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Finding a truly effective treatment for Parkinson’s disease - that goes beyond simply managing symptoms - has long been a challenging task and, to this day, there are no available therapeutic options that can effectively slow or stop the underlying disease. However, research and trials to find treatments are ongoing and, as World Parkinson’s Day takes place on April 11, we explore whether developing a vaccine for Parkinson’s could be a feasible option to prevent the development of the disease. The first detailed medical description of Parkinson’s was published in 1817, in an essay titled ‘An Essay on the Shaking Palsy’, written by British physician James Parkinson - whom the disease is named after. This essay helped to establish Parkinson’s as a recognized medical condition. Fast-forward six decades to the mid-1800s, and it was Jean Martin Charcot - a French neurologist - who refined and expanded James Parkinson’s earlier description of the disease by describing the clinical spectrum of Parkinson’s, and separating it from multiple sclerosis (MS) and other disorders that were characterized by tremors. Now, after more than two centuries of study, we know Parkinson’s to be a neurodegenerative disease that is caused by the death and dysfunction of neurons in the part of the brain called the substantia nigra, leading to a reduction of dopamine - a chemical that coordinates movement. Due to this reduction, the disorder causes motor symptoms, such as tremor, slowness, stiffness, and balance and walking problems. Although ‘treatments’ for Parkinson’s first appeared as early as the 19th century - based on empirical observation and anticholinergic drugs - the first effective treatment for the symptoms of Parkinson’s came in the 1960s after the discovery of the dopaminergic deficits in the disease. This led to the development of Levodopa, which works by being converted into dopamine in the brain, and is still the most widely used medicine for Parkinson’s today. But, despite its wide usage, there is no getting away from the fact that Levodopa only treats the symptoms of Parkinson’s rather than slowing or stopping the progression of the disease. Given that more than 10 million people are living with Parkinson’s worldwide, there is an unmet need for a more preventative treatment option. With this in mind, alongside developing small molecule and monoclonal antibody treatments, researchers and biotechs are also exploring the possibility of creating a Parkinson’s vaccine that will prevent the development of the disease. What does a vaccine for Parkinson’s entail? Parkinson’s is associated with protein deposits in the brain called Lewy bodies, which are composed of an accumulation of alpha-synuclein. In Parkinson’s, alpha-synuclein misfolds and aggregates into Lewy Bodies. For that reason, it is thought that preventing alpha-synuclein aggregation and removing existing clumps could be an effective way to treat Parkinson’s. “In order to develop a therapy, you really need to have the technology which specifically - or as specifically as possible - targets the Parkinson’s protein, which is alpha-synuclein, and targets the misfolded pathological form of this alpha-synuclein,” explained Andrea Pfeifer, co-founder and chief executive officer (CEO) of AC Immune, which is currently developing an investigational vaccine for Parkinson’s. The current approach to Parkinson’s vaccines is the introduction of a molecule that induces the body to produce its own antibodies against alpha-synuclein, leading to active immunity. In doing this, the idea is that the antibodies will bind to clumped alpha-synuclein and help to break them down. One of the specific benefits of creating a vaccine for Parkinson’s comes in the form of both efficiency and cost-effectiveness. As Mei Mei Hu, CEO of Vaxxinity, pointed out, “as a modality for delivering medicine, vaccines are easy to take, easy to make, and inexpensive to produce.” Pfeifer also agreed with this sentiment and said that AC Immune hopes to be able to get away with only giving one or two vaccinations per year with its vaccine candidate, which is important not just from a cost perspective, but also a convenience standpoint. Vaccines in clinical development showing promise There are currently two notable vaccines in clinical development making use of active immunity that have been seen to produce promising results from phase 1 trials. AC Immune is working on the development of one of these vaccines, known as ACI-7104. This came after it acquired Affiris’ portfolio of therapeutics targeting alpha-synuclein, including Affitope PD01A, which was Affiris’ clinically-validated active vaccine candidate for the treatment of Parkinson’s. The phase 1 trial of PD01A demonstrated its long-term safety, efficacy and tolerability. “We started out with a clinically validated product candidate, which we are now taking into phase 2. We did repeat quite a few studies because when you acquire a product, it’s very important that you have full confidence and that your basis is clear. So, we repeated many of the data and it was very, very good, and we manufactured the product, we went to different countries for regulatory approval and we got all of this,” explained Pfeifer. According to Pfeifer, it is only a matter of time before the company announces the dosing of the first patients and, if everything goes to plan, they expect to have the first immunogenicity data by the end of the year. Another investigational vaccine with promising results so far from its phase 1 trial is UB-312, which is being developed by Vaxxinity. Once again targeting toxic forms of aggregated alpha-synuclein in the brain, it is intended to treat Parkinson’s and other synucleinopathies, such as dementia with Lewy Body (DLB) and multiple system atrophy (MSA). Part A of the phase 1 trial has already been completed and demonstrated that UB-312 was well tolerated and immunogenic in healthy volunteers, with a higher responder rate and antibodies that cross the blood brain barrier. Meanwhile, part B of the phase 1 trial is currently ongoing, but has already shown some positive results. “We saw that UB-312 was also well tolerated and immunogenic in Parkinson’s patients, based on an end-of-treatment analysis of the ongoing Part B of the Phase 1 trial. We expect to complete this trial in mid-2023,” said Hu. Vaxxinity uses its Vaxxine Platform in order to activate the immune system and stimulate the production of antibodies. This technology specifically makes use of synthetic peptides to mimic and optimally combine biological epitopes. The challenges of developing a vaccine for Parkinson’s Although a vaccine could be an accessible, affordable and effective treatment for Parkinson’s, developing one presents a number of challenges. “Designing clinical trials in Parkinson’s disease presents multiple challenges. First, neurodegeneration evolves for many years prior to diagnosis, thus identifying patients at early stages of the disease is important. A vaccine might eventually be well suited for prevention of neurodegeneration, but we are still lacking diagnostic biomarkers that would help identify patients at very early stages of the disease (i.e., before symptoms occur),” explained Hu. “Moreover, symptoms are generally slow progressing and heterogenous, meaning that assessing a beneficial effect of an investigational drug needs to be conducted over long periods of time and in a large patient population.” Pfeifer also mentioned diagnostics being a challenge in the development of a Parkinson’s vaccine, and said that diseases like MSA, which is a subtype of Parkinson’s, have a relatively high rate of misdiagnosis, which is one of the reasons why it is so difficult to have successful clinical trials. “We don’t have the tools yet to diagnose people correctly to include the correct patients in the clinical trial, and then obviously follow the impact of the treatment,” said Pfeifer. At AC Immune, they are trying to tackle this problem by overseeing the parallel development of diagnostics and therapeutic candidates, so they can ensure they are selecting the correct patients for the correct diseases. Meanwhile, Dr. Arthur Roach, director of the Parkinson’s Virtual Biotech, said that a lack of understanding around how alpha-synuclein works, means that there is still a long way to go before we see a Parkinson’s vaccine. “The reality is that at the moment, there’s still a lot more that we need to learn and understand about alpha-synuclein and its behavior in the brain to be able to properly target it in a bid to deliver a Parkinson’s vaccine,” said Roach. “This isn’t to say it’s impossible that there would ever be a vaccine, but on current evidence, it’s likely to take decades to hone and produce. We’re starting to see progress in potential cancer vaccines where molecular targets have been identified, but in neurological conditions like Parkinson’s, our understanding is probably 10-15 years behind that.” Although a Parkinson’s vaccine might one day be possible - particularly considering the initial promising results from the recent trials of AC Immune’s ACI-7104 and Vaxxinity’s UB-312 - it’s difficult to say whether we will see the successful development of an effective vaccine anytime soon. However, there is reason to be hopeful that a cure for the disorder might be within touching distance, with a variety of investigational treatments currently being developed for it. “The pipeline of therapies in development for Parkinson’s is robust and varied; the scientific research community continues to show an impassioned interest in reducing the debilitating impact of the disease…Encouragingly, investigational drugs aiming at stopping or slowing down the neurodegeneration process have advanced to late-stage clinical trials, and might become available before the end of the decade, assuming that efficacy and safety are confirmed,” said Hu.

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