A combination of two human monoclonal antibodies cures symptomatic rabies

Melo, Guilherme Dias de; Sonthonnax, Florian; Lepousez, Gabriel; Jouvion, Grégory; Minola, Andrea; Zatta, Fabrizia; Larrous, Florence; Kergoat, Lauriane; Mazo, Camille; Moigneu, Carine; Aiello, Roberta; Salomoni, Angela; Brisebard, Elise; Benedictis, Paola De; Corti, Davide; Bourhy, Hervé

doi:10.15252/emmm.202012628

Cited by 32 publications

(37 citation statements)

References 38 publications

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“…It is not currently understood why AAV-CR4098 generates such low VNA titers compared with AAV-CR57. Newly developed mAbs such as RVC20 and RVC58 were found to have a higher potency than CR57 and CR4098 ( De Benedictis et al, 2016 ; de Melo et al, 2020 ; Hellert et al, 2020 ). Combined utilization of these mAbs may improve the effectiveness of postexposure prophylaxis.…”

Section: Discussionmentioning

confidence: 99%

“…A live RABV vaccine, on the other hand, is unlikely to be authorized for therapeutic use in human rabies patients. Most recently, de Melo et al (2020) showed that a combination of RABV-neutralizing antibodies (RVNA) RVC20 and RVC58 could rescue symptomatic mice post RABV infection by concomitantly administration of RVNA in the CNS through intracerebroventricular infusion, sheding a light for an effective rabies therapy in humans.…”

Section: Introductionmentioning

confidence: 99%

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Preexposure and Postexposure Prophylaxis of Rabies With Adeno-Associated Virus Expressing Virus-Neutralizing Antibody in Rodent Models

et al. 2021

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Rabies, a fatal disease in humans and other mammals, is caused by the rabies virus (RABV), and it poses a public health threat in many parts of the world. Once symptoms of rabies appear, the mortality is near 100%. There is currently no effective treatment for rabies. In our study, two human-derived RABV-neutralizing antibodies (RVNA), CR57 and CR4098, were cloned into adeno-associated virus (AAV) vectors, and recombinant AAVs expressing RVNA were evaluated for postexposure prophylaxis after intrathecal injection into RABV-infected rats. At 4days post-infection with a lethal dose of RABV, 60% of the rats that received an intrathecal injection of AAV-CR57 survived, while 100% of the rats inoculated with AAV-enhanced green fluorescent protein (EGFP) succumbed to rabies. Overall, these results demonstrate that AAV-encoding RVNA can be utilized as a potential human rabies postexposure prophylaxis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preexposure and Postexposure Prophylaxis of Rabies With Adeno-Associated Virus Expressing Virus-Neutralizing Antibody in Rodent Models

et al. 2021

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“…Drug cocktails containing Favipiravir, Ribavirin, Interferon α/β, a Caspase-1 inhibitor, a TNF-α inhibitor, a MAPKs inhibitor and human rabies immune globulin (HRIG) have been explored in mouse RABV models (Smreczak et al ., 2019) but no clear therapeutic effect was noted. A cocktail of two human monoclonal antibodies RVC20/RVC58 delivered directly into the brain could cure half of the symptomatic rabid mice in the research(de Melo et al ., 2020). One part of the current PEP protocol involves the injection of RIG around the exposure wound that can prevent the transport of the virus via the neuromuscular junction to the peripheral nervous system and subsequently to the CNS.…”

Section: Discussionmentioning

confidence: 99%

TheUrtica DioicaAgglutinin Prevents Rabies Virus Infection in a Muscle Explant Model

Wang

Terrie

et al. 2021

Preprint

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Infection with the rabies virus (RABV) causes fatal encephalitis and paralysis in humans and animals. Post-exposure prophylaxis (PEP) consists of vaccination and the injection of anti-rabies immunoglobulins (RIGs) around the (bite) wound. This is 100% effective in preventing disease if administered in a timely manner. However, the costs, the required cold chain for storage and transport and the limited availability of RIGs makes the treatment challenging. Cheaper and easier to produce alternatives are urgently needed. To aid in the discovery and development of such alternative therapeutics, we developed a physiological relevant infection model. Strips of freshly dissected swine skeletal muscle were placed under tension in culture medium and infected with RABV. Viral antigens were produced in the muscle explants and the virus production increased significantly over time, indicating that RABV infects and replicates in the muscle explants. Subsequently, in a search for inhibitors of RABV entry in muscle cells, we first screened a panel of 34 different lectins in a RABV / BHK-21J cell assay. The Urtica Dioica (stinging nettle) Agglutinin (UDA; a N-acetyl-D-glucosamine specific agglutinin) was found to be able to completely inhibit infection of cells with the RABV (EC50 8.2 μg/mL) by preventing binding of the virus to the host cell. When the infection of the muscle strips was carried out in the presence of UDA, infection of the tissue was completely prevented. We thus developed a physiological relevant RABV muscle infection model and identified an easy to produce component that (i) may serve as a reference for further studies and (ii) holds promise as an alternative for RIGs in PEP.

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“…Access of antibodies to sites of viral replication in the clinical phase of the disease, when RABV is widely distributed in the CNS, is however problematic. Recently, de Melo et al ( 47 ) showed that continuous intracerebroventricular infusion for up to 20 days of two mAbs (RVC20 and RVC58) against the viral glycoprotein led to 56% survival of RABV-infected mice when initiated in the prodromal phase of the disease. Survival decreased to 33% when treatment was initiated one day later, in the early acute neurological phase.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

A One Medicine Mission for an Effective Rabies Therapy

et al. 2022

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Despite the disease's long history, little progress has been made toward a treatment for rabies. The prognosis for patient recovery remains dire. For any prospect of survival, patients require aggressive critical care, which physicians in rabies endemic areas may be reluctant or unable to provide given the cost, clinical expertise required, and uncertain outcome. Systematic clinical research into combination therapies is further hampered by sporadic occurrence of cases. In this Perspective, we examine the case for a One Medicine approach to accelerate development of an effective therapy for rabies through the veterinary care and investigational treatment of naturally infected dogs in appropriate circumstances. We review the pathogenesis of rabies virus in humans and dogs, including recent advances in our understanding of the molecular basis for the severe neurological dysfunction. We propose that four categories of disease process need to be managed in patients: viral propagation, neuronal degeneration, inflammation and systemic compromise. Compassionate critical care and investigational treatment of naturally infected dogs receiving supportive therapy that mimics the human clinical scenario could increase opportunities to study combination therapies that address these processes, and to identify biomarkers for prognosis and therapeutic response. We discuss the safety and ethics of this approach, and introduce the Canine Rabies Treatment Initiative, a non-profit organization with the mission to apply a One Medicine approach to the investigation of diagnostic, prognostic, and therapeutic options for rabies in naturally infected dogs, to accelerate transformation of rabies into a treatable disease for all patients.

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A combination of two human monoclonal antibodies cures symptomatic rabies

Cited by 32 publications

References 38 publications

Preexposure and Postexposure Prophylaxis of Rabies With Adeno-Associated Virus Expressing Virus-Neutralizing Antibody in Rodent Models

Preexposure and Postexposure Prophylaxis of Rabies With Adeno-Associated Virus Expressing Virus-Neutralizing Antibody in Rodent Models

TheUrtica DioicaAgglutinin Prevents Rabies Virus Infection in a Muscle Explant Model

A One Medicine Mission for an Effective Rabies Therapy

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