Hypertension is a common noncommunicable condition estimated to affect over one billion adults worldwide, with a prevalence that has doubled over the past 20 years [1]. From 2012 to 2013 in the United States, the economic burden of hypertension was estimated to be 50 billion dollars annually [2]. The benefits of optimal blood pressure (BP) control have been proposed, with a 10 mmHg reduction in systolic BP leading to a 13% reduction in all-cause mortality [3]. However, the BP of a substantial proportion of the hypertensive population remains uncontrolled partially due to low drug adherence. Thus, there is still a need for novel therapeutic options to control BP optimally.

As a form of immunotherapy for hypertension, therapeutic vaccines have been proposed and have been researched in animal models for almost 50 years [4]. Most vaccines for hypertension target the renin-angiotensin system [5,6,7,8,9,10,11,12,13,14,15,16]. In a preclinical study, an angiotensin I vaccine (PMD3117) reduced blood pressure in hypertensive rat models [5], and an angiotensin II vaccine (AngQb-Cyt006) was reported to be effective in producing anti-angiotensin II antibodies in rodents [6]. In addition, therapeutic vaccines for renin and angiotensin II type 1 receptor were also shown to be effective in a hypertensive rat model [7, 8]. Based on these preclinical results, a clinical trial of angiotensin I and II vaccines was conducted. The administration of an angiotensin I vaccine (PMD3117) significantly increased the anti-angiotensin I antibody titer in a phase clinical trial but did not reduce BP [9]. The administration of an angiotensin II vaccine (AngQb-Cyt006) significantly increased anti-angiotensin II antibody titers [6, 10], but BP was significantly decreased only in the high-dose group. This study was the first to report a successful reduction in BP using vaccine therapy; however, further clinical studies of AngQb-Cyt006 failed to reproduce the reduction in BP [11]. We also started to evaluate the efficacy of an angiotensin II vaccine in an animal model [12, 13]. The administration of an angiotensin II vaccine resulted in not only BP reduction but also organ-protective effects, and angiotensin II-induced perivascular fibrosis in the heart was significantly attenuated in immunized mice and rats [12, 13]. Moreover, an angiotensin II vaccine was effective in preventing heart failure in a rat model of myocardial infarction established through permanent left anterior descending artery ligation [14] and in preventing cerebral infarction after middle cerebral artery occlusion in rats [15]. We conducted a placebo-controlled dose escalation study to investigate the safety, tolerability, and immunological responses of this angiotensin II vaccine (AGMG0201). AGMG0201 was administered to twelve participants in the low-dose and high-dose groups. The subjects were randomly assigned to receive either the active study drug or a placebo. Each participant received a single intramuscular injection, followed by a second injection 30 days later, and was monitored for 360 days after the second dose. The results showed that most treatment-related adverse events were pain and erythema at the injection site, which were classified as mild or moderate in severity, indicating that AGMG0201 was well tolerated. Anti-angiotensin II antibodies were observed in AGMG0201 patients, especially in the high-dose group [16]. In the next clinical trial, the effect of the vaccine on BP reduction should be evaluated.

Although vaccines for the renin-angiotensin system are still in clinical trials, vaccines for another target have been proposed to treat hypertension. Calcium channel blockade is a common drug mechanism for treating hypertension, and vaccines for the L-type calcium channel have already been reported for the treatment of hypertension in hypertensive rats [17]. In the design of this peptide vaccine, an antigen was selected from the epitope of the third extracellular region of domain IV of the human L-type calcium channel [18, 19], and after four injections of the calcium channel vaccine, systolic BP was significantly decreased in hypertensive rats. Recently, Ke et al. proposed a novel therapeutic vaccine, named ABRβQ-006, which targets the β1-adrenergic receptor [20]. In the rat hypertension model, ABRβQ-006 lowered systolic blood pressure (approximately 10 mmHg) and attenuated vascular remodeling, myocardial hypertrophy and perivascular fibrosis. In the myocardial infarction model, ABRβQ-006 effectively improved cardiac remodeling and reduced cardiac fibrosis and inflammatory infiltration. The vaccine targeting the β1-adrenaergic receptor showed effects on hypertension and heart rate control, leading to the attenuation of myocardial remodeling and the protection of cardiac function. Looking toward clinical application, a combination of these vaccines is expected in the future. Multivalent vaccines are commonly used for the prevention of infectious diseases. Interestingly, a bivalent vaccine against the renin-angiotensin system and calcium channel has been reported to decrease BP in hypertensive rats [17]. Although an efficient method to induce antibodies for multiple antigens without bias will be needed for this type of bivalent vaccine, the efficient treatment of hypertension with a combination of multivalent vaccines could be realized in the future.

An attractive option is targeting angiotensinogen with RNA-based therapeutics, which bind to RNA and change the expression of any protein [21, 22]. Antisense oligonucleotides consist of a single-stranded DNA containing 15–30 nucleotides and inhibit RNA translation by binding the target mRNA. In contrast, RNA interfering (RNAi)-based therapies utilize double-stranded RNA and interfere with mRNA expression. The majority of RNAi-based therapies employ noncoding small interfering RNAs (siRNAs) 21–23 bases in length. At present, the use of siRNAs is a novel therapeutic strategy; for example, inclisiran evolved from use in the treatment of rare genetic disorders to the treatment of familial hypercholesterolemia and then to the treatment of common diseases such as primary dyslipidemia [23]. In terms of progression in drug delivery systems, N-acetylgalactosamine (GalNAc)-conjugated chemically modified siRNA specifically targets the proprotein convertase subtilsin/kexin type 9 (PCSK9) mRNA in the liver because GalNAc binds to the asialoglycoprotein receptor that is highly expressed on hepatocytes, resulting in rapid endocytosis [24]. Indeed, this approach has been employed to enhance siRNA delivery to hepatocytes by more than 10-fold in a preclinical model. Similarly, siRNA for angiotensinogen has been developed for the treatment of hypertension [25]. Angiotensinogen is the sole precursor of angiotensin I or II, and it is a promising target for gene silencing. The deletion of angiotensinogen will suppress angiotensin I or II formation without renin angiotensin system escape phenomena, which includes the counterregulatory rise in plasma. Thus, the deletion of angiotensinogen might result in a major advantage of more effective renin angiotensin system inhibition and stable BP control. An siRNA for angiotensinogen is currently being tested in clinical trial for the treatment of hypertension. However, these therapies have faced a number of challenges, such as off-target effects, immunoreaction and toxicity.

The development of long-term agonists using vaccines and nucleic acid drugs in the treatment of hypertension is attractive (Fig. 1) and may correct inadequate hypertension control due to low drug adherence. The practical application of vaccines or nucleic acid drugs requires the simultaneous promotion of blood pressure management at home and personalized medicine. As an advantage of these novel therapies, for patients taking multiple antihypertensive medications, such novel therapies will be introduced to lower the base blood pressure and fine-tune it in combination with the antihypertensive effects. Looking forward to the future, a variety of antihypertensive treatment methods will provide the best individualized medical care of choice.

Fig. 1
figure 1

Vaccine or siRNA development for the treatment of hypertension. The target molecules for hypertension treatment are the renin-angiotensin system (angiotensinogen, angiotensin I or II, angiotensin II type 1 receptor), L-type calcium channels and β1 adrenergic receptors. The major antihypertensive drugs are renin inhibitors, ACE (angiotensin converting enzyme) inhibitors, ARBs (angiotensin receptor blockers), CCBs (calcium channel blockers) and β blockers. The current challenge is to develop vaccines or siRNAs for the same target molecules