Program Director/Principal Investigator (Last, First, Middle):
Significance: Alzheimer’s disease (AD) is the most common cause of dementia. By 2050, the cost of treating
AD in the US is expected to increase to $1.1 trillion a year from the current $200 billion. Obviously, new
therapeutic approaches for treating AD are essential. Data from active and passive immunizations trials had
shown that in immunized AD patients the highest anti-Aß antibody titers correlated with a reduction in brain
pathology, suggesting that pathology-modifying benefits (Clinical Dementia Rating - Sum of Boxes and Mini
Mental State Examination scores) were closely linked to the antibody titers. Rationale: Due to the enormous
costs associated with the long-term passive immunotherapy, we believe that it is critical to develop a safe and
immunogenic active vaccine targeting simultaneously two disease-related post-translationally modified proteins
(PTM) involved in the pathogenesis of AD. Importantly, we plan to compare the therapeutic efficacy of well-
characterized unmodified B cell epitopes of Aß and tau that have shown efficacy in transgenic models of AD
with PTM Aß and tau that occur early in AD pathogenesis. Innovation: We have developed a universal
MultiTEP platform and showed that it is extremely immunogenic in inbred mice of different immune haplotypes,
as well as in outbred rabbits and monkeys. We have also identified a novel safe adjuvant, AdvaxCpG that has
previously been used in human clinical trials, which provides additional immune enhancement for the MutiTEP-
based anti-Aß, Tau, and a-syn vaccines. Finally, we have modified our MultiTEP platform by incorporating
click chemistry to generate conjugate vaccines targeting several PTM molecules involved in AD pathogenesis.
Design: This study is based on the evidence that abnormal PTM Aß and tau play an important role in the
onset and progression of AD making them attractive targets for active immunotherapy. Based on the literature
we have chosen AßpE3, AßpE11, pTau202/205, pTau396/404, and pTau422 B cell epitopes that we attached
to modified MultiTEP platform. These adjuvanted vaccines designed for clinical trials can potentially (i)
activate a broad repertoire of naïve and memory Th cells specific to MultiTEP; (ii) generate high titers of
antibodies specific to only PTM proteins, but not native molecule, and (iii) they can’t generate potentially
harmful autoreactive Th cells or induce high titers of unfavorable anti-MultiTEP antibodies. We suggest that (i)
vaccines targeting PTM can be more effective than that targeting unmodified species of tau and Aß; (ii)
vaccines targeting simultaneously two pathological proteins, Aß and tau, could be more therapeutically
effective than targeting a single protein. To test these hypotheses we will evaluate the immunogenic and
therapeutic efficacy of multiple MultiTEP vaccines in three complementary Aims using pathologically robust Aß
(5XFAD), tau (THY-Tau22), and the bigenic 5XFAD crossed to THY-Tau22 (T5x) mouse models. The
following Specific Aims will be explored to determine the best candidate vaccines. If successful, this strategy
will form the basis of future clinical trials for AD.
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