Historical Development – Failed Attempts of Vaccine Development
Because beta-amyloid accumulations are prominent in the brains of individuals with Alzheimer's disease (AD), scientists have sought treatments that would prevent the accumulation of beta-amyloid or remove it after it has accumulated. One approach is to immunize people against beta-amyloid through vaccination. Immunization would use the body's immune system to prevent the accumulation or promote the removal of beta-amyloid in the same way immunization for infectious agents such as tetanus, diphtheria, typhoid and polio prevents them from causing those illnesses. The vaccination concept is clear and well proven and there is some promising evidence from animal models of AD. However, developing a vaccine against beta-amyloid that is both safe and effective in humans is proving to be a substantial challenge.
In 1999, researchers reported that a vaccine called AN-1792 prevented formation of beta-amyloid plaques in young transgenic mice (mice genetically programmed to have specific characteristics) that develop many beta-amyloid plaques. They also found that when older mice with already formed beta-amyloid plaques were vaccinated with AN-1792, they had reductions in brain beta-amyloid. The next step was to determine whether reduction in beta-amyloid deposits improved "mouse memory" using standard models of memory in mice. The results were positive. Nevertheless, optimism was tempered by awareness that the mouse strain studied did not have neurofibrillary tangles. Many times studies in animal models do not generalize to human disease in terms of benefit, tolerability or both.
The first substantial trial of AN-1792 in humans resulted in symptoms of inflammation of the brain and spinal cord in enough patients that the study was stopped. The concept of vaccination against excessive accumulation of beta-amyloid remained promising and an aggressive research program on vaccination continued.
Later, in February 2004, a clinical trial testing a vaccination against Alzheimer's Disease was dealt another crushing blow when some of patients showed side effects of brain inflammation. The trial was stopped and it looked like the great hope of an Alzheimer's vaccine was lost.
The immunologists weren't to be beaten so easily. This trial has failed, but many scientists continued to believe that the human immune system can be trained to fight off Alzheimer's Disease by attacking the beta-amyloid peptide. This peptide is a short chain of amino acids (up to 42) like a molecular string of beads. When they are produced in the brain during Alzheimer's Disease the peptides all line up and stick together causing hard, microscopic chunks called amyloid plaques to appear in the brain. Many scientists believe that either the peptides themselves or the microscopic amyloid plaques actually cause the damage to the brains of patients with Alzheimer's Disease. The thinking goes that if an individual's immune system can be trained to attack the peptides (whether individually or in the plaques) then perhaps they will be protected against the damage the peptides may cause to the brain that leads to Alzheimer's.
At first it was thought that the vaccine worked by prompting the immune system to make antibodies that would actually get into the brain and attack the peptides where they lay. This may be the case, but the brain protects itself from invasion by preventing large molecules like antibodies from passing through the so called blood-brain barrier. Indeed, one of the first things you may expect to see if the brain were invaded in this way would be inflammation. More recent research has suggested that there may be an exchange of the peptides between the brain and the blood, so that if the antibodies in the bloodstream can attack the peptides here, more peptides will seep out of the brain only to be attacked themselves. If this is the case then the blood would be acting as a kind of waste disposal where the peptides would be destroyed and then more peptides fed in from the brain.
Clinical Research Development for Alzheimer’s Vaccine
University of California, Irvine, USA (2008)
A promising vaccine being tested for Alzheimer’s disease does what it is designed to do – clear beta-amyloid plaques from the brain – but it does not seem to help restore lost learning and memory abilities, according to a University of California, Irvine study.
The findings suggest that treating the predominant pathology of Alzheimer’s disease – beta-amyloid plaques – by itself may have only limited clinical benefit if started after there is significant plaque growth. However, a combination of vaccination with therapies that also target related neuron damage and cognitive decline may provide the best treatment opportunity for people with this neurodegenerative disease.
“We’ve found that reducing plaques is only part of the puzzle to treat Alzheimer disease,” said study leader, UC Irvine neurobiologist Elizabeth Head. “Vaccines such as this one are a good first step for effective Alzheimer’s treatment, but complimentary treatments must be developed to address the complexity of the disease.”
Head and colleagues studied for a two-year period in aging canines the effect of a vaccine that is currently under clinical development for treating patients with Alzheimer’s disease. The vaccine contains the beta-amyloid 1-42 protein and stimulates the immune system to produce antibodies against this same protein that is in the brain plaques. Dogs are used for such studies because beta-amyloid plaques grow naturally in their brains and they exhibit cognitive declines similar to those seen in humans.
After the aged dogs with beta-amyloid-plaque growth were immunized (which is similar to starting a treatment in patients with Alzheimer’s disease), the researchers found, in comparison with non-treated aged dogs, little difference in the results of behavioral tests that measure cognitive loss. Later, brain autopsies showed that although plaques had been cleared from multiple brain regions – including the entorhinal cortex, a region of the brain involved with learning and memory and primarily affected by Alzheimer’s – damaged neurons remained.
Head said this discovery helps explain why there was little difference in the behavioral test results between immunized and nonimmunized dogs. In addition, she added, it implies that after clearing beta-amyloid plaques from the brain, the next step is to repair these neurons. This approach will be critical for treating and reversing the effects of the Alzheimer’s disease.
Currently, Head and her colleagues are developing approaches to repair these damaged neurons and hope to test them clinically.
University of Beersheva, Israel (2009)
An Israeli researcher working on a vaccine to combat Alzheimer's disease announced important progress following tests on gene-altered laboratory mice.
"We have been able to stimulate an immune response and forecast the effects in inoculated mice carrying human genes," Alon Monsonego, who works with British and U.S. researchers, told Agence France Presse.
"It is an important development" that could help find vaccines which could be used for individuals with a predisposition to Alzheimer's, said the University of Beersheva researcher.
Monsonego added that "inoculated mice were able to reduce plaques of beta-peptides, as well as inflammations and neuronal damage associated with the disease."
"We have been able to stimulate an immune response and forecast the effects in inoculated mice carrying human genes," Alon Monsonego, who works with British and U.S. researchers, told Agence France Presse.
"It is an important development" that could help find vaccines which could be used for individuals with a predisposition to Alzheimer's, said the University of Beersheva researcher.
Monsonego added that "inoculated mice were able to reduce plaques of beta-peptides, as well as inflammations and neuronal damage associated with the disease."
Industrial Research Development for Alzheimer’s Vaccine
Araclon Biotech, Spain (2009)
Araclon Biotech has obtained its first European Patent for a vaccine therapy for Alzheimer’s disease. The company hopes to start the regulatory pre-clinical development of the vaccine this year, with the aim of starting clinical trials on humans at the end of 2010.
The conclusions obtained concerning toxicity and efficacy in the animal models used has encouraged the company’s high expectations for future clinical results. Receiving the patent in the European Union, granted by the European Patent Office is a big break for the company’s ambitious project.
Does this step mean that this remedy can be used? No, not yet. Until now, researchers, led by Dr. Manuel Sarasa, Professor of Anatomy and Comparative Pathology of the University of Zaragoza, have used animal models, mainly dogs. “Dog reproduces quite well Alzheimer’s injuries in human beings and because of that we chose it”, Pilar de la Huerta, Araclon Biotech executive advisor, pointed out.
“This is the first vaccine developed in Spain as a therapy for this disease and one of the few in the world”, Sarasa, who has been studying Alzheimer for twenty years, added.
However, although it is very difficult to foresee the efficiency that this therapy will have in human beings, the truth is that in animal experimentation it is 100%.
To achieve this, several antibodies, which have led to this vaccine, were developed and patented. At the moment, researchers are very optimistic with the future. ‘Other companies have developed vaccines that, when they passed to the testing-in-humans phase, were effective but toxic, so they could not be used’ - Pilar de la Huerta explains -. ‘Nonetheless, our studies show that this one, at the moment, is not”.
Professor Sarasa’s last discoveries show that Amyloid-Beta protein, which is related to the disease, is not only in senile plaques but also in neurofibrillary tangles. The objective of the vaccine is to go directly to the molecule, which is considered the cause of the disease, and reduce its levels. This is a bet to the detriment of other solutions as enzymes inhibiting therapies.
On the other hand, this team thinks that the mistake of previous researches to heal the disease has been that they chose persons who already had the problem. Because of that, they want to begin testing with healthy volunteers.
Affiris, Austria (2010)
An Austrian biotechnology company, Affiris, has brought its new vaccine (AD02) through the first testing phase in which it was shown to be safe and relatively free of intolerable side effects. The new vaccine is designed to be therapeutic and is aimed at helping those who are already in the throes of Alzheimer’s.
Slightly more than 400 volunteer patients are being recruited for the second phase testing of the new vaccine. This next-step testing will be in several European countries. The tests will be for vaccine effectiveness; that is, efficacy in the mitigation of the disease rather than for its prevention. Results may be available as soon as 2012.
Alzheimer’s attacks the brain by way of buildup of amyloid plaques. Those plaques cause nerve cell damage and the consequent loss of brain function. The AD02 vaccine causes production of antibodies which counter plaque production by attacking the beta-amyloid protein that is at or near the center of plaque formation.
An Affiris representative has asserted that, should the AD02 vaccine be therapeutically successful, the technology used in its development as a therapeutic tool could also be applied to the development of a vaccine for prevention of Alzheimer’s Disease in healthy individuals.
Slightly more than 400 volunteer patients are being recruited for the second phase testing of the new vaccine. This next-step testing will be in several European countries. The tests will be for vaccine effectiveness; that is, efficacy in the mitigation of the disease rather than for its prevention. Results may be available as soon as 2012.
Alzheimer’s attacks the brain by way of buildup of amyloid plaques. Those plaques cause nerve cell damage and the consequent loss of brain function. The AD02 vaccine causes production of antibodies which counter plaque production by attacking the beta-amyloid protein that is at or near the center of plaque formation.
An Affiris representative has asserted that, should the AD02 vaccine be therapeutically successful, the technology used in its development as a therapeutic tool could also be applied to the development of a vaccine for prevention of Alzheimer’s Disease in healthy individuals.
Sources and Additional Information:
