Multiple Approaches to Abeta Vaccination in Animal Models

Agadjanyan, Michael; Cribbs, David

Abstract

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-A? 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 A? and tau that have shown efficacy in transgenic models of AD with PTM A? 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-A?, Tau, and ?-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 A? 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 A?pE3, A?pE11, 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 nave 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 A?; (ii) vaccines targeting simultaneously two pathological proteins, A? 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 A? (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. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page

Public Health Relevance

Our novel, safe and immunogenic vaccines based on universal MultiTEP platform technology provide substantial benefits over other vaccines currently in Alzheimer?s disease (AD) clinical trials. More specifically, MultiTEP based vaccines are designed to (i) be especially beneficial for the elderly because they utilize memory T cells that are in abundance in elderly patients instead of relying on the activation of nave T cells, which decline with age; (ii) be effective in more than 95% of the human population; (iii) be safe because they do not contain parts of the Alzheimer?s pathological proteins that can induce dangerous adverse immune responses known as autoimmunity. Thus, in this renewal application, we propose using recently modified MultiTEP to develop vaccines targeting disease-related forms of amyloid and tau proteins that represent the two hallmarks of AD. In this renewal application we will test combinations of MultiTEP-based vaccines targeting two pathological molecules in relevant mouse models of AD with the aim to translate the research to clinical trials.