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VIA Report Summary

Project ID: 603131
Funded under: FP7-HEALTH
Country: Netherlands

Periodic Report Summary 2 - VIA (Vaccination In Atherosclerosis)

Project Context and Objectives:
Cardiovascular disease is still a leading cause of death in the European Union (EU) accounting for nearly half of all deaths in Europe (48%). In addition, complications due to cardiovascular disease lead to a vast number of hospitalizations and thus to a great burden of health care costs in the EU.
Atherosclerosis is the main underlying pathology of cardiovascular disease and it is estimated that atherosclerosis is responsible for 70% of all cases of cardiovascular disease. Atherosclerosis is an inflammatory process that proceeds in the context of enhanced plasma cholesterol levels and leads to the narrowing of medium and large sized arteries. The final complication of atherosclerosis is plaque rupture leading to a heart infarct or stroke. More than 30 years of research into the pathology of atherosclerosis shows that its aetiology is found in a combination of dyslipidaemia and a related inflammatory response with an established autoimmune component. The major cause of acute cardiovascular disease events, plaque rupture, is the consequence of an inflammatory destabilization of the atherosclerotic lesion. Cardiovascular disease is therefore an autoimmune-like disease in the context of a metabolic disorder: dyslipidaemia. Thus far, therapeutic approaches to treat cardiovascular disease have been focused at normalizing dyslipidaemia in order to lower and normalize plasma cholesterol levels. Statins are widely used drugs that inhibit the cholesterol synthesis in the liver and achieve a significant beneficial reduction in the plasma (Low Density Lipoprotein, LDL) cholesterol level, in combination with additional surgical approaches such as angioplasty and bypass surgery, an impressive 30% risk reduction for cardiovascular disease has been achieved during the last 10-15 years. However, additional approaches focusing on the treatment of dyslipidaemia by for instance improving the level of the anti-atherogenic lipoprotein High Density Lipoprotein (HDL) have failed in a number of clinical trials, although PCSK9 directed therapies may be applicable in the future for patients suffering from familial hypercholesterolemia. These findings indicate that new therapeutic approaches are urgently needed to narrow down the remaining 70% risk for cardiovascular disease and we think that a therapy aimed at correcting the derailed inflammatory response during atherosclerosis development, progression and plaque destabilization is a new approach to limit the impact of cardiovascular disease.
Within the present VIA consortium, we aim to develop a new immunomodulatory treatment, a therapeutic vaccine that permanently restores the immune balance within the arterial wall by inhibiting the inflammatory responses during atherosclerosis. The VIA consortium focusses on two types of vaccines, one vaccine will be directed at improving the function of regulatory T cells or neutralizing the effect of modified LDL on the immune system, while the second vaccine will aim to improve the antibody response towards modified lipids present LDL. We will carefully dissect the immune pathways underlying the beneficial effect of the vaccines, optimize the composition and the route of administration of the vaccine, test its safety in advanced humanized mouse models of atherosclerosis and carefully monitor possible side and toxic effects of the vaccine in order to perform a phase I clinical trial using the atheroprotective vaccine. The preclinical, experimental data obtained in the humanized mouse models will form the basis for the execution of a First-in-Humans clinical trial and we foresee that a vaccine will result in permanent beneficial effect on the immune response and result in a long-term protection leading to a substantial lowering of the risk for cardiovascular disease.

Project Results:
The VIA consortium has worked according to plan during the first 36 months to perform preclinical work needed to pave the road for the First-in-Humans clinical trial. The work is divided into a focus on a lipid-based vaccine and on a peptide-based vaccine; both based on native and/or modified LDL.
The experiments on the development of a lipid-based vaccine have culminated in the execution of a clinical trial in which we vaccinate against S. pneumoniae. The vaccine of choice is Prevenar 13, since the preclinical studies have shown that a repeated vaccination with this registered vaccine elicits an atherosclerosis protective immune response involving the induction of IgM directed against modified phospholipids present in oxidized LDL. The PC-specific IgM correlated inversely with atherosclerotic lesion size in mice. We therefore started a clinical trial in 2016 vaccinating against S. pneumococcus by the use of Prevenar and we will carefully monitor the induction of atheroprotective antibodies in a group of volunteers. The study will be finalized by mid-2017 and we will subsequently publish the outcome.
In order to find an optimal apoB100 peptide based vaccine, several experiments were designed which led to the identification of new peptides that can be presented via human HLA molecules to T cells. These peptides are in addition to the previously identified apoB100 peptides, such as P2, P45 and P210, studied for their capacity to modify the outcome of atherosclerosis. Basically two approaches were tested focussing on either classic vaccination involving the induction of a protective antibody response or the induction of protection via regulatory T cells. For these studies we are using relevant mouse models to prepare for the First-in-Humans clinical trials and we generated a mouse model that expresses full length human apoB100 (the main constituent of LDL) in combination with the expression of the human antigen presenting molecules.
For the preparation of the preclinical mouse studies, the consortium has decided to initially select three apoB100 derived peptides, P2, P45 and P210. These peptides in combination with Cholera Toxin subunit
B (CTB) have been successfully produced in E. Coli and two of them were used in an initial vaccine study. Within the VIA consortium oral administration of these vaccines in combination with the use of a trypsin inhibitor to limit degradation of the vaccine in the stomach has been studied in mice overexpressing human apoB100 and the preliminary findings point clearly towards the beneficial effect of P45-CTB complex to induce oral tolerance. Additional studies aimed to induce high titers of peptide-specific antibodies show very promising results and antibody levels towards apoB100 based vaccines will also be used as a biomarker to monitor the success of both types of immunomodulation.
Preparations for the execution of the First-in-Humans clinical trial have been made in terms of designing protocols for efficient, preclinical studies to demonstrate the pharmacological effect of the vaccine (the mode of action), the safety of the vaccine and the production of a GMP qualified vaccine.

Potential Impact:
Overall we think that the expected final results and impact of the VIA project will be highly relevant and we anticipate that we will be able to propose a prototype vaccine that has been tested in a First-in-Humans clinical trial.

We are currently testing an existing S. pneumococcus vaccine for its beneficial effect on circulating antibody levels against modified Low-Density Lipoprotein (LDL), the main antigen involved in the induction of atherosclerosis. Based on these studies we can conclude whether a lipid-based vaccine will induce a long term beneficial change in the derailed immune response that underlies the process of atherosclerosis, the main underlying pathology of the development of cardiovascular disease. Positive results in this trial using Prevenar can easily be translated into a larger clinical trial to study the effect of S. pneumoniae vaccination on the incidence and complications of cardiovascular disease.
The second major focus of the consortium is the development of a peptide-based vaccine and the results so far are promising and we anticipate that we will finalize the planning of a clinical trial around this second vaccine in the upcoming period.

We expect that the development of an active vaccination protocol against cardiovascular disease based on epitopes derived from LDL will reduce the burden of atherosclerosis and will especially have a beneficial effect on the most critical phase of cardiovascular disease, heart and brain infarct. The last complications predominantly result from plaque rupture that on its turn results from a local inflammatory process in the atherosclerotic plaque. We therefore anticipate that a vaccine that specifically addresses inflammation will limit mortality and morbidity associated with atherosclerotic cardiovascular disease. Since the atheroprotective vaccine under development is highly specific as it is based on the antigen involved in the development and progression of cardiovascular disease, we anticipate that this vaccine will prove to be superior to other biological therapies under development, such as cytokine neutralizing monoclonal antibodies. We also anticipate that we will achieve a long-term protection and the vaccine will also cope with compliance and provide an additional value on top of existing lipid-lowering therapy. Overall, cardiovascular disease is estimated to cost the EU economy almost 200 billion Euro per year. This immense economic burden can be differentiated into direct health care costs, costs due to productivity losses and costs due to the informal care of people with cardiovascular disease. The atheroprotective vaccine that will be developed is expected to provide a highly favourable cost-medical benefits ratio and the vaccine is expected to meet the enormous public health need to improve the treatment of cardiovascular disease. We expect that the atheroprotective vaccine also provides an excellent costs-medical benefits ratio. Both industry and SMEs are actively involved in the essential parts of the VIA project. Their input and the collaboration with an excellent team of Universities and University Medical centres will not only strengthen the project but will also strengthen the position of the industrial and SME partners and will thus have a positive effect on the EU economy.
Overall we anticipate that the outcome of the VIA project will improve the outcome of one of the major causes of death in Europe and the European Union.

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