Recent Advances in Therapeutic Vaccines to Treat Hypertension
2018; Lippincott Williams & Wilkins; Volume: 72; Issue: 5 Linguagem: Inglês
10.1161/hypertensionaha.118.11084
ISSN1524-4563
AutoresHironori Nakagami, Ryuichi Morishita,
Tópico(s)Atherosclerosis and Cardiovascular Diseases
ResumoHomeHypertensionVol. 72, No. 5Recent Advances in Therapeutic Vaccines to Treat Hypertension Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBRecent Advances in Therapeutic Vaccines to Treat Hypertension Hironori Nakagami and Ryuichi Morishita Hironori NakagamiHironori Nakagami Correspondence to Hironori Nakagami, Department of Health Development and Medicine and Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita 565-0871, Japan, Email E-mail Address: [email protected] From the Department of Health Development and Medicine (H.N.), Graduate School of Medicine, Osaka University, Japan. and Ryuichi MorishitaRyuichi Morishita Ryuichi Morishita, Department of Health Development and Medicine and Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita 565-0871, Japan, Email E-mail Address: [email protected] Department of Clinical Gene Therapy (R.M.), Graduate School of Medicine, Osaka University, Japan. Originally published10 Sep 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.11084Hypertension. 2018;72:1031–1036Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 10, 2018: Ahead of Print High blood pressure is known to be one of the most significant risk factors for cardiovascular diseases. Effective antihypertensive drugs, such as calcium channel blockers, diuretics, and Ang II (angiotensin II) receptor blockers, are widely used in the treatment of hypertension and display relatively minor side effects. However, serious issues remain, including the need for daily, often lifelong, medication, implying significant financial burdens, particularly in developing countries. The number of adults with high blood pressure increased from 594 million in 1975 to 1.13 billion in 2015. Most of this increase is accounted for by middle- and low-income countries, particularly in South Asia and sub-Saharan Africa.1 A stark contrast is observed between these areas and high-income countries, in which a strong decline in the proportion of hypertensive subjects has occurred during the last decades. Therefore, the development of next-generation treatments complementing, or possibly replacing, antihypertensive drugs, would be highly desirable, also in economic terms. Moreover, by dispensing patients from compliance to long-term therapeutic regimens, effective vaccines may improve overall drug adherence.Although vaccines are commonly used to prevent infectious diseases, their application has recently been expanded to treat conditions such as cancer, rheumatoid arthritis, and Alzheimer's disease, by targeting self-antigens.2–7 In this review, we will discuss the history and recent progress of vaccines for hypertension and discuss the clinical advantages of this novel immunotherapy.History of Therapeutic Vaccines for the Renin-Angiotensin SystemIn the long history of immunotherapy, vaccines for hypertension targeting the renin-angiotensin system have been reported since the 1950s.8–12 The first target to be explored was renin, and a renin vaccine was reported to successfully reduce blood pressure in animal models. However, the vaccine was also found to induce autoimmune disease in the kidneys of 2 animal models,11,12 after which no further research on the renin vaccine has been reported. Recently, renin vaccines based on a truncated version of renin coupled to keyhole limpet hemocyanin (KLH) were raised in rats.13 Antibody titers and renin binding were elevated after vaccination, and some vaccines significantly decreased systolic blood pressure in hypertensive rats. In addition, no significant immune-mediated damage was detected in the vaccinated rats. Ang I and Ang II vaccines, as well as vaccines against Ang receptors, have been shown to successfully reduce blood pressure in rat and mouse models.14–20 An Ang I vaccine, based on antigen coupling to either tetanus toxoid or KLH carrier proteins, reduced blood pressure in rat and mouse models.14 An Ang II vaccine was also developed by Cytos Biotechnology Ag (Switzerland). This vaccine consisted of an Ang II peptide, a CysGlyGly spacer, and a virus-like particle (VLP), derived from the coat protein of the bacteriophage Qb, as a carrier protein. As a small self-antigen, Ang II alone is poorly immunogenic under normal conditions because of nonrecognition or tolerance. VLP is one of the viral self-assembled nanoparticles, composed of multiple units of coat protein devoid of viral genome. A VLP-conjugated Ang II vaccine (AngQb-Cyt006) was reported to be effective in producing anti–Ang II antibodies in rats.15We have examined the potential of developing an Ang II vaccine in mice.16 When Ang II-KLH, with or without an adjuvant, was administered to mice, only Ang II-KLH with an adjuvant successfully induced the production of anti–Ang II IgG antibodies. After Ang II infusion (1000 ng kg−1 min−1), the systolic blood pressure increased in the control mice, but not in the vaccinated mice. Furthermore, immunized mice exhibited amelioration in both the heart-to-body weight ratio and fibrotic changes induced by Ang II. Further experiments were conducted to evaluate whether preexposure to Ang II vaccination leads to cerebroprotective effects after permanent middle cerebral artery occlusion in rats.17 Twenty-four hours after middle cerebral artery occlusion, the infarction volume was not reduced in the plasma low-titer (VL) group but was reduced in the plasma high-titer (VH) group. Parenchymal anti–Ang II antibody levels in the ischemic hemisphere were significantly higher in the VH group than in the VL group. Further experiments were conducted to evaluate whether the Ang II vaccine is effective for preventing heart failure in a rat model of myocardial infarction.18 Male SD rats were subcutaneously injected with saline or the Ang II-KLH vaccine and then subjected to either permanent left anterior descending coronary artery ligation or sham operation. The anti–Ang II antibody titer was markedly elevated only in the Ang II vaccine-injected rats. Treatment with the Ang II-KLH vaccine attenuated cardiac dysfunction, inflammation, and fibrosis in association with a reduction in plasma BNP (B-type natriuretic peptide) levels. Thus, Ang II vaccination may represent a promising therapeutic strategy for preventing stroke or heart failure. Recently, a VLP-based therapeutic vaccine against AT1R (angiotensin II receptor type 1) has been reported to significantly reduce the blood pressure and protect target organs of hypertensive animals.19,20 The antigen peptide of these vaccines is a linear B-cell epitope composed of 7 amino acids (Ala-Phe-His-Tyr-Glu-Ser-Gln), derived from the extracellular loop 2 of human AT1R. As this self-antigen is small, the conjugation with VLP may induce antigen processing by antigen-presenting cells. This can be a suitable strategy to overcome self-tolerance and achieve optimal humoral immune response to AT1R.19,20Novel Types of Vaccines to Induce Antibodies Against Self-AntigensVaccines are used in preventive medicine for protection against infectious diseases worldwide and are usually designed for invaders, such as viruses, bacteria, or cancer. Recently, vaccines have also been used as a therapy against common diseases, such as Alzheimer's disease and hypertension.13–21 In a clinical trial for Alzheimer's disease, the use of a vaccine targeting β-amyloid as a self-antigen was halted because the participants developed aseptic meningoencephalitis, because of autoimmune response.21 Thus, immunologic reactions should be more thoroughly considered when designing therapeutic vaccines targeting self-antigens. After vaccine administration, phagocytic, antigen-presenting cells present epitopes to T cells through the major histocompatibility complex. In our system, we preferred to select short antigen peptides that do not include a T-cell epitope. As major histocompatibility complex classes I and II epitopes usually consist of 8 to 10 and 10 to 20 amino acids, respectively, short peptides with fewer than 8 amino acids are preferred as antigens, for safety issues.The goal of vaccines against cancer or viruses is the activation of cytotoxic T cells, in addition to antibody production. Therefore, these types of vaccine mimic the immune response against pathogens such as bacteria and viruses. As shown in Figure 1, the pathogens strongly induce innate immunity, promoting the CD26/B7 interaction between antigen-presenting cells (dendritic cells) and T cells. Coactivation of innate immunity and antigen presentation induces T-cell activation, which, in turn, may trigger both cytotoxic T cells and antibody production. On the other hand, vaccination against lifestyle-related diseases including hypertension should only result in antibody production, without cytotoxic T-cell activation. Therefore, short antigen peptides not including a T-cell epitope were selected in our system, and a carrier was used to provide for foreign T-cell epitopes (Figure 2).Download figureDownload PowerPointFigure 1. Typical immune response against a pathogen. Pathogens (ie, bacteria, virus) strongly induce the activation of innate immunity through TLR (Toll-like receptor) activation, which leads to the CD26-B7 interaction between dendritic cells and T cells. The antigen-presenting cells (APCs) phagocytose the pathogen and present a T-cell epitope to T cells through the major histocompatibility complex (MHC). Coactivation of innate immunity and antigen presentation may induce T-cell activation, resulting in both cytotoxic T cell and antibody production.Download figureDownload PowerPointFigure 2. Conceptual schematic of therapeutic vaccines for self-antigens. The antigen-presenting cells (APCs) phagocytose the antigen (Ang II [angiotensin II])-carrier (keyhole limpet hemocyanin [KLH]) conjugate and present a T-cell epitope of KLH to T cells through the major histocompatibility complex (MHC). The cotreatment of adjuvants effectively induces the CD28-B7 interaction through the activation of innate immunity. Thus, T cells recognize the epitope through T-cell receptors and become activated. B cells specifically recognizing the target antigen differentiate into plasmacytes and proliferate with the help of activated T cells. B cells then produce anti–Ang II antibodies. Because Ang II alone does not include a T-cell epitope, cytotoxic T cells are not activated for Ang II and do not attack the angiotensinogen-producing cells.Ang II is an 8 amino acid hormone increasing blood pressure. We and others have attempted to design vaccines inducing the production of Ang II–antagonizing antibodies without causing a cytotoxic immune response. In the human immune tolerance system, the reaction against Ang II is tightly controlled via the repression of self-reactive T cells. However, self-reactive B cells are still active and can be induced by T-cell activation.9 Thus, efficient antibody production by B cells (plasmablasts) requires helper T-cell activation, to prevent immune tolerance. The major mechanism for immune tolerance is driven by T cells and includes central and peripheral tolerance. Central T-cell tolerance blocks the egress of self-reactive T cells from the thymus, whereas peripheral tolerance is based on inactivation of T cells by induction of anergy. To fully activate B cells, CD4+ T cells must first differentiate into plasma and memory cells. Because of T-cell immune tolerance, self-reactive B cells, albeit responsive to antigens, cannot function without the help of CD4+ T cells, targeting the self-antigen. As our antigens do not include the T-cell epitope, T cells cannot be activated, and B-cell–induced antibody production does not occur. To overcome this problem, peptide antigens may be used in combination with foreign T-cell epitopes, which results in antibody production.22Therefore, to design a therapeutic vaccine against Ang II, we used KLH as a carrier protein and included foreign T-cell epitopes.23,24 The mice or rats were immunized with the Ang II-KLH conjugate, with the addition of adjuvants, to circumvent T-cell tolerance (Figure 2). During the immunization phase, antigen-presenting cells internalize Ang II-KLH and present a KLH-derived T-cell epitope to T cells that become activated (ie, differentiate into effector T cells). Importantly, Ang II itself is not presented to T cells through the major histocompatibility complex. When the major histocompatibility complex is recognized, T cells do not receive costimulation as a result of the CD28/B7 interaction, leading to T-cell anergy. However, the adjuvant effectively induces the CD28/B7 interaction via the activation of innate immunity. Thus, the combination of Ang II-KLH and adjuvants successfully induces proliferation and differentiation of T cells against Ang II-KLH. Ang II–specific B cells internalize the Ang II-KLH complex and present the T-cell epitope of Ang II-KLH to T cells. B cells then differentiate into plasmacytes and produce antibodies with the help of effector T cells. Because Ang II does not include a T-cell epitope, cytotoxic T cells are not activated by Ang II and do not attack the angiotensinogen-producing cells.The described approach strongly induced anti–Ang II antibodies, without cytotoxic T-cell activation.16 T-cell proliferation and Enzyme-Linked ImmunoSpot assays were conducted to confirm the results and identify the involved T-cell isotopes. The results showed that Ang II-KLH and KLH alone induced T-cell activation, whereas Ang II alone did not, suggesting that only KLH contains a T-cell epitope. To further assess our results, the presence of self-antibodies was evaluated after continuous infusion of Ang II. Interestingly, no increase in the titer of anti–Ang II antibodies was detected in immunized mice. Therefore, this vaccine system did not induce an autoimmune reaction, because of the nonself recognition of Ang II-KLH and KLH foreign T-cell epitopes.In terms of adjuvant selection, our therapeutic vaccine is substantially different from the previous ones. For traditional vaccines, requiring activation of cytotoxic T cells, adjuvants that activate the Th1 pathway and involve the production of IFN (interferon)-γ are preferred, such as CpG (Figure 3). On the other hand, as our vaccine aims at inducing antibody production without cytotoxic T-cell activation, adjuvants promoting the Th2 pathway are more appropriate (ie, Alum). In addition, our vaccine may induce IgG2, which has no effector functions. The correct combination of carriers and adjuvants is critical for managing safety issues during the development of therapeutic vaccines.Download figureDownload PowerPointFigure 3. Comparison of vaccines for cancer, infectious diseases, and lifestyle-related diseases. The goal of vaccines against cancer or viruses is the activation of cytotoxic T cells (CTL: cytotoxic T lymphocytes). Their antigens should present a T-cell epitope through the major histocompatibility complex (MHC), and a carrier is not required for this system. Therefore, these vaccines use adjuvants that activate the Th1 pathway (ie, CpG), which involves the production of IFN (interferon)-γ. For lifestyle-related diseases, the goal is the induction of antibodies without cytotoxic T-cell activation. In this case, antigens should not include a T-cell epitope, and a carrier is used to provide for the foreign T-cell epitope. Adjuvants that activate the Th2 pathway (ie, Alum) are preferable for this type of vaccine.Clinical Trials of Therapeutic Vaccines for HypertensionSeveral types of vaccines targeting the renin-angiotensin system have been reported to be effective at producing anti–Ang II antibodies in mice and rats; however, some problems still hamper their translation to the clinics, such as insufficient reduction of blood pressure.25,26 Previous or ongoing clinical trials for angiotensin vaccines are summarized in Table. The administration of the PMD3117 vaccine significantly increased the titer of anti–Ang I antibody, both in phase 1 (healthy subjects) and in phase 2 (hypertensive patients, double blind); however, blood pressure was not significantly reduced in the vaccinated group compared with the placebo group.27,28 The administration of an Ang II vaccine (AngQb-Cyt006) significantly increased anti–Ang II antibody titers in phases 1 and 2.7,15 The latter study was a multicenter, double-blind, randomized, placebo-controlled clinical trial. In phase 2a, 72 patients with mild-to-moderate hypertension were randomly assigned to receive subcutaneous injections of either 100 or 300 μg of conjugate (CYT006-AngQb) or placebo at weeks 0, 4, and 12. Each group consisted of 24 patients. The 24-hour ambulatory blood pressure was measured before treatment and at week 14. Whereas blood pressure was unaffected in the low-dose (100 μg vaccine) and in the placebo group, it significantly decreased in the high-dose group (300 μg vaccine). In the latter patients at week 14, the mean ambulatory daytime blood pressure was reduced by −9.0/−4.0 mm Hg, compared with baseline level. Interestingly, the 300 μg dose reduced the early morning blood pressure surge. During the evaluation of safety issues, 5 serious adverse events were reported (2 in the 100 µg group, 2 in the 300 µg group, and 1 in the placebo group); none were deemed to be treatment related. Most of the side effects were mild, transient reactions at the injection site. This study was the first to report a successful reduction in blood pressure using vaccine therapy, with no serious adverse events. However, further developments of the study failed to reproduce these results. Notably, an accelerated immunization schedule was employed (0, 2, 4, 6, and 10 weeks) in the attempt to induce higher antibody titers, compared with the initial protocol (0, 4, and 12 weeks). The authors concluded that the accelerated regimen may have led to the induction of high titer antibodies with low affinities for the antigen. However, the involvement of this factor in the lack of therapeutic effect is hard to demonstrate. Moreover, it is unclear whether an accelerated treatment regimen is required to foster antibody production because usually, antibody titer is maintained for at least a few months after vaccination, without the need of further injections. We believe that an increased dose of vaccine, rather than an accelerated injection regimen, would have better chances to result in higher antibody titers.29 Another angiotensin vaccine using a novel adjuvant, CoVaccine HT, was also reported in a randomized, double-blind, placebo-controlled phase 2 clinical trial; however, this study was terminated because of dose-limiting adverse effects (from URL: https://clinicaltrials.gov/ct2/show/NCT01015703).Table. Clinical Trials of Vaccines for HypertensionYearVaccinesPhase/Sample SizeResultsReference2003Ang I analog with KLH (PMD3117)Phase 1: 50 healthy menIncrease in anti–Ang I antibody titer. No changes in blood pressure. No problems in safety evaluation.252004Ang I analog with KLH (PMD3117)Phase 2: 27 hypertensive patients (double blind)Increase in anti–Ang I antibody titer. No changes in blood pressure. No problems in safety evaluation.272006Ang II (AngQb) with AlumPhase 1: 16 healthy men (12 vaccine; 4 placebo)Increase in anti–Ang II antibody titer. No changes in blood pressure. No problems in safety evaluation.282008Ang II (AngQb) with AlumPhase 2: 72 hypertensive patients (24 high-dose vaccine, 24 low-dose vaccine, 24 placebo)Increase in anti–Ang II antibody titer. Significant decrease in blood pressure only for the high-dose vaccine group. No problems in safety evaluation.72010Angiotensin therapeutic vaccine by novel adjuvant, CoVaccine HTPhase 2b: Randomized, double blind, placebo-controlledTerminated because of dose-limiting adverse effects.None2018Ang II DNA vaccine (AGMG0201)Phase 1/2a: 24 patients (9 high dose, 9 low dose, 6 placebo)OngoingOngoingAng indicates angiotensin; and KLH, keyhole limpet hemocyanin.A clinical trial (phase 1/2a) using the Ang II DNA vaccine (AGMG0201) has recently begun in Australia. Detailed information is available on the website (www.anzctr.org.au/). The aim of the study is to evaluate safety and efficiency of this novel vaccination protocol. In addition to antibody titer and blood pressure, safety blood and urine tests will be performed, and adverse events will be monitored. The study design consists in a randomized, double-blind, and placebo-controlled study. To evaluate the efficiency, the stability of the antibody titer will be evaluated over at least 6 months, and the association between antibody titer and blood pressure will be verified. As AGMG0201 may potentially cause hypotension, patients with moderately high blood pressure will be enrolled in this clinical trial. Rescue therapy will be applied in case of emergency. For example, if hypotension occurs, it will be managed by salt administration and norepinephrine injections. Another potential source of adverse reactions may be related to local site discomfort, as is the case for other commercially available vaccines. Vaccine injections may result in soreness, redness, itching, swelling, or burning at the injection site for 1 to 2 days. A small, hard lump may persist for some weeks or months post-vaccination. However, this is not usually a serious concern, and no treatment is required. The trial is currently in progress and may provide us with important insights into the future development of therapeutic vaccines.ConclusionsHypertension can be adequately controlled with the available drugs. Nevertheless, the success of treatment is often limited by incomplete adherence of patients to treatment. It is estimated that ≈50% of patients do not comply with their medication regimen.30 Poor medication adherence is a pervasive problem in patients with hypertension. In addition, elderly patients with dementia or those with severe frailty cannot manage medication by themselves. Thus, vaccination against Ang II has the potential to become a useful antihypertensive treatment, providing long-lasting effects and avoiding the problem of patient noncompliance with drug regimens.The number of adults with high blood pressure has largely increased in low- and middle-income countries worldwide. Effective vaccines may potentially complement, or replace, antihypertensive drugs, thus also allowing for a reduction in medical costs. The development of therapeutic vaccines for the renin-angiotensin system has a long history, in basic as well as translational research. However, some problems still hamper their routine clinical use, such as an insufficient reduction of blood pressure.The development of therapeutic vaccines for lifestyle-related and cardiovascular diseases is a challenging task.31 However, the achievement of this objective may have enormous implications from a clinical, social, and economic standpoint, especially in our aging societies.AcknowledgmentsWe thank all lab members in the Department of Health Development and Medicine of Osaka University Graduate School of Medicine for supporting this project.Sources of FundingThis work was partly supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.DisclosuresThe Department of Health Development and Medicine was financially supported by Daicel, Mitsubishi-Tanabe, AnGes, and Funpep. The Department of Clinical Gene Therapy is financially supported by Novartis, AnGes, Shionogi, Boehringer Ingelheim, Fancl, Saisei Mirai Clinics, Rohto, and Funpep. R. Morishita is a founder of AnGes and a stockholder and is a stockholder of Funpep. The other author reports no conflicts.FootnotesCorrespondence to Hironori Nakagami, Department of Health Development and Medicine and Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita 565-0871, Japan, Email [email protected]med.osaka-u.ac.jpRyuichi Morishita, Department of Health Development and Medicine and Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita 565-0871, Japan, Email [email protected]med.osaka-u.ac.jpReferences1. NCD Risk Factor Collaboration (NCD-RisC). 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