Promising Breakthrough: Vaccine That Could Curb Alzheimer’s Begins Human Trials

Researchers have developed an experimental vaccine that helps the body fight an abnormal protein called tau, which builds up in the brain and is linked to diseases such as Alzheimer's. The vaccine has shown good results in mice and monkeys, reducing the buildup of this protein, improving memory and being well tolerated. This suggests that, in the future, this vaccine could help prevent or treat neurodegenerative diseases.

Tauopathies are a group of neurodegenerative diseases, such as Alzheimer's disease (AD), characterized by the abnormal buildup of the protein tau in the brain. Normally, this protein helps to stabilize microtubules, structures that act as tracks for transporting substances within neurons.

However, in people with tauopathies, tau undergoes a chemical modification called hyperphosphorylation, which means that excess phosphate groups are added to it.

This causes the protein to become disorganized, lose its normal function, and begin to assemble into toxic structures such as soluble oligomers, paired helical filaments (PHFs), and neurofibrillary tangles (NFTs). These deposits damage neurons and contribute to the cognitive decline seen in these diseases.

Recent research using advanced microscopy techniques has shown that these tau deposits are varied and may be related to the different clinical manifestations of tauopathies. A specific type of altered tau, called phosphorylated tau (abbreviated as pTau), appears early in the disease.

The most commonly phosphorylated residues of the tau protein are threonine 181 (pT181), 205, 217, and 231. Elevated levels of pT181 and pT217 in the blood or cerebrospinal fluid are considered important markers for the diagnosis of Alzheimer's disease, and have therefore been the subject of many studies and therapeutic attempts.

With recent advances in treatments targeting beta-amyloid protein, another protein linked to Alzheimer's disease, such as the antibodies lecanemab and donanemab, interest in immunotherapy against the tau protein has grown again.

The immunotherapy strategy involves using monoclonal antibodies (produced in the laboratory) to bind to pTau and help the immune system eliminate it. Although some early tests have shown promising results in animal models, many of them have failed in human clinical trials, as was the case with the ABBV-8E12 antibody.

Reasons for these failures include poor choices of which part of the tau to target, the doses administered, and the way the treatment was delivered. In addition, these treatments are often expensive, require frequent infusions over long periods, and can cause side effects related to immune system activation.

As an alternative, scientists have been exploring active vaccination, which is a way to train a person’s own immune system to produce antibodies against pTau, in a more lasting way and with fewer medical interventions. However, to date, trials of specific tau vaccines (such as AADvac1 and ACI-35) have shown that the antibody responses generated are weak and short-lived.

This may be a result of both the way the vaccine was developed and the body’s natural tendency to tolerate this protein, as it is originally from the body itself (an autoantigen).

Based on these challenges, researchers have developed a new vaccine called pT181-Qß, which uses a virus-like particle (VLP) derived from a bacteriophage (a virus that infects bacteria) known as Qß. In this version, the virus presents on its surface a large number of copies of the small fragment of the tau protein with phosphorylation at threonine 181 (pT181), which helps to stimulate a more intense immune response.

Scientists chose this fragment for several reasons: it is a well-established biomarker for diagnosing tauopathies; it is released by neurons into the extracellular space, which facilitates access by antibodies; it is located in a part of the tau protein that is not eliminated early during the cellular release process; and its levels in the blood strongly correlate with the clinical severity of Alzheimer's disease.

The pT181-Qß vaccine has been successfully tested in genetically modified mice that develop pathologies similar to human tauopathies.

In these studies, vaccination led to the production of high levels of antibodies against pTau, reduced toxic accumulations of tau in the brain, decreased neural inflammation, and improved functions such as memory and motor coordination.

The pT181-Qß vaccine induced a strong and long-lasting immune response against the altered tau protein, which is involved in Alzheimer’s. In panel (A), we see the schematic of the experiment in mice with a mutation that causes tau accumulation (PS19 model). They were vaccinated with a virus-like particle (VLP) containing a part of the modified tau protein (pT181), bound to the surface of the particle. This process allows the immune system to recognize the protein as a “target” to fight. Image (B) shows that the vaccine was well prepared, with up to three pieces of the protein bound per particle. In graphs (C) and (D), we see that the vaccinated mice produced many antibodies specific to pTau, and this response lasted for at least 9 months. Finally, the images in panel (E) show that the antibodies generated by the vaccine were able to identify and bind to the altered tau protein in brain tissue, similar to what the control antibody AT8 (widely used to detect tau in Alzheimer’s) does. Mice that did not receive the specific vaccine did not show this reaction. Furthermore, these effects were achieved without triggering unwanted T-cell responses, which could lead to dangerous autoimmune reactions. One particularly important result was that the antibodies produced also reacted with samples of human brains with Alzheimer's, suggesting that this vaccine may have real clinical applicability.

To verify whether this approach is safe and effective in other species, the researchers administered the vaccine to adult rhesus monkeys, which are biologically closer to humans.

As with the mice, two doses of the vaccine, even without adjuvants (substances that normally help to increase the immune response), were sufficient to induce a strong and long-lasting antibody response.

The antibodies generated not only circulated in the blood but were also found in the central nervous system, which is crucial for a treatment aimed at eliminating brain tau deposits.

The experimental vaccine pT181-Qß was tested in monkeys and was shown to be safe, able to activate the immune system, and reach its intended target in the brain. The diagram (A) shows how the experiment was done: monkeys aged about 6 years were given three doses of the vaccine, and their blood and cerebrospinal fluid (spinal cord fluid) samples were collected. After 8 weeks (B), the vaccinated animals produced many antibodies against the phosphorylated tau protein (pT181), which is involved in Alzheimer's. As a result, the levels of this protein in the blood decreased (C), indicating that the antibodies were working (D). These antibodies were also detected in the monkeys' cerebrospinal fluid (E), suggesting that they had reached the brain. In addition, these antibodies recognized the abnormal tau protein in real samples of human brains with Alzheimer's (F). A graph (G) shows that this same protein (pT181) is found in people with mild cognitive impairment (an early stage of Alzheimer's), but not in healthy people. Finally, a (H–I) test showed that the vaccine antibodies were able to “fish” for and bind to the tau protein present in human brains with Alzheimer’s, proving its efficacy in recognizing the target.

Now, due to the positive results in animal tests, researchers at New Mexico University of Health Sciences are preparing to begin clinical trials in humans.

In summary, the results of these experiments show that the pT181-Qß vaccine holds promise as a strategy to prevent or reduce the damage caused by tauopathies. It has been shown to be safe, effective in multiple species, capable of inducing a potent and long-lasting immune response, and of significantly reducing the burden of pathological tau in the brain.

This suggests real potential for the development of a therapeutic vaccine against diseases such as Alzheimer’s, with important advantages over current approaches based on antibody infusions.

READ MORE:

Targeting of phosphorylated tau at threonine 181 by a Qβ virus-like particle vaccine is safe, highly immunogenic, and reduces disease severity in mice and rhesus macaques

Nicole M. Maphis, Jonathan Hulse, Julianne Peabody, Somayeh Dadras, Madelin J Whelpley, Manas Kandath, Colin Wilson, Sasha Hobson, Jeff Thompson, Suttinee Poolsup, Danielle Beckman, Sean P Ott, Jennifer W. Watanabe, Jodie L. Usachenko, Koen K Van Rompay, John Morrison, Reed Selwyn, Gary Rosenberg, Janice Knoefel, Bryce Chackerian and Kiran Bhaskar

Alzheimer’s & Dementia. Volume21, Issue3 March 2025 e70101

DOI: 10.1002/alz.70101

Abstract:

Pathological accumulation of tau (pTau) contributes to various tauopathies, including Alzheimer's disease (AD), and correlates with cognitive decline. A rapid surge in tau-targeted approaches via anti-sense oligonucleotides, active/passive immunotherapies suggests that targeting p-Tau is a viable strategy against tauopathies. We describe a multi-species validation of our previously described Qß virus-like particle (VLP)–based vaccine technology targeting phosphorylated tau on threonine 181 (pT181-Qß). Two vaccine doses of pT181-Qß, without any adjuvants, elicited robust antibody responses in two different mouse models of tauopathy (PS19 and hTau) and rhesus macaques. In mouse models, vaccination reduced AT180+ hyperphosphorylated, Sarkosyl insoluble, Gallyas silver positive tau, inflammasomes/neuroinflammation, and improved recognition memory and motor function without inducing adverse T-cell activation. Anti-pT181 antibodies are reactive to pTau in human AD brains, engage pT181+ tau in human brain lysates, and are central nervous system bioavailable. Our results suggest the translational utility of pT181-Qß against tauopathies.