Several Alzheimer’s vaccines enter clinical trials amid success of innovative treatments

Innovative Alzheimer’s treatments that remove toxic proteins from the brain have revived interest in vaccines to treat the memory-robbing disease, potentially offering a cheaper, easier-to-administer option for millions of people, according to interviews with 10 scientists and executives. of companies.

Clinical trials are underway or have been completed for at least seven Alzheimer’s vaccines designed to harness the immune system to clear the brain of beta amyloid or tau proteins linked to the disease, according to a review of the ClinicalTrials database. gov from the US government. More are on the way.

The renewed interest in Alzheimer’s vaccines follows a promising first attempt more than 20 years ago that was abandoned after 6% of study volunteers developed a life-threatening brain inflammation known as meningoencephalitis.


The researchers then opted for a safer route, infusing patients with highly specific artificial antibodies that evade the body’s immune machinery.

Eisai and Biogen’s newly launched Leqembi and Eli Lilly’s donanemab, now under US regulatory review, are two such treatments that cemented the view that clearing amyloid is key to fighting Alzheimer’s in people with early-stage disease. That success followed years of failures that left many experts questioning the amyloid theory.

Scientists, including those at Vaxxinity, AC Immune and Prothena, believe they now understand what went wrong with the first vaccine and are testing shots that they hope will trigger an immune response without causing excessive inflammation. The U.S. Food and Drug Administration has given the first two fast-track status, which should speed up the review of those vaccines.

Dr. Reisa Sperling, an Alzheimer’s researcher at Mass General Brigham in Boston, said she believes vaccines will play an important role as researchers look to prevent Alzheimer’s. “I’m very interested that that’s where we need to go.”

Sperling is leading a trial in cognitively normal people with Alzheimer’s proteins in the brain. He is considering vaccines for his next study in asymptomatic people with Alzheimer’s proteins in their blood, but not enough to register on brain scans.

Alzheimer’s vaccines are still in the early stages and will require large, years-long trials to prove they work.

Still, a vaccine administered quarterly or twice a year could offer a respite from Leqembi’s expensive bimonthly infusions, expanding access among the estimated 39 million people with Alzheimer’s worldwide.

“They could be from all over the world and not as expensive,” said Dr. Walter Koroshetz, director of the division of neurological disorders at the U.S. National Institutes of Health.

A doctor points out possible evidence of Alzheimer’s disease detected in a PET scan at Brigham And Women’s Hospital in Boston, March 30, 2023. (REUTERS/Brian Snyder/File Photo)

‘The doors have opened’

Vaxxinity may be further along, having completed a small Phase 2 trial of its vaccine, UB-311. Chief executive Mei Mei Hu said Leqembi’s success validated a long-questioned hypothesis.

“What we know is that if we remove certain bad forms of amyloid, we will see an effect on clinical outcomes, and that is surprising,” he said of Leqembi’s ability to slow cognitive decline.

Data from Vaxxinity’s Phase 2a trial with 43 volunteers in Taiwan published in August showed the vaccine was safe and tolerable after 78 weeks, with nearly all participants producing an antibody response. There were no cases of brain swelling, but 14% (6) developed brain hemorrhage, a side effect also common to infusion treatments.

Vaxxinity has been looking for a partner to help fund a larger confirmatory trial, but found the climate in recent years to be “pretty cold,” Hu said. “With (Leqembi’s) approval, the doors have opened and there is much more enthusiasm, much more investment.”


What went wrong

The first Alzheimer’s vaccine showed signs of benefit, but it also triggered an uncontrolled response from the immune system’s T cells, which are only supposed to destroy infected cells.

Most of the newer vaccines target B cells, immune cells that produce antibodies. AC Immune’s vaccine only activates B cells, said Dr. Michael Rafii of the University of Southern California. In a Phase 1 trial led by Rafii, the AC vaccine did not cause any meningoencephalitis, but only a subset of participants developed an immune response. The company is now testing a reformulated version.

Andrea Pfiefer, CEO of AC Immune, suggested that the sustained immune response to its vaccine in some patients explains the lack of brain swelling or bleeding seen with monoclonal antibodies like Leqembi, which peaks after each infusion. More data is expected in the first half of 2024. AC is also collaborating with Johnson & Johnson on a vaccine targeting tau, a toxic Alzheimer’s protein associated with brain cell death. Prothena, which emerged a decade ago from a company that co-developed that first vaccine, hopes to begin a trial next year of a vaccine that targets both beta amyloid and tau with the goal of preventing Alzheimer’s.

Prothena also has an anti-amyloid antibody in Phase 1 trials and an anti-tau antibody in-license from Bristol Myers Squibb.

Gene Kinney, chief executive of Prothena, said the company’s vaccine produces high levels of mature antibodies. Generating a strong immune response is critical for these types of vaccines, which would typically be given to older people with weaker immune systems, he said.


Consider that vaccines are ideal for people with presymptomatic Alzheimer’s. “What you want to do is, in the first place, prevent the disease from occurring.”

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