Vaccines for Alzheimer’s and Parkinson’s Disease

(December 2018)

Since AN-1792 vaccine induced autoimmune encephalitis, several pharmaceutical companies are now concentrated in developing antibody therapy in Alzheimer’s disease (AD). Each antibody has own characteristics. Thus, it is unpredictable at present which antibody is the most beneficial until we see the result of clinical trials. If disease modifying antibodies were found, they will be widely used for treatment of AD in near future. As a candidate of such antibodies, we have developed TAPIR-like antibody with much higher affinity to Abeta42 than Abeta40, and it effectively deleted senile plaque amyloid and Abeta oligomers without increasing microhemorrhages. Although passive immunization can avoid autoimmune encephalitis, it is expensive and it is not suitable for prevention. Thus, safe vaccines by active immunization would be better. Vaccines that induce Th2 type immune responses such as oral vaccine or per-nasal vaccine would be promising.
Neurodegenerative diseases (NDs) have a serious impact on global health with no effective treatments available to date. Vaccination has been proposed as a therapeutic approach for NDs, and clinical evaluations of some candidates for Alzheimer’s disease and multiple sclerosis are ongoing. Moreover, monoclonal antibodies for passive immunotherapy are under evaluation for Alzheimer’s, synucleinopathies, and multiple sclerosis
With the consolidation of plant-based systems for the production and oral delivery of biopharmaceuticals, interesting perspectives arise in the fight against NDs. Based on analysis of the current biomedical literature, the role of plant-made biopharmaceuticals and the outlook on how this technology is leading to new therapeutic candidates and potential developments for NDs are presented in this review. Expert commentary: Substantial innovations in the following years are expected as a consequence of applying molecular pharming in the fight against NDs.
There has been a recent expansion of vaccination and immunotherapeutic strategies from controlling infectious diseases to the targeting of non-infectious conditions including neurodegenerative disorders. In addition to conventional vaccine and immunotherapeutic modalities, gene-based methods that express antigens for presentation to the immune system by either live viral vectors or non-viral naked DNA plasmids have been developed and evaluated. This mini-review/commentary summarizes the advantages and disadvantages, as well as the research findings to date, of both of these gene-based vaccination approaches in terms of how they can be targeted against appropriate antigens within the Alzheimer and Parkinson disease pathogenesis processes as well as potentially against targets in other neurodegenerative diseases. Most recently, the novel utilization of these viral vector and naked DNA gene-based technologies includes the delivery of immunoglobulin genes from established biologically active monoclonal antibodies. This modified passive immunotherapeutic strategy has recently been applied to deliver passive antibody immunotherapy against the pathologically relevant amyloid β protein in Alzheimer disease. The advantages and disadvantages of this technological application of gene-based immune interventions, as well as research findings to date are also summarized. In sum, it is suggested that further evaluation of gene based vaccines and immunotherapies against neurodegenerative diseases are warranted to determine their potential clinical utility.


In order to develop a cell-based vaccine against the Parkinson disease (PD) associated protein α-synuclein (α-Syn) 3 peptides were synthesized based upon predicted B cell epitopes within the full length α-Syn protein sequence. These peptide fragments as well as the full length recombinant human α-Syn (rh- α-Syn) protein were used to sensitize mouse bone marrow-derived dendritic cells (DC) ex vivo, followed by intravenous delivery of these sensitized DCs into transgenic (Tg) mice expressing the human A53T variant of α-Syn. ELISA analysis and testing of behavioral locomotor function by rotometry were performed on all mice after the 5th vaccination as well as just prior to euthanasia. The results indicated that vaccination with peptide sensitized DCs (PSDC) as well as DCs sensitized by rh-α-Syn induced specific anti-α-Syn antibodies in all immunized mice. In terms of rotometry performance, a measure of locomotor activity correlated to brain dopamine levels, mice vaccinated with PSDC or rh- α-Syn sensitized DCs performed significantly better than non-vaccinated Tg control mice during the final assessment (i.e. at 17 months of age) before euthanasia. As well, measurement of levels of brain IL-1α, a cytokine hypothesized to be associated with neuroinflammation, demonstrated that this proinflammatory molecule was significantly reduced in the PSDC and rh- α-Syn sensitized DC vaccinated mice compared to the non-vaccinated Tg control group. Overall, α-Syn antigen-sensitized DC vaccination was effective in generating specific anti- α-Syn antibodies and improved locomotor function without eliciting an apparent general inflammatory response, indicating that this strategy may be a safe and effective treatment for PD.

Idiopathic Parkinson’s disease (PD) is, like other neurodegenerative diseases such as Alzheimer’s disease (AD) considered a proteinopathy. Thus, a disease that is driven by the accumulation and aggregation of misfolded proteins, in case of PD α-synuclein (aSyn) is incriminated. Accordingly, removal of aSyn is assumed of having the potential to modify the course of the disease. Both active and passive aSyn targeting immunotherapy were found to modify disease in mice overexpressing human aSyn and recapitulating various aspects of synucleopathies. Translating immunotherapy to humans needs to consider the issue of potential autoimmunity. PD vaccines developed by AFFiRiS integrate the safety concept as applied for the company’s AD vaccine candidates. This includes the use of short antigens, precluding activation of aSyn-specific T cells and, thus, cellular autoimmunity.  Moreover, the selection of AFFITOPES® for clinical development is based on the principle of exclusive aSyn reactivity of vaccine-induced Abs excluding crossreactivity to β-synuclein (bSyn), which is ensured by the AFFITOME® platform technology. PD01, the first in class aSyn vaccine developed by AFFiRiS is about to enter the clinical phase of development.

A novel Parkinson’s vaccine will now be tested in a clinical Phase I trial in Austria by an EU-funded consortium. The vaccine was developed by the Austrian biotech company AFFiRiS AG and targets a protein called alpha-Synuclein. The protein plays a key role in the onset and progression of Parkinson’s as well as multiple system atrophy (MSA), an orphan disease. This vaccine has the potential to modify disease progression, rather than only symptomatic improvements available with current treatment strategies. The start of the Parkinson’s trial follows in the wake of positive results from a similar Parkinson’s vaccine trial recently conducted by AFFiRiS with support from the Michael J. Fox Foundation.
Today the EU-consortium SYMPATH starts recruitment for a Phase I study of a Parkinson’s vaccine candidate called AFFITOPE® PD03A. This vaccine is one out of a designated pool of promising vaccine candidates based on AFFiRiS‘ proprietary AFFITOME® technology. These candidates aim at disease modification of Parkinson’s instead of only ameliorating the severe motor symptoms of the disease, such as tremor. All vaccines in this pool target alpha-Synuclein, a protein that is key to the onset and the progression of both, Parkinson’s and multiple system atrophy (MSA). Recently, encouraging clinical results of a Parkinson’s trial of one other of the pool’s vaccines, namely PD01A, were presented by the Michael J. Fox Foundation and AFFiRiS. These confirmed the safety and tolerability of the vaccine, as well as its ability to induce an immune response and even achieve functional stabilization.
Commenting on the latest clinical trial, Prof. Achim Schneeberger, Chief Medical Officer at AFFiRiS and coordinator of SYMPATH, explains: „The results we achieved with the Parkinson’s vaccine PD01A were very encouraging. Now, PD03A will be tested in a comparable setting and we are eagerly awaiting the results. „The current trial of PD03A is a multi-centric patient blinded, randomized, placebo-controlled, parallel group Phase I trial. It will be conducted in Vienna and Innsbruck, Austria. Prof. Werner Poewe, chairman of the Department of Neurology at the Medical University of Innsbruck and principal investigator of the study, explains the objectives of the trial: „The primary endpoint of the trial aims to demonstrate the safety and tolerability of the vaccine. It will also assess the vaccine’s immunological and clinical activity in vaccinated patients as its secondary endpoint.“
Dr. Dieter Volc of PROSENEX Ambulatorium BetriebsgmbH, leading the trial in Vienna, adds: „PD03A is one of the first medications worldwide aiming for clinical efficacy by modulating the metabolic pathway of alpha-Synuclein. It has the potential to treat the cause of Parkinson’s – not just the symptoms.“ Current scientific understanding is that Parkinson’s – as well as MSA – is caused by deposits of pathological forms of alpha-Synuclein in the nervous system. The reduction of pathological alpha-Synuclein levels is believed to have a beneficial impact on the progress of the diseases. PD03A aims to accomplish this by inducing the production of antibodies that target and promote clearance of alpha-Synuclein in order to neutralize its toxic impact.
The start of the clinical trial comes only a year after the SYMPATH-Consortium was launched. This rapid progress is owed to the high expertise in Parkinson’s and related diseases of all members of the consortium including the Forschungszentrum Jülich in Germany, the INSERM F-CRIN Toulouse, the Departments of Neurology at the University Hospitals of Bordeaux and Toulouse, France, as well as the Medical University of Innsbruck’s Department of Neurology and PROSENEX, Vienna, Austria.
Additionally, the successful track record of the AFFiRiS AFFITOME® platform that forms the basis of PD01A and PD03A significantly accelerated the vaccine development. Dr. Markus Mandler, head of the Neurodegeneration Department at AFFiRiS explains: „Both vaccines are based on AFFiRiS‘ AFFITOME®technology. This technology delivers not only a single vaccine for the treatment of a certain disease but a whole pool of product candidates with excellent safety profiles and strong specificity to their targets.
SYMPATH (α-synuclein-dependent neurodegeneration: clinical development of therapeutic AFFITOPE vaccines for Parkinson’s disease and multiple system atrophy“) is a collaborative project of the Seventh Framework Programme of the European Union, holding Grant Agreement No. HEALTH-F4-2013-60299. SYMPATH aims to advance the clinical development of therapeutic vaccines targeting alpha-Synuclein-driven neurodegenerative diseases including Parkinson’s disease (PD) and multiple system atrophy (MSA) where no causal therapy currently exists. The project will run for 48 months. It has received 5.99 million Euros in funding from the European Union. AFFiRiS AG located in Vienna, Austria serves as the coordinator for the projects ambitious research program and is supported by Biolution in project management tasks. Project partners include 5 universities and 3 SMEs:
AFFiRiS AG (Austria) – Prof. Dr. Achim Schneeberger
Biolution GmbH (Austria) – Dr. Iris Grünert
University Hospital Bordeaux (France) – Prof. Wassilios Meissner, MD
INSERM F-CRIN Toulouse (France) – Claire Levy Marchal, MD, MSc
Prosenex Ambulatoriumsbetriebs-GmbH (Austria) – Dieter VOLC, MD
Medical University Innsbruck, Department of Neurology (Austria) – Prof. Werner Poewe, MD & Prof. Klaus Seppi, MD Forschungszentrum Jülich GmbH (Germany) – Prof. Dr. Dieter Willbold
University Hospital Toulouse (France) – Prof. Olivier Rascol, MD
Based on its proprietary IP positions AFFiRiS develops tailor-made drugs mainly as Peptide-based vaccines. Target diseases include Alzheimer, Parkinson, Diabetes and other indications with attractive markets and unmet medical need. Alzheimer is the lead indication. Current investors are: MIG-Fonds and Athos Service GmbH, both Munich, Germany. AFFiRiS is located at the campus of the Vienna Biocenter, Vienna Austria and employs 80 highly qualified employees.
About Parkinson’s disease
Parkinson’s disease is the second most common neurodegenerative disorder among the elderly with approximately 1.2 Mio European patients alone. Currently there is no cure for the disease and existing therapeutic measures are only able to treat its symptoms. Its classical motor symptoms result from the death of dopamine-generating cells in the substantia nigra, a specific region of the midbrain. The disease typically starts with non-motor symptoms, progresses slowly but steadily to a debilitating state.
About Multiple System Atrophy
Multiple system atrophy is a rare, orphan status neurodegenerative disorder. It progresses rapidly leading to death of the affected individual within, on average, 6-9 years. There is currently no cure for the disease. MSA is associated with the degeneration of nerve cells in specific areas of the brain. This causes problems with movement, balance, and autonomic functions of the body. Unlike Parkinson’s disease, where symptomatic treatments are well established, there are no drugs approved for the treatment of MSA.

First Clinical Data of Therapeutic Parkinson’s Disease Vaccine. AFFiRiS AG announced today at a press conference in New York results of AFF008, a Phase I clinical trial of PD01A, a vaccine against Parkinson´s disease. PD01A is the first therapy against the protein alpha-synuclein, a promising Parkinson’s drug target, to enter clinical testing.
The Michael J. Fox Foundation for Parkinson’s Research (MJFF) supported the study with a $1.5 million grant, and presented at the press conference on the impact a disease-modifying therapy would have for patients. The Foundation will support a follow-up study testing a boost vaccination, the next step toward a Phase II trial.
„A treatment that could slow or stop Parkinson’s progression would be a game changer for the five million worldwide living with this disease and the many more who will become at risk as our population ages,“ said MJFF CEO Todd Sherer, PhD. „The AFF008 trial is one of the most promising efforts toward that goal, and we’re proud to support this work of AFFiRiS AG.“
In this study, two different doses of PD01A were safe and well tolerated, meeting the primary endpoint of the trial. Secondary endpoints of the study included the induction of an alpha-synuclein-specific antibody response. A hallmark pathology of Parkinson’s disease is aggregates of protein — chiefly alpha-synuclein — called Lewy bodies that accummulate in brain cells, leading to cell degeneration and cell death. Researchers hypothesize that reducing alpha-synuclein accumulation will be neuroprotective; AFFiRiS is using active immunotherapy to test that theory and develop a disease-modifying treatment.
PD01A was applied at two different doses (15 µg and 75 µg) to 12 patients per group. All received four vaccinations in monthly intervals, and all completed the study. Eight patients on best medical care, including standard symptomatic medication, served as a control group. Each patient was regularly seen and evaluated during a 12-month period.
Fifty percent of the vaccinated patients generated alpha-synuclein-specific antibodies as measured in serum samples. Additionally, vaccine-induced antibodies were detectable in cerebrospinal fluid. This induction of antibodies against alpha-synuclein is strong preliminary evidence in support of the principle of AFFiRiS‘ proprietary therapeutic vaccine.
Furthermore, analysis of clinical endpoints revealed a trend, consistent over all parameters, towards functional stabilization of the vaccinated groups as compared to non-vaccinated control patients. The pharmacodynamic profile of PD01A and its clinical effects will be the basis of later phase studies, should development continue.
„The safety and tolerability observed in this study, especially in a protein such as alpha-synuclein where we do not yet know its normal function, are encouraging,“ said Walter Schmidt, PhD, Co-founder and CEO of AFFiRiS AG. „We are grateful for the continued support of The Michael J. Fox Foundation as we progress in clinical development.“
The next study will take place in Vienna, Austria and focus on assessing the immunological and clinical effects of a boost vaccination. Recruitment is expected to begin September.
Based on its proprietary IP positions AFFiRiS develops tailor-made drugs mainly as Peptide-based vaccines. Target diseases include Alzheimer, Parkinson, Diabetes and other indications with attractive markets and unmet medical need. Alzheimer is the lead indication. Current investors are: MIG-Fonds and Athos Service GmbH, both Munich, Germany. AFFiRiS is located at the campus of the Vienna Biocenter, Vienna Austria and employs 95 highly qualified employees.
About The Michael J. Fox Foundation for Parkinson’s Research
As the world’s largest nonprofit funder of Parkinson’s research, The Michael J. Fox Foundation is dedicated to accelerating a cure for Parkinson’s disease and improved therapies for those living with the condition today. The Foundation pursues its goals through an aggressively funded, highly targeted research program coupled with active global engagement of scientists, Parkinson’s patients, business leaders, clinical trial participants, donors and volunteers. In addition to funding more than $450 million in research to date, the Foundation has fundamentally altered the trajectory of progress toward a cure. Operating at the hub of worldwide Parkinson’s research, the Foundation forges groundbreaking collaborations with industry leaders, academic scientists and government research funders; increases the flow of participants into Parkinson’s disease clinical trials with its online tool, Fox Trial Finder; promotes Parkinson’s awareness through high-profile advocacy, events and outreach; and coordinates the grassroots involvement of thousands of Team Fox members around the world.

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