Chin Med J 2009;122(1):106-109 106

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Angiotensin II vaccine promising for patients with chronic
heart failure

CHEN Yang-xin, YAO You-jie, NIE Ru-qiong, ZHOU Shu-xian and WANG Jing-feng

Keywords: angiotensin II vaccine; chronic heart failure

hronic heart failure (CHF), as the end-stage
presentation of all kinds of heart diseases, is a major
public health problem as well as a pressing public policy
issue. There are more than 5 million patients diagnosed
with CHF in USA alone and approximately 550 000 new
cases appear per year. About 0.4%2% of the European
population is affected by symptomatic heart failure.
Hence heart failure is the leading cause of hospitalization
especially in older people around the world.

Primary hypertension, the main risk factor of CHF and
coronary artery disease (CAD), is a multifactorial and
probably polygenic disease. The rennin-angiotensin-
aldosterone system (RAAS) is thought to be the single
most important regulator, but in fact, this system also
plays a pivotal role in the development of CHF. The
binding of angiotensin II (Ang II) to its receptor, the
angiotensin receptor subtype 1 (AT1R), leads to all kinds
of effects including vasoconstriction and aldosterone
secretion, thus resulting in myocardial remodeling and
accelerating the development of heart failure. Many
studies have shown that the overactive RAAS
participated in the myocardial remodeling and influenced
the prognosis of CHF. Interruption of the RAAS pathway
either by angiotensin converting enzyme inhibitor (ACEI)
or Ang II type 1 receptor blocker (ARB) or aldosterone
receptor antagonists has been highly successful to
improve symptom and long-term prognosis of patients
with CHF, as demonstrated by many evidences from
randomized controlled multi-center clinical trials.

Despite the availability of these efficacious agents, the
treatment of CHF is still limited by many factors, for
instance, long-term and even lifelong drug intake
contributes to the decline of compliance from patients. If
a drug can antagonize the overactive RAAS, it may be
promising to improve the prognosis by increasing the
compliance. Ambhl et al
1
used an immunological
approach to induce auto-antibodies against endogenous
Ang II by conjugating antigens to the surface of highly
repetitive structure of virus-like particles (VLPs) and
injecting it into the body, in which the VLP is also called
as Ang II vaccine. The emerging data have showed that
the high affinity and concentration of antibodies lead to a
significant blockade of the RAAS, a decrease in blood
pressure, and a consequent increase in total Ang II
(antibody-bound and free). But the amount of antibodies
is enough to alleviate the increase in Ang II and obtain
expected effects. Besides, the vaccine is safe and
effective except for some mild reversible side-effects
such as erythema, oedema, mild pain and induration at
the injection site. Recently, the phase IIa study has shown
that immunization with CYT006-AngQb (the vaccine
based on the aforementioned VLP) is not associated with
serious adverse events but most of the events are
consistent with local or systemic responses similar to
those of other vaccines.
2
Active immunization with
angiotensin peptide analogue vaccines selectively is
found to reduce the effects of exogenous angiotensin in
some other studies.
3-5


THE RAAS IN THE DEVELOPMENT OF
CARDIAC REMODELING AND CHF

Before the 1980s, the pathogenesis of heart failure was
deemed to mainly arise from the abnormality of
hemodynamics, but some phenomena and research results
could not be well explained only by the abnormality of
hemodynamics, because even it is well improved by
cardiotonic agents, diuretics or ordinary vasodilating
agents, the long-term prognosis has not been improved
and even worse in some patients treated with cardiotonic
agents. Some studies have showed that the activation of
neurohormone has direct toxic effect on the myocardium
or accelerates the development of heart failure. After the
1990s, it has been confirmed that cardiac remodeling is
the basic pathogenesis of CHF. Therefore preventing the
progression of CHF by slowing or reversing the
remodeling process to reduce morbidity and mortality
should be a target for therapy except for improving
symptoms by traditional treatment.

Cardiac remodeling may be defined as genome
expression, molecular, cellular and interstitial changes
that are manifested clinically as changes in size, shape
and function of the heart after cardiac injury. Although
several factors such as wall stress, volume or pressure
overload load, neurohormonal activation, and ischemia
C
DOI:10.3760/cma.j.issn.0366-6999.2009.01.020
Department of Cardiology, Second Affiliated Hospital of Sun
Yat-sen University, Guangzhou, Guangdong 510120, China (Chen
YX, Yao YJ, Nie RQ, Zhou SX and WANG JF)
Correspondence to: Dr. WANG Jing-feng, Department of
Cardiology, Second Affiliated Hospital of Sun Yat-sen University,
Guangzhou, Guangdong 510120, China (Tel: 86-20-81332475.
Fax: 86-20-81332853. Email: dr_wjf@163.com)
Chinese Medical Journal 2009; 122(1):106-109 107
can accelerate the process of cardiac remodeling, there is
substantial evidence that the activation of endogenous
neurohormonal systems plays an important role in cardiac
remodeling and thereby in the progression of HF, and that
the RAAS appears to be one of the most significant
factors.
6
Ang II, the principal effector peptide of the
RAAS with the potent effect of vasoconstriction and
stimulating secretion of aldosterone from the adrenal
gland, has far-reaching effects on myocardial structure,
growth and fibrosis, and it is a key regulator of vascular
and myocardial remodeling.
7-9
Patients with CHF have
elevated circulating or tissue levels of rennin, Ang II,
aldosterone, and cytokines, which can act (alone or in
concert) to adversely affect the structure and function of
the heart. These neurohormonal factors not only increase
the hemodynamic stress on the ventricle by causing
sodium retention and peripheral vasoconstriction but also
exert direct toxic effects on cardiac cells and stimulate
myocardial fibrosis, thus altering the architecture of the
failing heart and impairing its performance.

BACKGROUND OF VACCINE AGAINST
THE RASS

There have been more than 200 years since cowpox
vaccine was used by Edward Jenner, a doctor of England,
to prevent cowpox. Since there is still no universally
effective drug to kill virus at present, vaccine has been
used in fighting against viral diseases. In fact, some
scientists have been interested in therapeutic vaccines for
some non-viral diseases for a long time.
10-15
Various
attempts have been made to lower BP with vaccine by
intervening in the RASS. After the earliest attempts made
by Goldblatt et al
16
to actively immunize against renin
lowered BP, a series publications reported the effect of
active immunization.
17-19
Unfortunately, anti-renin
antibody deposition was found in the juxtaglomerular
apparatus with progressive interstitial inflammatory
injury of the kidney.
19,20
Afterwards, progress in this field
was slow because of severe autoimmune disease of the
kidney found in many studies. But the progress is never
to stop, and attention has been focused on production of
antibodies, by active immunization, against downstream
effector molecules of renin such as Ang I vaccine or Ang
II vaccine. For example, Gardiner et al
21
actively
immunized rats with angiotensin I peptide analogue
vaccines. They successfully measured high-titer specific
antibody and found depressed responses to exogenous
angiotensin I. Moreover, lowered serum levels of rennin
and aldosterone were observed, whereas responses to
exogenous angiotensin II were not observed. These
findings indicated that active immunization against AI
might be useful to treat cardiovascular disorders
involving the renin-angiotensin system. Brown et al
22
also
actively immunized hypertensive patients by injecting
angiotensin I vaccine, and they found that vaccination
significantly blunted the fall in plasma renin following
withdrawal of ACEI or ARB but did not influence blood
pressure. They thought it was due to the lower titres.
Researchers
23
from China designed three oligopeptides of
AT1R which was used to immunize spontaneously
hypertensive rats (SHR). After immunization of SHR
with different oligopeptides including ATR112185,
ATR10014 and ATR12181, antibodies were measured in
each group, and depressor responses were observed in the
ATR12181 group. The above mentioned studies showed a
new direction of study to intervene in the RASS and
control hypertension. A recent study
1
used a kind of
virus-like particle, coupled with an Ang II peptide to
provoke an immune response against Ang II. In this study
the vaccine exhibited a pronounced BP-lowering effect in
the early morning and it was well tolerated. Most adverse
events were mild and were related to local injection site
reactions, and there were no serious treatment-related
adverse events.

SYNTHESES AND USE OF ANG II VACCINE

As reported,
1
Ang II was modified with amino acids CGG
at its N-terminus to permit directional conjugation to
VLPs. The peptide was synthesized by solid phase
chemistry, and VLPs derived from the RNA
bacteriophages Q. The VLPs were macromolecular
assemblies formed from 180 copies of their respective
coat protein monomer, which spontaneously assembled
into a capsid structure, and then the VLPs were
recombinantly expressed in Escherichia coli, purified,
and covalently coupled to the target antigen. Conjugation
of the peptide to VLPs was verified by lithium
dodecylsulphate-polyacrylamide gel electrophoresis
under reduced conditions. Thus the peptide was coupled
at a high density to the Q VLP and vaccine was prepared.
The vaccine for clinical trial was injected subcutaneously.

EFFECT OF ANG II VACCINE ON CHF

As mentioned above, Ang II, the most significant effector
peptide in the RAAS, plays a key role in cardiac
remodeling and development of CHF. ACEI and ARB act
on the process of angiotensin I converting into Ang II and
Ang II binding to AT1R respectively, which block the
forming of Ang II and disturb its pathophysiological
function to decrease hypertension and slow or reverse the
cardiac remodeling process. Both ACEI and ARB play an
important role in improving the long-term prognosis of
patients with CHF. Ang II vaccine is produced by an
immunological approach and injected into the body to
induce auto-antibodies. Once the antibodies are formed
and reach a titer, Ang II will be combined and lose its
pathophysiological function including contribution to
cardiac and vascular remodeling by activating the signal
transduction pathways that promote cell growth,
inflammation and fibrosis and increasing the expression
of chemokines and cytokines, which participate in cell
growth by stimulating hyperplasia, hypertrophy and
apoptosis.
24
In addition, aldosterone, the downstream
bioactive peptide of RAAS secreted by adrenal glands but
regulated by Ang II, will be decreased because Ang II is
Chin Med J 2009;122(1):106-109 108
sealed and loses its effects. Aldosterone is known to
impair endothelium-related vasodilatation and contributes
to inflammation and vascular and cardiac remodeling.
25
Chronic elevation of aldosterone is also associated with
left ventricular (LV) remodeling and increased incidence
of adverse cardiovascular events.
26
It is an important
mediator in the pathogenesis of heart failure, and high
serum levels of circulating aldosterone are an indicator of
poor prognosis in patients with HF, ie the adverse effects
of aldosterone on patients with CHF also can be
improved by the vaccine. Therefore, Ang II vaccine may
slow or reverse cardiac remodeling and improve
long-term prognosis by blocking the adverse effects of
Ang II and aldosterone mentioned above.

POTENTIAL PROBLEMS IN APPLICATION OF
ANG II VACCINE

Medicine is a special field involving the life of the human
being. We can never overemphasize the safety of drugs.
But how many of us remember Jesse Gelsinger, who died
following a retrovirus injection to treat a relatively benign
hepatic condition?
27
And how many of us still think about
Ellen Roche, who died during pulmonary investigation
after a series of minor errors?
28
The Ang II vaccine was
demonstrated to be effective and safe in the study
mentioned above, but the longest period of clinical
observation was only 16 weeks, and it was limited. It is
unknown how about the long-term safety and tolerability
of the vaccine. Besides, it is also unknown how many
titers of the anti-angiotensin II antibody should be
appropriate. After all, Ang II is an endosomatic bioactive
peptide and possesses important physiological activities,
so extremely decreased level of Ang II might be unfit.

CONCLUSIONS

At present, many effective therapies, drug or non-drug,
have been used to improve life quality and long-term
prognosis in patients with CHF. But pharmacotherapy is
still the essential method for these patients. Although
existing drugs including ACEI, ARB, aldosterone
receptor antagonists, blocker and others can improve
the prognosis of patients with CHF, a few of patients may
forget to take pills or be unwilling to take every day for
the rest of their lives. Thus the compliance may be
influenced. Ang II vaccine is superior to existing drugs in
blocking the RAAS. For example, it can be conveniently
used only by injection once a month. Accordingly, this
vaccine is promising in the treatment of CHF. Certainly,
its long-term safety, tolerability and effect should be
monitored.

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(Received May 20, 2008)
Edited by QIAN Shou-chu and WANG Mou-yue