# Amyloid-inspired Vaccine Delivery for the Elderly

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2022 · $196,875

## Abstract

PROJECT SUMMARY / ABSTRACT
Despite 20 years of research, there are no approved Alzheimer’s disease (AD) vaccines to date and the results
of recent phase III clinical trials have been disappointing. A key difference between developing infectious disease
vaccines and vaccines for AD is that Aβ/tau are self-antigens. The failure to respond to self-antigens is a hallmark
of the immune system. To subvert this tolerance, Aβ/tau epitopes are conjugated to bacterial/viral proteins and
mixed with adjuvants to induce robust antibody titers. Data from clinical studies indicate that proinflammatory
immune responses can aggravate pre-existing neuroinflammation in AD and lead to serious side effects like
encephalomyelitis. Also, most AD cases (~95%) are diagnosed in the elderly (>65 years). Studies show that in
contrast to younger adults, adjuvant-related inflammation obstructs immune responses in older adults and that
this effect can be mitigated by delivering anti-inflammatory therapies. An analysis of the current AD vaccine
literature strongly supports the idea that vaccines that drive robust anti-inflammatory antibody responses are
attractive for AD treatment.
In the parent grant, we are testing the toxicity and safety of amyloid-like peptide nanofiber (PNF) vaccines which
are known to be self-adjuvanting and anti-inflammatory using yeast models. We are also assessing their efficacy
in aged mice against influenza infection. Within this scope, here, we propose to develop nanovaccines targeting
Aβ and tau using PNFs to combat AD. We hypothesize that (i) PNFs are not neurotoxic and do not seed the
formation of toxic oligomeric species and that (ii) PNFs bearing Ab/tau epitopes will elicit robust titers of functional
antibodies in mice. In aim 1, we will synthesize and characterize PNFs bearing relevant Aβ/tau epitopes and use
established cell culture models to assess that conjugation of Aβ/tau does not impart toxicity. We will use
biosensor cells to test the capacity of the constructs to seed amyloid aggregation and complement these studies
using Thioflavin T assays and electron microscopy. We will also confirm the lack of Aβ and tau pathology of the
vaccine constructs in primary neurons. In aim 2, mice will be immunized with nanofiber vaccines bearing Ab/tau
epitopes currently used in clinical trials and the magnitude and persistence of the antibody response will be
assessed and affinities of Abs in the serum to monomeric and oligomeric forms of Ab/tau will be analyzed along
with their ability to prevent aggregation of amyloids. The synthetic nature of the constructs allows for high purity,
minimal contamination, and biochemical and biophysical validation representing a significant advantage over
current adjuvants which are heterogeneous mixtures of plant- or animal-derived byproducts. Due to the modular
nature of fibril assembly, peptides linked to different antigens or conformers of Ab/tau can be mixed to improve
the breadth of protection. Completion of th...

## Key facts

- **NIH application ID:** 10499306
- **Project number:** 3R21AG068733-02S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Meredith E. Jackrel
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,875
- **Award type:** 3
- **Project period:** 2021-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499306

## Citation

> US National Institutes of Health, RePORTER application 10499306, Amyloid-inspired Vaccine Delivery for the Elderly (3R21AG068733-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10499306. Licensed CC0.

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