodothy- sure with angiotensin II vaccination than observed with ACE in-
ronine are similar to the plasma concentration of angiotensin II. hibitor or ARB therapy [42-44].
Thus, the relationship between TBG, thyroxine, and triiodothy-
ronine is similar to that between angiotensin II and its antibodies. 4. IMMUNIZATION AGAINST THE AT1 RECEPTOR
Most importantly, inherited abnormalities of TBG, including its Zhu et al. [45] immunized spontaneously hypertension rats with
absence, do not affect the normal supply of thyroid hormone to the peptide Ala-Phe-His-Tyr-Glu-Ser-Arg (ATR12181) coupled
tissues [40]. By analogy, one could predict that angiotensin II anti- with glutaraldehyde to tetanus toxoid. ATR12181 corresponds to
bodies of similar capacity and affinity to that of TBG for thyroxine amino acids 181-187 of the second extracellular loop of the rat
1008 Current Pharmaceutical Design, 2012, Vol. 18, No. 7 Duncan J. Campbell

AT1A receptor. The first immunization was administered with Immunization with a hormone may result in the production of
complete Freund's adjuvant and subsequent immunizations were not only antibodies that recognize the hormone but also anti-
administered with incomplete Freund's adjuvant. The rats received idiotype antibodies. These anti-idiotype antibodies may recognize
their first immunization at 6 weeks of age and immunizations were not only the binding site of the hormone-binding antibodies but also
repeated at 4, 8, 12, 16, 24, 32, 40, and 52 weeks. Pathological ex- the receptor for the hormone [49]. For example, when type 2 dia-
amination was performed 64 weeks after the first immunization. betic patients are treated with insulin, half of those who develop
Immunization produced antibody titres approaching 1/10,000. Im- insulin antibodies also develop antibodies to the insulin receptor
munized rats had approximately 20 mmHg lower blood pressure [50]. Given that anti-idiotype antibodies to angiotensin II antibodies
than control rats that were not immunized, but they remained hyper- bind to angiotensin II receptors [51], it is possible that long term
tensive. Surprisingly, the immunized rats had markedly higher body angiotensin II vaccination of individuals with hypertension may
weights than non-immunized rats at 64 weeks (538 g vs. 383 g). lead to anti-idiotype antibodies that bind to the angiotensin II recep-
However, immunized rats had lower heart weights and heart tor.
weight/body weight ratios than non-immunized rats. In addition, the Anti-idiotype antibodies resulting from angiotensin II vaccina-
immunized rats had reduced myocardial fibrosis and attenuated tion may both attenuate and accentuate blood pressure reduction,
renal fibrosis and glomerular damage and there were no signs of and have other consequences. By binding to the angiotensin II anti-
immune injury of the kidney of immunized rats [45]. There are, as body they may prevent the binding of angiotensin II to the antibod-
yet, no reports of clinical studies examining the effectiveness of ies, thereby attenuating any reduction in blood pressure due to
immunization against the AT1 receptor. lower free angiotensin II concentrations. Conversely, anti-idiotype
antibodies may bind to the angiotensin II receptor and prevent the
5. CONCERNS ABOUT THE SAFETY AND EFFICACY OF
binding of angiotensin II, thereby amplifying the hypotensive ef-
VACCINATION AGAINST COMPONENTS OF THE RENIN
fects of angiotensin II vaccination. However, anti-idiotype antibod-
ANGIOTENSIN SYSTEM
ies that bind to receptors may also stimulate the receptor. Agonistic
There are a number of concerns about the safety and efficacy of AT1 receptor antibodies are implicated in the pathogenesis of pre-
vaccination against components of the renin angiotensin system eclampsia [52] and renal allograft rejection [53]. Moreover, binding
(Table 1). Given the severe autoimmune renal disease that accom- of anti-idiotype antibodies to angiotensin II receptors may produce
panied renin vaccination [19], there has been concern about the autoimmune disease. Thus, the vasculitis in the kidney observed in
long-term safety of angiotensin vaccination for treatment of hyper- spontaneously hypertensive rats immunized against C-terminal-
tension, and questioning of the justification for such an approach modified angiotensin I may represent the effects of anti-idiotype
[19,20,46-48]. Moreover, as mentioned above, Hong et al. reported antibodies because the rats generated antibodies to both angiotens-
vasculitis in the kidney of two of 9 spontaneously hypertensive rats ins I and II [31]. However, in contrast to the effects of renin and
examined 28 days after the last immunization with C-terminal- angiotensin vaccination, the one reported study of immunization
modified angiotensin I conjugated to bovine serum albumin [31]. against the AT1 receptor did not detect any evidence of autoim-
Table 1. Concerns about Safety and Efficacy of Vaccination. mune disease [45].
Another concern about the safety and efficacy of angiotensin
vaccination is the possibility of release of angiotensin from antibod-
Difficulty obtaining sufficient antibody titre and affinity to produce
ies under conditions of low “free”” angiotensin concentration, lead-
effective renin angiotensin system blockade
ing to stimulation of angiotensin II receptors.
Local and systemic side effects of vaccination, including skin reactions, There are important safety concerns about the delayed reversi-
influenza-like illness, and rigors bility of renin angiotensin system blockade by immunization strate-
gies, particularly during disturbances of volume and electrolyte
Autoimmune disease produced by antibodies to the ligand that may homeostasis where an active renin angiotensin system contributes
produce immune complex disease to survival [48]. It may, however, be argued that a similar concern
applies to ACE inhibitor and ARB therapies in acute medical emer-
Autoimmune disease produced by anti-idiotype antibodies (in response gencies when the effects of these therapies may take up to 24 hours
to angiotensin vaccination) that bind to the angiotensin II receptor to decay. Another safety concern is that angiotensin vaccination
may exacerbate postural hypotension by inhibiting the early morn-
Anti-idiotype antibodies (in response to angiotensin vaccination) that ing surge in blood pressure in elderly patients with both hyperten-
bind to the antibody, thereby preventing binding of angiotensin to the sion and autonomic insufficiency. Moreover, as indicated by the
antibody, and/or activating the angiotensin II receptor results of Tissot et al. [28], we can expect a wide variation between
patients in their antibody response (both titre and affinity) to vacci-
Release of angiotensin from the antibody under conditions of low “free” nation and a wide variation in the renin response [54], which will
angiotensin concentration, leading to stimulation of angiotensin II re- impact on the efficacy of blood pressure reduction by this strategy.
ceptors There are also uncertainties about how a vaccination strategy
should be monitored, and it will be much more difficult to titrate a
Wide variation between patients in their antibody response (both titre vaccination strategy than oral therapy for hypertension.
and affinity) and their renin response to vaccination
These safety concerns need to be balanced against possible
Delayed reversibility of renin angiotensin system blockade by vaccina- advantages of vaccination strategies that inhibit the renin angio-
tion, particularly during episodes of hypovolemia tensin system. More than two-thirds of hypertensive individuals
cannot be controlled with one drug and require two or more anti-
Exacerbation of postural hypotension hypertensive agents [5]. Thus, if vaccination were to successfully
lower blood pressure, it may be possible to reserve this therapy for
Difficulty monitoring extent of renin angiotensin system blockade by those patients for whom renin angiotensin system inhibition was
vaccination only one part of multimodal therapy. A particular group of patients
who may benefit from such a strategy are those with resistant hy-
Difficulty titrating renin angiotensin system blockade by vaccination pertension [55]. Moreover, a vaccination strategy aimed against the
renin angiotensin system offers the prospect of therapeutic benefits
beyond blood pressure control, such as improved prevention and
Vaccination Against High Blood Pressure Current Pharmaceutical Design, 2012, Vol. 18, No. 7 1009

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Joint National Committee on Prevention, Detection, Evaluation,
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tions, but the antibody response was not sufficient to produce the left ventricular ejection fractions. New England Journal of
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[10] Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan
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Received: October 28, 2011 Accepted: December 15, 2011