Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization

Orgogozo, J. M.; Gilman, Sid; Dartigues, Jean‐François; Laurent, Bernard; Puel, Michèle; Kirby, L.; Jouanny, P.; Dubois, Bruno; Eisner, Larry S.; Flitman, Stephen; Michel, Bernard‐François; Boada, Merçé; Frank, Ana; Höck, Christoph

doi:10.1212/01.wnl.0000073623.84147.a8

Cited by 1,242 publications

(914 citation statements)

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Section: Nih-pa Author Manuscriptmentioning

confidence: 90%

“…The temporal relationship to vaccination suggests mechanisms for the vasculitis in our study could include a strong cytokine production or enhanced reactions to Env antigen resulting from the adjuvant used, and/or another unknown immune activation mechanism resulting in an amplified reaction to the protein-adjuvant mix when the host is DNA primed. In support of a role for an adjuvant in the systemic events observed, reactogenic events associated with several well known adjuvants, including QS21 have been reported [15,21,22,[25][26][27][28][29].The design of the phase I study does not allow firm conclusions to be drawn regarding the etiology of these unusual local and systemic reactions. Given their occurrence in association with the high antibody and cellular immune responses to HIV Env induced by this DNA primeprotein boost vaccine, along with the recognition that HIV infected individuals display a varied autoimmune antibody repertoire to self-antigens [30][31][32][33][34][35], a potential relationship to HIV Env warrants consideration in the design and analysis of this and other vaccine trials.…”

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confidence: 99%

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The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

Kennedy

Green

et al. 2008

Vaccine

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This report describes the safety observations following administration of a polyvalent DNA primeprotein boost HIV-1 vaccine formulated with adjuvant QS21. Local injection site reactionswere the most common (65% of subjects), and included type IV delayed-type hypersensitivity (DTH) reactions at prior DNA inoculation sites in 12 of 28 (43%) subjects following protein vaccination. Systemic reactions revealed two cases of vasculitis temporally related to inoculation with recombinant Env protein + QS21 adjuvant. Questions remain regarding the cause of the vasculitis, but the unique DTH observation may have contributed to the high level of immune responses previously reported for this vaccine. Keywords HIV; vaccine; adverse event; vasculitisOver the past two decades, various HIV vaccines have been tested for safety and several for efficacy in humans. However, the majority have not reproduced, in humans, the high immunogenicity seen in preclinical testing. Recently, we reported that a novel multi-gene, polyvalent DNA prime-recombinant protein boost HIV vaccine formulation, DP6-001, elicited strong and balanced humoral and cell-mediated immunity in healthy, HIV-1-negative adult subjects [1]. Preclinical testing of DP6-001 demonstrated no significant adverse reactions in either rabbits or non-human primates despite the induction of robust immunity [2,3]. Previously tested HIV DNA vaccines have demonstrated excellent human safety profiles [4][5][6][7][8][9]. Recombinant protein-based HIV vaccines formulated with QS21 adjuvant have reported local reactions, but have shown limited systemic adverse events in humans [10][11][12][13][14][15]. The current report summarizes the phase 1 clinical safety and tolerability data, highlighting local and *Address correspondence to: Jeff Kennedy, M.D., Division of Molecular Medicine, Wadsworth Center, Biggs Laboratory, ESP, C606, NYS Department of Health, P.O. Box 509, Albany, New York 12201-0509, P: 518-473-8421, F: 518-473-2900, E: jsk07@health.state.ny.us. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The clinical trial was an open-label, 3-arm design requiring each subject to receive two vaccine components; three sequential inoculations using a DNA plasmid vaccine administered either intradermally (ID) or intramuscularly (IM) followed by two sequential inoculations using a protein vaccine as shown in Table 1. Healthy HIV-negative adults (aged 18-50) were enrolled under informed consent as previously described [1]. This study involved 2 dose levels of DNA vaccines (1.2mg (Groups A and B); 7.2mg (Group C)) expressing five gp120 Env ant...

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Section: Nih-pa Author Manuscriptmentioning

confidence: 90%

mentioning

confidence: 99%

The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

Kennedy

Green

et al. 2008

Vaccine

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“…197 This is an important finding, especially in the light of the first clinical A␤ immunization trial, which was terminated after the detection of profound neuroinflammation in some immunized patients. 206 …”

Section: Tau Vaccinationmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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“…These studies led to the development of several active and passive vaccination strategies in clinical trials. One of the earliest trials, based on active vaccination, was interrupted due to a subset of patients that developed meningoencephalitis [97], but the results of this trial proved informative. An over-exuberant T cell response appears to have been responsible for the meningoencephalitis that was observed in patients [98,99].…”

Section: Extracellular Clearance Degradation and Prevention Of Uptamentioning

confidence: 99%

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Kaufman

Diamond

2013

Neurotherapeutics

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Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization

Abstract: Postvaccination meningoencephalitis occurred without clear relation to serum anti-Abeta42 antibody titers. Potential mechanisms such as T-cell and microglial activation may be responsible and are under consideration to develop a safer anti-Abeta immunotherapy for AD.

Cited by 1,242 publications

References 29 publications

The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

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