A vaccine for Alzheimer’s disease. It sounds amazing, even fantastical – but we are a lot closer to this goal than you might think. As well as providing a new and innovative therapeutic option for a disease that has been notoriously difficult to treat, vaccination could unlock the door to that most elusive of objectives: prevention. We’ve dived into the latest science and spoken to an expert at the cutting edge of this field to bring you the lowdown on where this research is headed, with the aim of answering the all-important question, “Just how close are we to a vaccine for Alzheimer’s disease?”
There are lots of different types of dementia, but Alzheimer’s disease is the most common. It is a huge, and ever-growing, public health concern. The National Institutes of Health currently ranks Alzheimer's disease as the seventh leading cause of death in the United States.
Scientists are still working to try to fully unpick the causes of Alzheimer’s, as well as developing ways to detect it as early as possible, before symptoms like memory loss start to appear. It’s a complex disease, so it’s unlikely that any one treatment will ever be developed that will work for all patients.
The principal hallmarks of Alzheimer’s disease that are visible in the brains of patients are agglomerations of two proteins: amyloid-beta and tau. Amyloid-beta forms plaques that build up between neurons, while tau molecules clump together in tangles inside the neurons themselves.
Currently, there are some approved drug treatments that can help with the cognitive symptoms of Alzheimer’s, at least for a time. An important aspect of caring for someone with Alzheimer’s is maximizing their emotional and physical wellbeing for as long as possible – it’s common for patients with dementia to experience sleep problems, anxiety, and behavioral symptoms that can be difficult to manage, so finding strategies to keep things as stress-free as possible is key.
There's been a lot of buzz recently about a new class of medications: monoclonal antibodies. Aducanumab hit the headlines in 2021 when it became the first new drug approved for use in Alzheimer’s for 18 years. Since then, early trials of lecanemab and donanemab have also shown promise. However, there are some notable downsides to monoclonal antibodies that make them unlikely to be suitable for everyone. For example, they require multiple, regular doses to work effectively. There is also a risk of off-target, or unintended, effects.
All three of these Alzheimer’s drugs target the pathological amyloid-beta protein. One off-target effect that can occur with such medications is amyloid-related imaging abnormalities, or ARIA. There are two different types, causing either swelling or small bleeds in the brain. In rare cases, ARIA can lead to death, so it’s something drug developers have to be very cautious of.
Immunization is a different approach. Like with monoclonal antibodies – and many vaccines for infectious diseases, like the flu – immunizations for Alzheimer’s disease would need to be repeated over the course of someone’s life, but probably much less frequently. A highly specific immunization could also have minimal off-target effects, and therefore a lower risk of complications.
How would a vaccine work?
We’re going to focus on active immunization approaches, an area where a lot of exciting research is happening. One organization at the vanguard of this is Florida-based Vaxxinity, which is currently developing and trialing several immunization candidates for Alzheimer’s, as well as other neurodegenerative diseases.
For Alzheimer’s, Vaxxinity has focused on vaccines that can neutralize the toxic proteins that build up in the brain, particularly amyloid-beta but also tau. As diagnosis becomes more advanced, the hope is that these vaccines could be administered at earlier and earlier stages, treating the disease before the pathology has progressed too far or even preventing neuronal damage altogether.
“Vaccines for Alzheimer’s disease are not a new concept, but optimization of vaccine technologies has been necessary to overcome immune tolerance in a safe way,” Jean-Cosme Dodart, PhD, Senior Vice President, Research at Vaxxinity, told IFLScience. “Vaxxinity’s peptide technology platform was optimized to safely stimulate the immune system, turning the body into its own antibody ‘drug factory’ and has been able to overcome that immune tolerance.”
Of the neurological vaccine candidates currently in Vaxxinity’s pipeline – which include treatments targeting migraine and Parkinson’s disease – the UB-311 Alzheimer’s vaccine is the most advanced, having completed Phase 1 and Phase 2a trials.
UB-311 targets amyloid-beta. Importantly, given the risks of off-target effects that we know are associated with amyloid-modulating therapies, the trials have so far shown that UB-311 has a favorable safety profile. “Clinical trials to date have shown UB-311 to be well tolerated in mild-to-moderate Alzheimer’s patients, with a safety profile comparable to placebo and no cases of amyloid-related imaging abnormalities-edema, or ARIA-E, in the Phase 2a trial,” Dodart said. “UB-311 also elicited robust and durable anti-amyloid beta antibody responses in patients with Alzheimer’s.”
After these promising early results, the development of UB-311 is ongoing. Meanwhile, another candidate called VXX-301 is also in the preclinical testing stages – that’s the earliest period of experimentation before a drug is ready to be trialed in humans. VXX-301 is a little different in that it targets tau protein. Up to now, the signs point toward it being potentially more effective than tau-targeting monoclonal antibodies that are going through clinical trials.
Vaxxinity believes that there are some huge advantages to an active immunization approach compared with other drug treatments, even biologics like monoclonal antibodies.
“Scaling [monoclonal antibody] production to meet the needs of the global population would be challenging because they are extremely expensive to make and scale, requiring large bioreactors, and often have to be administered in specialized healthcare facilities like infusion centers, making it difficult to distribute to large masses of people especially when IV infusions have to be given every few weeks,” Dodart explained. “Active immunization may have an advantage in treating Alzheimer’s because vaccines are potentially safer, less costly by at least an order of magnitude, easier to administer, and more scalable.”
There’s a precedent for this too: COVID-19 vaccination campaigns demonstrated how, with a concerted effort, huge numbers of people can be immunized in a short space of time. “Monoclonal antibody technology simply cannot achieve this scale, which is especially critical given the pending dementia pandemic that we’re facing,” added Dodart.
Plus, there’s the tantalizing prospect of prevention. When we, somewhat cheekily, asked if prevention of Alzheimer’s disease is an achievable goal, Dodart was emphatic: “Of course, this is why we show up to work every day!”
As he went on to explain further, active immunization approaches are particularly well-suited to the pursuit of a prophylactic. “It has become clear that in the brain of patients with Alzheimer’s, there has been neurodegeneration for years prior to a diagnosis, so the earlier the treatment the better the outcome. Vaccines given before the neurodegeneration process occurs, long before an actual diagnosis, might provide the best chance of eradicating Alzheimer’s disease.”
The efforts of the team at Vaxxinity, as well as others working in this space – not to mention research that is still ongoing into passive immunization strategies as well – are bringing the world closer and closer to potentially game-changing treatments for a disease that continues to have a devastating impact across the globe.
We began this section by saying we would focus on active immunizations, but there’s another intriguing thread to this tale that it would be remiss of us not to mention.
In many parts of the world, people will remember receiving the BCG vaccine as children or teens – most of them probably still bear the scar! BCG stands for Bacillus Calmette-Guérin, and it’s a vaccine that was developed to combat tuberculosis (TB). In the UK, it’s no longer given out routinely – but for generations, it was a rite of passage for schoolkids to line up to get their shot. It’s a very safe vaccine, and is great at preventing the more serious complications of TB, although its effect on the spread of the infection is more limited.
It was soon noticed that BCG vaccination seemed to be doing more to protect the health of children than simply shielding them from one infectious disease. Scientists Peter Aaby and Christine Benn, who began to investigate this effect for the BCG and other vaccines in the 1970s, coined the term “non-specific effects”.
The research sparked by this observation has led to a new use for the BCG, in the treatment of non-muscle-invasive bladder cancer. This is a type of cancer where the tumor cells are limited to the inner lining of the bladder and have not yet invaded the deeper muscular tissue. Using a cohort of patients who had previously been treated for this type of cancer, with about half of them having received the BCG vaccine, a group of researchers recently set out to look at a possible protective effect of the vaccine against Alzheimer’s disease.
The findings, reported in May 2023 in JAMA Open Network, showed that treatment with the BCG vaccine was associated with a 20 percent lower risk of developing Alzheimer’s and related dementias, particularly in people aged 70 and above.
“A vaccine like BCG, if proven effective, is a perfect example of a cost-effective, population-health–based solution to a devastating illness like Alzheimer's disease,” said first author of the study Marc S. Weinberg in a statement. The results are so promising that the team is switching gears to investigate these observations in more detail. If it does look like the BCG is causally linked to a reduction in Alzheimer’s risk, there will be a lot of work to do to uncover the mechanism.
It’s early days yet, but it could just be that this old vaccine has some new secrets to share with us.
Where do we go from here?
We’re truly in an exciting era for research into Alzheimer’s disease and neurodegeneration more broadly. According to Dodart, lots of factors are coalescing to bring us closer than ever to real breakthroughs.
“While research into the mechanisms and potential treatments for Alzheimer’s have been ongoing for decades, only recently have we seen late-stage clinical validation for some of these targets. We also have more analytical tools now to evaluate various species of proteins that may be implicated in Alzheimer’s, as well as biomarkers of disease state and progression, which may open the door to even more medical options in the future.”
So just how close are we to a vaccine for Alzheimer’s disease? Closer than ever before, it’s fair to say. It’s no longer the preserve of hopes for a decades-distant future: this research is happening, and progressing, right now. And Dodart, for one, is unwavering in his optimism: “I believe in a matter of years there will be an approved immunization strategy for Alzheimer’s disease.”
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