Progress in the Active Immunotherapeutic Approach to Alzheimer’s Disease: Clinical Investigations into AN1792-Associated Meningoencephalitis

Pride, Michael W.; Seubert, Peter; Grundman, Michael; Hagen, Michael; Eldridge, John H.; Black, Ronald S.

doi:10.1159/000113700

Cited by 105 publications

(100 citation statements)

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“…10 The development of a Th1-type response was found to correlate with an adverse inflammatory reaction. 11 The development of an effective and safe immunotherapy protocol faces two challenges, namely, overcoming the low immunogenicity of the beta-amyloid peptide and avoiding detrimental inflammatory reactions in the brain.The N-terminus of beta-amyloid is considered the most promising antibody target for inclusion in recombinant vaccines. 1 We have previously observed reduced deposition of beta-amyloid plaques in mice that received monthly injections of phage-based vaccine fdAD (2-6), a bacteriophage that displays the epitope AEFRH of betaamyloid as an N terminal fusion to the major capsid protein pVIII.…”

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confidence: 99%

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A multimeric immunogen for the induction of immune memory to beta‐amyloid

et al. 2010

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The development of active immunotherapy for Alzheimer's disease (AD) requires the identification of immunogens that can ensure a high titer antibody response toward beta-amyloid, whereas minimizing the risks of a cell-mediated adverse reaction. We describe here two novel anti-beta-amyloid vaccines that consist of 'virus like particles' formed by a domain of the bacterial protein E2 that is able to self-assemble into a 60-mer peptide. Peptides 1-11 and 2-6 of beta-amyloid were displayed as N terminal fusions on the surface of the E2 particles. E2-based vaccines induced a fast-rising, robust and persistent antibody response to beta-amyloid in all vaccinated mice. The immune memory induced by a single administration of vaccine (1-11) E2 can be rapidly mobilized by a single booster injection, leading to a very high serum concentration of anti-beta-amyloid antibodies (above 1 mg ml À1 ). E2 vaccination polarizes the immune response toward the production of the anti-inflammatory cytokine interleukin-4 and does not induce a T cell response to beta-amyloid. Thus, E2-based vaccines are promising candidates for the development of immunotherapy protocols for AD. Alzheimer's disease (AD) is characterized by deposition of insoluble protein aggregates in the brain, known as amyloid plaques, which are mainly composed of beta-amyloid peptide. Active and passive immunization studies performed in transgenic mouse models of beta-amyloid deposition have demonstrated that antibodies against beta-amyloid are able to reduce plaques and improve cognition (reviewed in 1-3 ). In mouse models of AD, induction of a high titer of anti-beta-amyloid antibodies correlated with the therapeutic efficacy of vaccination [4][5][6] A clinical trial of immunization of AD patients with whole preaggregated beta-amyloid peptide has shown that immunization has the potential to reduce amyloid plaques in the brains of AD patients and delay disease progression. 7,8 However, the trial was interrupted when 6% of patients developed an adverse inflammatory reaction involving infiltration of T cells into the brain; moreover, only 59 of 300 individuals who received the vaccine mounted a humoral anti-beta-amyloid response with a titer higher than 1:2200. 9 Individuals with the highest titers of anti-beta-amyloid antibodies demonstrated the most pronounced depletion of plaques. 10 The development of a Th1-type response was found to correlate with an adverse inflammatory reaction. 11 The development of an effective and safe immunotherapy protocol faces two challenges, namely, overcoming the low immunogenicity of the beta-amyloid peptide and avoiding detrimental inflammatory reactions in the brain.The N-terminus of beta-amyloid is considered the most promising antibody target for inclusion in recombinant vaccines. 1 We have previously observed reduced deposition of beta-amyloid plaques in mice that received monthly injections of phage-based vaccine fdAD (2-6), a bacteriophage that displays the epitope AEFRH of betaamyloid as an N terminal fusion to the major capsid p...

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A multimeric immunogen for the induction of immune memory to beta‐amyloid

et al. 2010

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“…2 Initial phase I and phase II clinical (Elan/Wyeth AN1792) trials were conducted with aggregated Aβ1-42 and the QS-21; a Th1 response-activating adjuvant. 68,69 In the late stages of the phase I trial polysorbate 80, an emulsifying agent, was added to the active vaccine. It was at this time that immune responses shifted from a predominantly Th2-polarized response to a pro-inflammatory Th1 response 69 marked by meningoencephalitis and vascular T-lymphocyte infiltrations.…”

Section: Development Of Anti-aβ Vaccination In Humansmentioning

confidence: 99%

“…68,69 In the late stages of the phase I trial polysorbate 80, an emulsifying agent, was added to the active vaccine. It was at this time that immune responses shifted from a predominantly Th2-polarized response to a pro-inflammatory Th1 response 69 marked by meningoencephalitis and vascular T-lymphocyte infiltrations. 70 The mechanism of this self-reaction is unknown.…”

Section: Development Of Anti-aβ Vaccination In Humansmentioning

confidence: 99%

The central role of T-cell memory in Alzheimer’s disease vaccination

Giunta¹,

Ruscin²,

Salemi³

et al. 2010

Ageing Res

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Alzheimer's disease (AD) is the most common progressive neurodegenerative brain disease as well as the most common dementia among the elderly. In the future as the average lifespan continues to extend, the number of AD patients will continue to grow. Amyloidbeta (Aβ) peptides, in both soluble oligomeric, and insoluble forms, are key in the neuropathogenesis of AD and have thus been a therapeutic target for vaccines. Multiple Aβ vaccination strategies in animal models of AD have demonstrated a marked reduction in both amyloid burden and neurocognitive deficits. Due to the success of these studies, initial human clinical trials of an active Aβ vaccine were conducted. These were discontinued due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Studies examining the brains of Aβ-vaccinated patients developing meningoencephalitis implicate Aβ-reactive T-cell subsets as major components of this deleterious response to active Aβ vaccination. To subvert possible meningoencephalitis resulting from Aβ vaccination a second generation of vaccines has been more recently developed. These however have met with little success in humans. To build on these findings, an understanding of the role of T-cells in vaccination against Aβ is presented in this review. Various methods of Aβ immunotherapy are reviewed including studies in both animal models and humans. Recent works suggest that Aβ-derived peptides delivered intranasally or transcutaneously results in effective clearance of Aβ plaques and improvement of cognitive function in animal models of AD. Moreover, undesired T-cell reactivity appeared to be considerably reduced compared with other active immunization strategies. In spite of the past clinical studies, these findings imply that Aβ vaccination may be both efficacious and safe depending route of delivery, adjuvant choice, and Aβ epitope administered.

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“…32 During the later stages of the phase I trial, the emulsifier polysorbate 80 was added to the active vaccine, a change to the formulation after which the observed immune responses shifted from a predominantly Th2-biased response to a pro-inflammatory Th1 response. 33 Following the formulation change, an initial case with meningoencephalitis and vascular T-lymphocyte infiltrations occurred, 34 and in the subsequent phase II study, 18 further patients, or 6% of the patients treated with the active vaccine, developed forms of subacute aseptic meningoencephalitis after having received mostly two doses, and in some cases one or three of the initially planned six doses of the active vaccine. 35 Besides the T-cell reaction, the active vaccination also led to a humoral immune response in a subpopulation of the vaccinated patients with significantly increased IgG and IgM titers, 36 -38 but antibody titers were unrelated to the occurrence or the severity of meningoencephalitis.…”

Section: Initial Clinical Trialsmentioning

confidence: 99%

Targeting β-Amyloid Pathology in Alzheimer's Disease with Aβ Immunotherapy

Nitsch

Höck

2008

Neurotherapeutics

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Summary:More than 10 clinical trials of A␤ immunotherapy are currently underway in patients with Alzheimer's disease (AD). The aim is to identify safe approaches for the efficacious antibody-mediated removal of brain ␤-amyloid or its neurotoxic oligomeric precursors consisting of aggregated amyloid ␤-peptide (A␤). Initial experimental and neuro-pathological evidence for clearance of brain ␤-amyloid in response to A␤ immunotherapy is associated with structural and functional rescue of neurons, as well as initial signs of clinical stabilization and reduced rates of dementia progression. For the next steps in the future improvement of A␤ immunotherapy, major challenges in pharmacokinetics, safety, and tolerability need to be addressed. These include the low penetrations rates of IgG molecules through the blood-brain barrier, possible reductions in brain volume, the possibility of autoimmune disease related to unwanted crossreactivity with endogenous antigens on physiological structures, micro-hemorrhages related to cross-reaction with preexisting vascular amyloid pathology, possible relocalization of A␤ from ␤-amyloid plaques to brain blood vessels resulting in increased amyloid angiopathy, and the lacking activity of A␤ antibodies on pre-existing neurofibrillary tangle pathology, as well as the lacking molecular identification of the forms of A␤ to be therapeutically targeted. The solutions to these problems will be guided by the fine lines between tolerance and immunity against physiological and pathological structures, respectively, as well as by the understanding of the pathogenic transition of soluble A␤ into toxic oligomeric aggregation intermediates in the dynamic equilibrium of ␤-amyloid fibril assembly. Provided that the ongoing and planned clinical trials address these issues in a timely manner, there is a good chance for A␤ immunotherapy to be one of the first disease-modifying therapies of Alzheimer's disease to be introduced into clinical practice. Key Words: Humanized monoclonal antibody, neurodegeneration, vaccination, clinical trial, APP, passive immunization. PROOF OF CONCEPT IN EXPERIMENTAL ANIMALSThe concept of A␤ immunotherapy was first introduced by Schenk et al.1 who showed that vaccination with A␤1-42 and Freund's adjuvant prevented ␤-amyloid formation in brains of young transgenic mice and removed ␤-amyloid in older mice with pre-existing pathology. Subsequent active vaccinations in transgenic mice, nonhuman primates, and other species confirmed these findings 2-6 (For review, see references 7-10 ). Moreover, the passive transfer of antibodies against A␤ can efficiently reduce ␤-amyloid pathology.11-19 The immunotherapy-mediated clearance of ␤-amyloid pathology is paralleled by the recovery of neuronal and cytoskeletal morphology, 20,21 by the rescue of synaptic electrophysiological functions and neurotransmission, [22][23][24] and by signs of neuroprotection, 25 as well as by restored behavioral functions. 2,26 -28 While many antibodies show signs of efficacy in experimental animals, the...

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Progress in the Active Immunotherapeutic Approach to Alzheimer’s Disease: Clinical Investigations into AN1792-Associated Meningoencephalitis

Cited by 105 publications

References 14 publications

A multimeric immunogen for the induction of immune memory to beta‐amyloid

A multimeric immunogen for the induction of immune memory to beta‐amyloid

The central role of T-cell memory in Alzheimer’s disease vaccination

Targeting β-Amyloid Pathology in Alzheimer's Disease with Aβ Immunotherapy

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