University of New Mexico (UNM) researchers are preparing to launch human clinical trials for a groundbreaking vaccine designed to prevent the accumulation of pathological tau protein in the brain, a hallmark characteristic of Alzheimer's disease.
In a study recently published in Alzheimer's and Dementia: The Journal of the Alzheimer's Association, the experimental vaccine demonstrated robust immune responses in both mice and non-human primates, building upon earlier promising research.
"Because we've shown efficacy in the non-human primate, I think that is suggesting to us it's much closer to a clinical trial," said Dr. Kiran Bhaskar, professor in the Department of Molecular Genetics & Microbiology at UNM School of Medicine and lead researcher on the project.
The Science Behind Tau and Alzheimer's
Tau is a naturally occurring protein that helps stabilize neurons in healthy brains. However, when tau undergoes phosphorylation, it deforms and is ejected from neurons into the extracellular space, creating the tangles characteristic of Alzheimer's and other neurodegenerative diseases.
While several FDA-approved treatments target amyloid beta, another protein implicated in Alzheimer's pathology, these medications have shown only modest effects on disease progression. This limitation has led researchers to investigate whether targeting tau might provide a more effective therapeutic approach.
The UNM-developed active immunotherapy generates antibodies that specifically bind to pT181, a region of the altered tau protein identified as an Alzheimer's biomarker. This precise targeting mechanism is key to the vaccine's potential effectiveness.
Promising Preclinical Results
In a 2019 paper published in NPJ Vaccines, Dr. Bhaskar's team reported that mice bred to express pathological tau generated antibodies when given the vaccine. These mice showed reduced tangle formation in key brain structures and improved performance on cognitive tests.
The new research expands on these findings, demonstrating strong immune responses in two additional strains of mice bred to develop tau-related disease, including one with a human tau gene inserted into its genome.
Critically, the research team collaborated with the University of California, Davis, and the California National Primate Research Center to test the vaccine in macaques, whose immune systems and brains more closely resemble those of humans. These primates also showed strong and durable immune responses.
"This was important because it extends our work in an animal model that is more similar to humans," explained Dr. Nicole Maphis, postdoctoral researcher in the UNM Department of Neurosciences and first author on both vaccine papers. "Mice don't have a human immune response, but these non-human primates, their immune response is much more similar to humans."
Innovative Vaccine Technology
The vaccine utilizes a virus-like particle (VLP) platform developed by Bryce Chackerian and David Peabody, colleagues of Dr. Bhaskar in the Department of Molecular Genetics & Microbiology.
VLPs are essentially viruses whose DNA has been removed, rendering them harmless while maintaining their structural properties. The researchers attached snippets of the pT181 protein to the surface of these particles, making them visible to immune cells that can then mount a defense.
This approach offers several advantages over traditional vaccine technologies. VLP-based vaccines have demonstrated durable immunity with just one primary inoculation and two booster shots. They don't require adjuvants—substances like aluminum that are typically added to enhance immune response. Additionally, VLP platforms have established safety profiles in humans.
Translational Potential
To assess the vaccine's potential effectiveness in humans, researchers tested antibodies from the immunized monkeys on blood plasma samples from people with mild cognitive impairment, often a precursor to Alzheimer's. They also tested the antibodies on brain tissue from individuals who had died from Alzheimer's. In both cases, the antibodies successfully bound to the human version of the tau protein.
"Our results suggest the translational utility of pT181-Qβ against tauopathies," the researchers noted in their published abstract, referring to the specific formulation of their vaccine.
Path to Human Trials
Dr. Bhaskar and his colleagues are now seeking funding from venture capitalists and the Alzheimer's Association to launch a Phase 1 trial in humans. This initial trial would focus primarily on safety while providing preliminary data on immune response in human subjects.
If successful, this vaccine could represent a significant advancement in Alzheimer's treatment. Current therapies targeting amyloid beta have shown limited efficacy in slowing disease progression, creating an urgent need for alternative approaches.
The tau-targeting vaccine could potentially complement existing treatments or even provide a more effective standalone therapy for preventing or slowing the cognitive decline associated with Alzheimer's disease.
Broader Implications
Beyond Alzheimer's disease, the vaccine's approach could have implications for other tauopathies—neurodegenerative disorders characterized by the abnormal accumulation of tau protein. These include frontotemporal dementia, progressive supranuclear palsy, and certain forms of Parkinson's disease.
As the global population ages, the prevalence of Alzheimer's disease and related dementias continues to rise, creating enormous medical, social, and economic challenges. Innovative approaches like the tau-targeting vaccine represent critical avenues of research in addressing this growing public health crisis.
The advancement of this vaccine to human trials would mark a significant milestone in the quest for effective treatments for Alzheimer's disease and potentially open new therapeutic possibilities for millions of patients worldwide.
