Evaluation of two carrier protein–angiotensin I conjugate vaccines to assess their future potential to control high blood pressure (hypertension) in man

Abstract

Aims We aim to modulate the renin-angiotensin system (RAS) by active immunization against angiotensin I hormone (AI), potentially providing a novel conjugate vaccine treatment for hypertension in man. Methods Immunization studies in rat and human subjects compare the effectiveness of tetanus toxoid (TT) and keyhole limpet haemocyanin (KLH) vaccines for immunotherapy following conjugation with an AI peptide analogue ( AI ). Cardiovascular responses were assessed in immunized rats and human subjects (two-dose trial only), following increasing i.v. infusions of either AI or angiotensin II hormone (AII). Results The AI -TT and AI -KLH conjugate vaccines induced an equivalent immune response, and inhibition of the pressor effects to exogenous AI in rats. Single-dose clinical trials with both conjugate vaccines only resulted in an immune response to the KLH carrier protein. A two-dose clinical trial of AI -KLH conjugate vaccine resulted in a significant immune response to AI . A shift in diastolic blood pressure (DBP) dose-response was demonstrated following challenge with AI and AII for the study volunteer showing the largest anti-AI IgG induction. Conclusion KLH was shown to be a suitable alternative to TT as a carrier protein for AI , thus supporting continued evaluation of our AI -KLH conjugate vaccine for treatment of hypertension in man.

A therapeutic vaccine for nicotine dependence: preclinical efficacy, and phase I safety and immunogenicity

“…Only after boosting were anti-cocaine IgG antibodies measured. Similarly, in a phase I study using angiotensin I coupled to keyhole limpet hemocyanin, two immunizations were needed to induce an antiangiotensin-I immune response [26]. Taken together, this indicates that antigens presented on Qb VLP induce a higher responder rate at earlier time points in man than conventional carrier proteins do.…”

New Approaches in the Treatment of Hypertension

“…113 Although a renin vaccine successfully lowered BP in animal models, it induced autoimmune disease of the kidneys and further development was suspended. 114 An Ang I vaccine also lowered BP in animal models, 115,116 but was ineffective in a randomized, doubleblind, placebo-controlled clinical trial. 117 Further, a vaccine raised in response to an Ang II-derived peptide conjugated to a virus-like particle derived from the bacteriophage Qβ (AngQb) was effective in producing anti-Ang II antibodies and reducing BP in SHR, despite increasing circulating Ang II levels 118 (Figure 2; Table).…”

New Therapeutics in Hypertension

“…(Goldblatt, Haas & Lamfrom, 1951, Michel et al, 1987 Years later in the 60s, interest is focused on vaccines used against Ang I, but these had no antihypertensive effect. (Downham et al, 2003) At present, interest is focused on Ang II as an immunogen agent using a new immunization technology that combines antigens on the surface of a structure of virus like particles (VLP) generating a B cell response against autoantigens. VLPs conjugated to Ang II (CYT006-AngQb vaccine) have been tested in preclinical and clinical trials and have been observed to be well tolerated, immunogenic and with a high proportion of respondent individuals.…”