Data from various Alzheimer?s disease (AD) active vaccine clinical trials targeting A? pathology suggest that these trials were unsuccessful because the vaccines: (i) did not induce therapeutically potent titers of anti-A? antibodies in immunized elderly people with immunosenescence and (ii) were initiated too late in AD pathogenesis. We suggest that an optimal AD vaccine formulation, adjuvant selection and targeting of the right pathological molecules at the right stage of disease will be crucial to a successful immunotherapeutic approach. We have developed novel, safe and immunogenic vaccines, based on the MultiTEP platform technology, that offer substantial benefits over vaccine platforms presently used in clinical trials. Our MultiTEP-based vaccines are specifically designed for the immunization of humans and our pre-clinical data generated in various Tg mice, rabbits, and monkeys suggest that these vaccines potentially can (i) overcome high polymorphism of MHC class II genes by activating a broad repertoire of nave and memory Th cells specific to carrier (MultiTEP platform); (ii) induce high titers of antibodies specific to pathological molecules involved in AD (e.g., A?/tau), but not to the MultiTEP platform itself; and (iii) generate therapeutically potent immune responses in the vast majority of vaccinated subjects without induction of potentially harmful autoreactive Th cells. Currently, a growing body of evidence suggests that A? pathology emerges many years before accumulation of tau pathology and before the first signs of cognitive impairment. Importantly, the accumulation of tau rather than A? correlates most strongly with cognitive decline in AD. Hence, we hypothesized that while anti-A? vaccination should be initiated as a prophylactic measure in very early AD (prodromal) and/or in non-symptomatic subjects at risk for AD, tau-based immunotherapeutic(s) can be used as a therapeutic measure in patients with mild-moderate AD. Accordingly, in this proposal we suggest to conduct pre-clinical IND-enabling studies on MultiTEP-based therapeutic vaccine targeting N-terminus of pathological Tau (AV-1980R). Importantly, our data showed that the AV-1980R formulated in the novel cGMP grade AdvaxCpG adjuvant (AV-1980R/A) is likely to be safe and effective, since it is inducing therapeutic antibodies that efficiently reduce total and phosphorylated Tau in brains of vaccinated Tg mice without generating potentially harmful autoreactive cellular immune responses. Collectively, published data from different groups including ours and preliminary results on AV-1980R/A provide the strong support for (i) manufacturing of engineering run (aka first run cGMP) recombinant protein that is according to FDA guidance is sufficient for safety/toxicology studies; (ii) completing safety/toxicology studies in diseased mouse model of Tauopathy and healthy rabbits, (iii) manufacturing cGMP AV-1980R/A, and (iv) obtaining all necessary regulatory documents for the IND submission. Getting an FDA-cleared IND for AV-1980R/A will allow us to test for the first time the safety and immunogenicity of an active vaccine targeting the N-terminus of tau in Phase 1 clinical trials and develop an effective vaccination protocol for future Phase 2/3 clinical trials.
Current medications for Alzheimer?s disease may provide modest symptomatic improvement over the short term in some patients with mild-to-moderate AD, but do not alter disease progression, indicating that new prophylactic and/or therapeutic approaches for treating AD are essential: at the completion of these studies, the main goal of our multidisciplinary team is to obtain all of the necessary regulatory documents for an FDA-approved investigational new drug (IND) for AV-1980R/A clinical trials in patients with MCI due to AD and mild AD. Recently our multidisciplinary team of researchers reported on an adjuvanted recombinant Tau vaccine, AV- 1980R, formulated with highly potent and safe AdvaxCpG adjuvant termed as AV-1980R/A, based on a MultiTEP platform technology that is highly immunogenic in mice, rabbits and monkeys. In this U01 project we propose to manufacture cGMP adjuvanted vaccine, AV-1980R/A, complete IND-enabling safety/toxicology studies on AV- 1980R/A according to FDA recommendations from our pre-IND meeting and submit an IND application to the FDA.