[Show abstract][Hide abstract]ABSTRACT: Neutralization of the inflammatory cytokine interleukin-1β (IL-1β) is a promising new strategy to prevent the β-cell destruction, which leads to type 2 diabetes. Here, we describe the preclinical development of a therapeutic vaccine against IL-1β consisting of a detoxified version of IL-1β chemically cross-linked to virus-like particles of the bacteriophage Qβ. The vaccine was well tolerated and induced robust antibody responses in mice, which neutralized the biological activity of IL-1β, as shown both in cellular assays and in challenge experiments in vivo. Antibody titers were long lasting but reversible over time and not associated with the development of potentially harmful T cell responses against IL-1β. Neutralization of IL-1β by vaccine-induced antibodies had no influence on the immune responses of mice to Listeria monocytogenes and Mycobacterium tuberculosis. In a diet-induced model of type 2 diabetes, immunized mice showed improved glucose tolerance, which was mediated by improved insulin secretion by pancreatic β-cells. Hence, immunization with IL-1β conjugated to virus-like particles has the potential to become a safe, efficacious, and cost-effective therapy for the prevention and long-term treatment of type 2 diabetes.
[Show abstract][Hide abstract]ABSTRACT: Vaccination against GIP does not induce inflammation in the GIT. Female, C57BL/6 mice were immunized subcutaneously with 100 µg of Qβ-GIP or Qβ VLP on days 0, 14, 28 and 42. Animals were fed a high fat diet (35% fat w/v) from the start of the experiment. Mice were sacrificed on day 99. Tissue samples were fixed, sectioned and stained with H&E according to standard methods. One representative mouse from each group is shown. Histological analysis of the sample by a pathologist did not reveal any signs of inflammation in the gut in Qβ-GIP immunised animals compared to Qβ treated control animals. Similar results were obtained when animals were culled either on day 36 or 142 and analyzed by a pathologist.
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[Show abstract][Hide abstract]ABSTRACT: No cross reaction of Qβ-GIP induced antibodies with GLP1 and OXM in vivo. Qβ-GIP immunized mice. mice were challenged i.v. with 1 ng of I125-GIP, I125OXM or I125 GLP1. As a control naïve mice were challenged with 1 ng of I125-GIP. 30 minutes later the amount of antibody-bound GIP, OXM or GLP1 was determined. The percentage of antibody bound GIP, OXM or GLP-1±SEM (n = 4) is shown. Whereas most of the injected GIP was found associated with Antibodies only background levels of OXM or GLP1 were found associated with the antibody fraction in Qβ-GIP immunised mice.
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[Show abstract][Hide abstract]ABSTRACT: Vaccination against GIP results in weight loss in obese male mice. Male mice were fed a high fat diet for 4 month. By this time all animals were severely obese and had reached weights between 45–50 g. The animals were then immunized (days 0, 14, 36, 50 and 119) with Qβ-GIP or Qβ VLPs and kept on a high fat diet (35% fat w/v). Fat content in the diet was reduced to 20% fat (w/v) from day 42 onwards. Average changes in body weight±SEM (n = 10) are shown. Qβ-GIP treated animals lost significantly more weight than Qβ VLP-immunized animals from day 70 onwards (two way ANOVA F(1,162) = 9.82, p = 0.0057).
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[Show abstract][Hide abstract]ABSTRACT: According to the WHO, more than 1 billion people worldwide are overweight and at risk of developing chronic illnesses, including cardiovascular disease, type 2 diabetes, hypertension and stroke. Current therapies show limited efficacy and are often associated with unpleasant side-effect profiles, hence there is a medical need for new therapeutic interventions in the field of obesity. Gastric inhibitory peptide (GIP, also known as glucose-dependent insulinotropic polypeptide) has recently been postulated to link over-nutrition with obesity. In fact GIP receptor-deficient mice (GIPR(-/-)) were shown to be completely protected from diet-induced obesity. Thus, disrupting GIP signaling represents a promising novel therapeutic strategy for the treatment of obesity.
In order to block GIP signaling we chose an active vaccination approach using GIP peptides covalently attached to virus-like particles (VLP-GIP). Vaccination of mice with VLP-GIP induced high titers of specific antibodies and efficiently reduced body weight gain in animals fed a high fat diet. The reduction in body weight gain could be attributed to reduced accumulation of fat. Moreover, increased weight loss was observed in obese mice vaccinated with VLP-GIP. Importantly, despite the incretin action of GIP, VLP-GIP-treated mice did not show signs of glucose intolerance.
This study shows that vaccination against GIP was safe and effective. Thus active vaccination may represent a novel, long-lasting treatment for obesity. However further preclinical safety/toxicology studies will be required before the therapeutic concept can be addressed in humans.
[Show abstract][Hide abstract]ABSTRACT: Despite the availability of efficacious drugs, the success of treating hypertension is limited by patients' inconsistent drug intake. Immunization against angiotensin II may offer a valuable alternative to conventional drugs for the treatment of hypertension, because vaccines induce relatively long-lasting effects and do not require daily dosing. Here we describe the preclinical development and the phase I clinical trial testing of a virus-like particle (VLP)-based antihypertensive vaccine.
An angiotensin II-derived peptide was conjugated to the VLP Qbeta (AngQb). AngQb was highly immunogenic in mice and rats. To test for efficacy, spontaneously hypertensive rats (SHR) were immunized with 400 microg AngQb or VLP alone. Group mean systolic blood pressure (SBP) was reduced by up to 21 mmHg (159 +/- 2 versus 180 +/- 5 mmHg, P < 0.001), and total angiotensin II levels (antibody-bound and free) were increased ninefold (85 +/- 20 versus 9 +/- 1 pmol/l, P = 0.002) compared with VLP controls. SHR treated with the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg per day by mouth) reached an SBP of 155 +/- 2 mmHg. Twelve healthy volunteers of a placebo-controlled randomized phase I trial were injected once with 100 microg AngQb. Angiotensin II-specific antibodies were raised in all subjects (100% responder rate) and AngQb was well tolerated.
AngQb reduces blood pressure in SHR to levels obtained with an ACE inhibitor, and is immunogenic and well tolerated in humans. Therefore, vaccination against angiotensin II has the potential to become a useful antihypertensive treatment providing long-lasting effects and improving patient compliance.
No preview · Article · Feb 2007 · Journal of Hypertension
[Show abstract][Hide abstract]ABSTRACT: In mice, highly repetitive antigens, such as those present on bacterial or viral surfaces, efficiently cross-link B-cell receptors and therefore induce strong IgG responses. In this study we covalently coupled a synthetic 16-amino-acid sequence of the allergen Der p 1 to a virus-like particle derived from the bacteriophage Qbeta (Qbeta-Der p 1).
We evaluated the safety and immunogenicity of Qbeta-Der p 1 in human subjects and compared different doses and routes of immunization.
In a phase I trial 24 healthy volunteers were randomly assigned to one of 4 treatment groups. Group 1 received 50 microg of Qbeta-Der p 1 intramuscularly, group 2 received 50 microg of Qbeta-Der p 1 subcutaneously, group 3 received 10 microg of Qbeta-Der p 1 intramuscularly, and group 4 received 10 microg of Qbeta-Der p 1 subcutaneously. Boosting immunizations with 10 microg were given after 1 and 3 months. Antibody titers were measured after 1, 3, 4, 6, 12, and 18 months.
The vaccine Qbeta-Der p 1 was well tolerated. Significant IgG responses were observed 4 weeks after a single injection. Individuals receiving 50 microg of the vaccine had significantly higher IgG titers than those vaccinated with 10 microg. However, the route of immunization (subcutaneous vs intramuscular) had no effect. In the 50-microg dose group, strong antibody responses against Der p 1 with average titers of 1:2000 were obtained.
Vaccination with a peptide antigen covalently coupled to highly repetitive virus-like particles represents an adjuvant-free means of rapidly inducing high antibody titers in human subjects.
Allergens coupled to virus-like particles can be used to enhance the efficiency of allergen-specific immunotherapy.
No preview · Article · Jul 2006 · Journal of Allergy and Clinical Immunology