Effectiveness and Safety of a Therapeutic Vaccine Against Angiotensin II Receptor Type 1 in Hypertensive Animals

Abstract

H ypertension has become a leading disease in both developed (333 million) and undeveloped (639 million) countries. 1 The prevalence of hypertension is expected to increase to 29.2% in 2025 (29% of men and 29.5% of women).1 It is a complex disease caused by multiple factors, 1 of which is the renin-angiotensin system (RAS), which plays a critical role in the development and maintenance of blood pressure. Chemical drugs targeting RAS, including renin inhibitor, angiotensin convert enzyme inhibitor, and angiotensin II (Ang II) receptor blocker (ARB), have exhibited excellent therapeutic effects in clinical practice. Nevertheless, the control rate of blood pressure is still far from being satisfactory worldwide, and the treatment compliance is quite low. 1To address the compliance issue and improve therapeutic outcomes for patients, it is necessary to develop novel methods for hypertension treatment. Vaccines can elicit specific antibodies against hypertension related target molecules, providing a possible avenue toward accomplishing this goal. 2-4One potential target is the Ang II type 1 receptor (AT 1 R), a G protein coupling receptor, which has a second extracellular loop (ECL2) that plays an important role in activation of the receptor. 5 The 181 Ala and 183 His residues in the ECL2 are 2 possible binding sites of Ang II with AT 1 R. 5,6 In our previous work, we demonstrated that an epitope from the rat AT 1 R, designated as ATR12181, can decrease the systolic blood pressure (SBP) of spontaneously hypertensive rats (SHRs) and provide excellent protective effects in target organs. 7Following our work, another study team emphasized vaccination against AT 1 R for the prevention of l-NAME-induced nephropathy. 8 Here, a linear epitope ATR-001, derived from the ECL2 of human AT 1 R including 181 Ala and 183 His, was designed. To improve the low immunogenicity of ATR-001, it was conjugated with a virus-like particle (VLP) carrier protein, whose remarkable feature is the highly repetitive and ordered surface structure and have been used in the treatment of several chronic diseases. 9,10Abstract-Primary hypertension is a chronic disease with high morbidity, and the rate of controlled blood pressure is far from satisfactory, worldwide. Vaccination provides a promising approach for treatment of hypertension and improvement in compliance. Here, the ATRQβ-001 vaccine, a peptide (ATR-001) derived from human angiotensin II (Ang II)

New Approaches in the Treatment of Hypertension

“…Ongoing phase II trials in patients with mild-to-moderate hypertension are exploring these issues. 122 Preclinical studies are evaluating in hypertensive rodent models the safety and efficacy of vaccines against various peptide sequences within the Ang II type 1 receptor, ATRQB-001 and ATR12181, 123,124 against Ang II conjugated via the N-terminus to keyhole limpet hemocyanin 125 and against a chimeric protein (pHAV-4 Ang IIs) that presents 4 successive repeated Ang II sequences as the functional epitope on the surface of the hepatitis A virus-like particle 126 ( Figure 2; Table). In all cases, significant BP reductions were achieved, keeping alive the concept that vaccine therapy might be useful in the treatment of human hypertension and its complications.…”

Angiotensin II Peptide Vaccine Protects Ischemic Brain Through Reducing Oxidative Stress

“…Although vaccines have traditionally been used to prevent infectious diseases, their therapeutical use has been recently expanded against the adult common diseases, such as hypertension, 11 Alzheimer's disease, [12][13][14] and so on, by targeting self-antigens. Immunization is a cost-effective intervention compared with conventional therapy owing to its long-lasting effects and does not require daily intake of medication.…”

Therapeutic vaccine against DPP4 improves glucose metabolism in mice

“…Vaccines are a common method for the prevention of infectious diseases, and they have been recently expanded to treat chronic diseases, such as hypertension and Alzheimer's disease, by targeting self-antigens (13)(14)(15)(16). Immunization may provide a low-cost alternative to conventional therapy due to vaccines' relatively long-lasting effects and lack of daily dosage requirements (17,18).…”