Final Report Summary - VIA (Vaccination In Atherosclerosis)
Executive Summary:
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, cardiovascular disease complications 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 dyslipidemia and leads to the narrowing of medium and large sized arteries. The final complication of atherosclerosis is plaque rupture leading to a heart infarct in heart or stroke. More than 30 years of research into the pathology of atherosclerosis shows that its etiology is found in a combination of dyslipidemia 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: dyslipidemia.
Thus far, therapeutic approaches to treat cardiovascular disease have been focused at normalizing dyslipidemia 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 dyslipidemia 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 hypercholesteremia.
These findings indicate that new therapeutic approaches are urgently needed to narrow down the remaining 70% risk for cardiovascular disease and based on the outcome of clinical trials addressing IL-1ß it is evident that a therapy aimed at correcting the derailed inflammatory response during atherosclerosis development, progression and plaque destabilization is a valid approach to limit the impact of cardiovascular disease.
Within the present VIA consortium, we searched to develop a new immunomodulatory treatment, a therapeutic vaccine, that may permanently restore the immune balance within the arterial wall by inhibiting the inflammatory responses during atherosclerosis. We have focused on two types of vaccines, one vaccine will be directed at improving the function of regulatory T cells, while the second vaccine will improve the antibody response towards modified lipids present LDL. The first approached was performed in experimental models for atherosclerosis and resulted in new formulations of peptides derived from LDL combined with various types of adjuvants and immunomodulatory proteins. The immediate outcome of the studies is to develop monoclonal antibodies against apoB100 peptides to identify the optimal epitopes that can subsequently be used in the development of an atheroprotective vaccine. The second approach led to a First-in-Humans clinical trial in which an existing streptococcus vaccine was tested for its ability to induce antibodies that can neutralize modified LDL, which underlies the inflammatory response in atherosclerosis.
We foresee that managing the inflammatory response in atherosclerosis will receive large attention of the pharmaceutical industry and the development of anti-inflammatory response specifically addressing the immune response, such as therapeutic vaccines, will be a main focus point in future cardiovascular drug treatment.
Project Context and Objectives:
see attached pdf
Project Results:
see attached pdf
Potential Impact:
see attached pdf
List of Websites:
www.viavaccine.com
Johan Kuiper
Professor Therapeutic Immunomodulation
Head of the Division of BioTherapeutics
Leiden Academic Centre for Drug Research
Einsteinweg 55
PO Box 9502
2300 RA LEIDEN
The Netherlands
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, cardiovascular disease complications 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 dyslipidemia and leads to the narrowing of medium and large sized arteries. The final complication of atherosclerosis is plaque rupture leading to a heart infarct in heart or stroke. More than 30 years of research into the pathology of atherosclerosis shows that its etiology is found in a combination of dyslipidemia 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: dyslipidemia.
Thus far, therapeutic approaches to treat cardiovascular disease have been focused at normalizing dyslipidemia 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 dyslipidemia 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 hypercholesteremia.
These findings indicate that new therapeutic approaches are urgently needed to narrow down the remaining 70% risk for cardiovascular disease and based on the outcome of clinical trials addressing IL-1ß it is evident that a therapy aimed at correcting the derailed inflammatory response during atherosclerosis development, progression and plaque destabilization is a valid approach to limit the impact of cardiovascular disease.
Within the present VIA consortium, we searched to develop a new immunomodulatory treatment, a therapeutic vaccine, that may permanently restore the immune balance within the arterial wall by inhibiting the inflammatory responses during atherosclerosis. We have focused on two types of vaccines, one vaccine will be directed at improving the function of regulatory T cells, while the second vaccine will improve the antibody response towards modified lipids present LDL. The first approached was performed in experimental models for atherosclerosis and resulted in new formulations of peptides derived from LDL combined with various types of adjuvants and immunomodulatory proteins. The immediate outcome of the studies is to develop monoclonal antibodies against apoB100 peptides to identify the optimal epitopes that can subsequently be used in the development of an atheroprotective vaccine. The second approach led to a First-in-Humans clinical trial in which an existing streptococcus vaccine was tested for its ability to induce antibodies that can neutralize modified LDL, which underlies the inflammatory response in atherosclerosis.
We foresee that managing the inflammatory response in atherosclerosis will receive large attention of the pharmaceutical industry and the development of anti-inflammatory response specifically addressing the immune response, such as therapeutic vaccines, will be a main focus point in future cardiovascular drug treatment.
Project Context and Objectives:
see attached pdf
Project Results:
see attached pdf
Potential Impact:
see attached pdf
List of Websites:
www.viavaccine.com
Johan Kuiper
Professor Therapeutic Immunomodulation
Head of the Division of BioTherapeutics
Leiden Academic Centre for Drug Research
Einsteinweg 55
PO Box 9502
2300 RA LEIDEN
The Netherlands
