Immunization with two experimental vaccines targeting the toxic forms of amyloid-beta and tau protein — two hallmarks of Alzheimer’s disease — triggered an immune response that reduced the levels of both proteins in the brain of a mouse model of the disease.
The new combination vaccine, which could enter human trials within two years, could become a potential treatment to delay or slow down disease progression.
The findings were published in an article, “Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice,” in the journal Alzheimer’s Research & Therapy.
Current clinical trials have primarily tested therapies that target either amyloid-beta plaques or tau tangles, yet this approach has failed to delay disease progression.
Neuroimaging studies support that the interaction between amyloid-beta and tau promote the neurodegeneration and cognitive decline that characterize Alzheimer’s. “Therefore, combinatorial therapies that concurrently target both [amyloid-beta] and tau might be needed for effective disease modification,” the researchers wrote.
In line with this hypothesis, scientists at the Institute for Molecular Medicine, University of California, Irvine, and Flinders University, in South Australia, targeted both amyloid-beta and tau aggregates in the hopes of providing a more powerful therapeutic strategy to delay Alzheimer’s.
In a previous study, the team had developed both an amyloid-beta and tau-targeting vaccine, called AV-1959R and AV-1980R. When given to healthy mice, these vaccines induced a powerful antibody response against these proteins. The vaccines were generated using a specific type of technology, called MultiTEP, which generates very high levels of antibodies.
In the new study, the team administered both vaccines simultaneously to observe if they could induce a similar immune response in a mouse model of Alzheimer’s that develops both amyloid-beta and tau aggregates.
“Our approach is looking to cover all bases and get past previous roadblocks in finding a therapy to slow the accumulation of [amyloid-beta]/tau molecules and delay [Alzheimer’s disease] progression in a rising number of people around the world,” study author and vaccine developer Nikolai Petrovsky, professor at Flinders University, said in a press release.
Animals received four intramuscular injections of AV-1959R or AV-1980R plus an adjuvant (AV-1959R/A or AV-1980R/A) or the combination of both vaccines plus an adjuvant (AV-1959R/A plus AV-1980R/A) over the course of eight months. The adjuvant, developed by Vaxine Pty and called AdvaxCpG, is a secondary substance that works as a booster of the immune system.
All groups produced high levels of antibodies specific for amyloid-beta and/or tau. Importantly, these antibodies were able to recognize amyloid-beta and tau protein tangles in human Alzheimer’s brain sections.
Serum from animals immunized with the single vaccines recognized either amyloid plaques or tau tangles. The serum from animals immunized with the vaccine combo detected both amyloid plaques and tau tangles. The serum of mice immunized with the adjuvant alone (controls) had no reaction.
The levels of amyloid-beta (both its soluble and insoluble forms) were significantly reduced in mice treated with the AV-1959R/A vaccine. In the combo vaccination, only the insoluble form was significantly decreased.
Similarly, the levels of total tau protein and its hyperphosphorylated form — which is associated with disease development — were reduced with AV-1980R/A and with the combo vaccination.
The researchers further observed that sex influenced the vaccines’ capacity to affect these proteins. Female mice treated with the vaccine combo had a significant reduction in the soluble form of amyloid beta (called amyloid-beta42), which was not observed with the AV-1959R/A vaccine alone. In contrast, male mice had a significant reduction of amyloid-beta42 when immunized with AV-1959R/A alone but only a slight reduction with the vaccine combo.
This could indicate that sex is a relevant factor for this treatment strategy; however, further research is required to fully understand these differences.
The team then looked at brain cell composition to understand whether vaccine immunization led to changes in microgliosis and astrocytosis, two inflammatory events characterized by an increase in the number of activated microglia and astrocytes — two types of brain cells — which are associated with the development of Alzheimer’s.
No differences were observed in the activation of microglia and astrocytes.
“A growing amount of evidence suggests that prophylactic [preventive] vaccination delivered prior to clinical symptoms may be needed to prevent the development of [Alzheimer’s] fully,” the researchers wrote, adding that “a combined vaccination approach could potentially be used to induce strong immune responses against both of the hallmark pathologies [disease characteristics] of [Alzheimer’s] in a broad population of vaccinated subjects.”
“Taken together, these findings warrant further development of this dual vaccination strategy based on the MultiTEP technology for ultimate testing in human Alzheimer’s disease,” said study lead authors Anahit Ghochikyan and Mathew Blurton-Jones.
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