In 2002, the first Alzheimer’s disease vaccine candidate to enter clinical trials was dealt a devastating blow. On the heels of impressive data in animal models, Elan Pharmaceuticals’ AN-1792 entered a 372-patient Phase II trial in patients with early symptoms of Alzheimer’s disease. In theory, AN-1792 would induce antibodies against a potentially toxic plaque that forms in the brains of Alzheimer’s patients, slowing their cognitive decline. But these antibodies ended up attacking healthy cells in several patients’ brains, leading to severe cases of brain swelling—and the trial’s early termination.

In the two decades since, vaccines have largely receded to the shadows of Alzheimer’s drug development. Monoclonal antibodies (mAbs) have since taken the spotlight, spurred by the recent FDA approval of Biogen’s mAb Aduhelm (aducanumab) and a successful Phase III trial of Eisai’s and Biogen’s mAb lecanemab. A recent string of positive early-stage Alzheimer’s vaccine trials, however, has given the vaccine approach a faint glimmer of hope.

Experts say Alzheimer’s vaccines, if proven effective, would be cheaper, safer, and more convenient than mAbs. While vaccines induce the body to create its own antibodies, mAbs must be regularly injected directly into the bloodstream. This requires expensive, hours-long intravenous (IV) infusions administered roughly every other week, making mAbs unfeasible for most of the world’s 55 million people with Alzheimer’s disease, explains Dante Marciani, PhD, an Alzheimer’s researcher and CSO of Qantu Therapeutics. The mAb Aduhelm costs $23,000 a year, while experts say vaccines could cost less than $1,000 a year.

Still, the failure of AN-1792 highlights the central challenge of the vaccine approach: inducing an immune response strong enough to fight toxic proteins in the brain, but not so strong that it attacks otherwise healthy cells. Unlike most vaccines that target foreign infectious agents like measles or SARS-CoV-2, Alzheimer’s vaccines must attack toxicities that can naturally build up inside the brain.

“How do you get your body to produce antibodies against itself?” asks Mei Mei Hu, CEO of Vaxxinity, a Dallas, Texas-based biotech with an Alzheimer’s vaccine candidate at the Phase II development stage. “That is no small feat.”

Evolving Alzheimer’s targets

When Alois Alzheimer first documented the neurodegenerative disease in 1906, he described plaques in the brain as a defining disease characteristic. In the decades since, researchers have developed numerous drugs to remove amyloid beta plaques from the brain, theorizing this could slow or reverse Alzheimer’s progression, explains William Klein, PhD, a neuroscientist at Northwestern University and co-founder of the drug company Acumen. “It’s easy to relate amyloid plaques to Alzheimer’s because they’re so easy to see,” he says.

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Nevertheless, no therapies targeting these plaques have yielded clear positive results in trials, and many have also led to serious side effects, Klein explains. The mAb Aduhelm, which targets amyloid beta plaque, caused the brain swelling side effect known as ARIA-E in 35% of patients in Phase III trials. Ultimately, safety concerns and mixed efficacy data prompted Medicare to severely restrict coverage despite the drug’s controversial FDA approval in 2021.

Now, many Alzheimer’s disease vaccine and mAb developers are breaking with tradition to look beyond amyloid beta plaques. And vaccine manufacturers say their approach, which differs from mAbs, could avoid the brain swelling side effects common in Alzheimer’s clinical trials.

Both Vaxxinity and the Swedish biotech Alzinova have vaccines targeting amyloid beta oligomers, a type of neurotoxin that can interfere with synapse function. Unlike amyloid beta plaques, which can also accumulate in healthy individuals, oligomers are always “bad actors,” Klein explains. In September, lecanemab, which also targets oligomers, became the first Alzheimer’s mAb to meet its primary endpoint in a Phase III trial, slowing cognitive decline by 27%. But lecanemab also caused the brain swelling side effect ARIA-E in 12.5% of patients—less than Aduhelm but still a notable concern.

Vaxxinity’s Hu says lecanemab has validated amyloid beta oligomers as a therapeutic target, adding that the vaccine approach of targeting oligomers could reduce ARIA-E even further. In a smaller Phase II study of Vaxxinity’s UB-311 in mild-to-moderate Alzheimer’s, there were no reported cases of ARIA-E. In an ongoing Phase I trial of Alzinova’s vaccine ALZ101 in early Alzheimer’s disease, there have been no reported instances of ARIA-E, though it is too early to draw conclusions, CSO Anders Sandberg says.

Some mAbs use dose titration to reduce the risk of ARIA-E, which entails gradually increasing infusion volumes over many months to reduce the risk of side effects, Sandberg explains. But vaccines perform this process naturally—and more effectively—by gradually increasing antibody production to avoid an overreactive immune response, he notes.

Designing clinical trials

By the time someone has a heart attack, underlying risk factors like high cholesterol have usually been building for decades. The same is likely true for Alzheimer’s disease, which is preceded by decades of irreversible neuronal damage. “Ultimately, the best way to treat Alzheimer’s is to prevent it,” Vaxxinity’s Hu says.

For Alzheimer’s disease vaccine developers, a key challenge is selecting the right patients for clinical trials, explains Andrea Pfeifer, CEO of AC Immune, a Swiss biotech with two Alzheimer’s vaccine candidates in development. AC Immune is planning a biomarker-based approach for a late-stage trial of the vaccine ACI.35.030, which had positive Phase I/II data reported in November. ACI.35.030 is designed to remove phosphorylated-Tau, which is linked to synaptic impairment and neuronal damage in Alzheimer’s disease. The trial would identify biomarkers associated with a greater risk of developing Alzheimer’s disease, and measure whether ACI.35.030 affects these metrics. Ideally, Pfeifer says researchers will develop blood tests that can determine someone’s relative risk of developing the disease.

Meanwhile, Vaxxinity is planning a Phase III trial of UB-311 with early Alzheimer’s disease patients, the same population used in lecanemab’s successful Phase III study, Hu says. The 18-month trial will enroll 700–800 patients, assessing cognitive decline as the primary outcome measure, she notes. Before beginning the study, Vaxxinity is looking for a co-development partner to support the Phase III trial and eventually commercialize UB-311.

Another critical question for vaccine trials is the frequency of vaccination. Vaxxinity is planning to give three priming shots of UB-311, followed by boosters once every three months. AC Immune and Alzinova, which are in earlier stages of vaccine development, say boosters may only be necessary every six months. For comparison, both Aduhelm and lecanemab require infusions in a hospital every two weeks.

Overall, Hu views Alzheimer’s vaccine development as a “step-wise approach,” with the eventual goal of testing vaccines in people without Alzheimer’s as a tool for prevention. In these cases, vaccinations may not be needed as frequently. Eventually, the strategy for preventing Alzheimer’s disease could mirror that of heart disease, where at-risk patients take medicines to lower high cholesterol, Hu says. If a patient in their 40s has high levels of amyloid beta oligomers in some type of blood test, there could be a day when a doctor recommends putting them on a vaccine or therapeutic to lower their risk.

An overlooked immune approach?

Around three years ago, an unlikely run-in at Massachusetts General Hospital led to an even more unlikely Alzheimer’s disease trial. The neurologist Dr. Steven Arnold, who studies Alzheimer’s disease and aging, bumped into Dr. Denise Faustman, an immunologist focused on type 1 diabetes. Faustman was running a Phase I trial to discover why an anti-tuberculosis vaccine appeared to awaken the immune system in type 1 diabetes. The two doctors began  wondering whether the same tuberculosis vaccine could spur the immune response to protect against Alzheimer’s disease. “We didn’t know each other at all,” Arnold recalls. “But once we started talking about our science it was like, whoa, maybe there’s something here.”

Arnold is now the principal investigator of a Phase I trial testing the tuberculosis vaccine—called Bacillus Calmette-Guérin (BCG)—in patients with mild-to-moderate Alzheimer’ disease. The 15-patient study (NCT05004688) uses the same basic protocol as Faustman’s ongoing Phase I trial in type 1 diabetes. Around the same time, a separate observational study using electronic medical records found BCG vaccination was associated with a 58% lower risk of developing Alzheimer’s disease in people over 75 years old.

In preliminary data from Arnold’s Phase I Alzheimer’s trial, which has not yet been published, the research team found that the BCG vaccine can alter the immune responsiveness of spinal fluid cells circulating in and around the brain. “Immune dysregulation is a known feature of Alzheimer’s disease,” Arnold says. “Beyond amyloid and tau, it could be inflammation that really drives degeneration.”

Meanwhile, several other trials are exploring the effects of distinct vaccinations on Alzheimer’s disease. A planned Phase I trial (NCT05183516), sponsored by Mindful Diagnostics and Therapeutics, is testing the effects of Tdap vaccination on Alzheimer’s disease biomarkers. The vaccine for Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis), which is not commonly used in the US, has previously been linked to a 42% lower risk in developing dementia.

Dr. Tom Dow, the principal investigator of the Tdap trial in Alzheimer’s disease, says the study has not yet started due to delays in funding. Still, he is encouraged by the therapeutic potential of vaccinations in Alzheimer’s: “The fact that we’re seeing a benefit in a variety of vaccinations that are targeting completely different organisms and diseases makes you think that the immune system really plays a significant role.”

Bioreactors in the body

The number of people with Alzheimer’s disease is expected to swell to more than 139 million by 2050, nearly tripling the burden of what is already the most prevalent neurodegenerative disease. In the US alone, the economic burden of Alzheimer’s reached $321 billion in 2022. Worldwide, that number is likely in the trillions.

As scientists pursue new vaccine targets and strategies to activate the immune system, there is also widespread recognition that much of Alzheimer’s disease is still poorly understood. Even the recent positive Phase III lecanemab data comes with a caveat: patients on lecanemab still deteriorated, just at a slower rate than patients on placebo. “Even though you’re getting rid of the amyloid beta oligomers in the brain, your disease is still progressing,” Arnold says. “To me, that says Alzheimer’s disease is more than just amyloid and there are still other factors that we’re not fully addressing.”

Alzheimer’s disease vaccines have come a long way since Elan’s failed study of AN-1792, and vaccine manufacturers recognize there is even more to do before a vaccine can be approved. But the underlying goal of making an affordable and effective Alzheimer’s vaccine remains unchanged. “MAbs are produced in giant vats in a very expensive process,” Hu says. “A vaccine teaches your body to be that bioreactor and make the antibodies yourself.”