Prolonging morbidity in rabid dogs by intrathecal injection of attenuated rabies vaccine

Baer, George M.; Shaddock, John H.; Williams, Lesley-Anne

doi:10.1128/iai.12.1.98-103.1975

Cited by 16 publications

(5 citation statements)

References 10 publications

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“…In addition, IT vaccination not only induced VNA production in the CSF but also enhanced the BBB permeability, as observed by the presence of total proteins and WBCs in the CSF. Similar IT vaccination in dogs has been reported by Baer et al, which not only induced VNA in the CSF, but also prolonged the morbidity [ 61 ]. Recent report of survival of rabid rabbits after IT immunization highlights the importance of CSF VNA on viral clearance [ 30 ].…”

Section: Discussionsupporting

confidence: 79%

Differential Host Immune Responses after Infection with Wild-Type or Lab-Attenuated Rabies Viruses in Dogs

et al. 2015

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Rabies virus (RABV) induces encephalomyelitis in humans and animals. One of the major problems with rabies is that the infected individuals most often do not develop virus neutralizing antibodies (VNA). In this study we have investigated the host immune response to RABV infection in dogs, using a live-attenuated (TriGAS) or a wild-type (wt) (DRV-NG11) RABV isolated from a rabid dog.Methodology/Principal FindingsThe experimental infection of dogs with TriGAS induced high levels of VNA in the serum, whereas wt RABV infection did not. Dogs infected with TriGAS developed antibodies against the virus including its glycoprotein, whereas dogs infected with DRV-NG11 only developed rabies antibodies that are presumably specific for the nucleoprotein, (N) and not the glycoprotein (G). We show that infection with TriGAS induces early activation of B cells in the draining lymph nodes and persistent activation of DCs and B cells in the blood. On the other hand, infection with DRV-NG11 fails to induce the activation of DCs and B cells and further reduces CD4 T cell production. Further, we show that intrathecal (IT) immunization of TriGAS not only induced high levels of VNA in the serum but also in the CSF while intramuscular (IM) immunization of TriGAS induced VNA only in the serum. In addition, high levels of total protein and WBC were detected in the CSF of IT immunized dogs, indicating the transient enhancement of blood-brain barrier (BBB) permeability, which is relevant to the passage of immune effectors from periphery into the CNS.Conclusions/SignificanceIM infection of dogs with TriGAS induced the production of serum VNA whereas, IT immunization of TriGAS in dogs induces high levels of VNA in the periphery as well as in the CSF and transiently enhances BBB permeability. In contrast, infection with wt DRV-NG11 resulted in the production of RABV-reactive antibodies but VNA and antibodies specific for G were absent. As a consequence, all of the dogs infected with wt DRV-NG11 succumbed to rabies. Thus the failure to activate protective immunity is one of the important features of RABV pathogenesis in dogs.

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Section: Discussionsupporting

confidence: 79%

Differential Host Immune Responses after Infection with Wild-Type or Lab-Attenuated Rabies Viruses in Dogs

et al. 2015

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“…In the future, however, more effective treatment of rabies encephalitis may become possible. A promising method is injection of an attenuated rabies virus intrathecally, or perhaps iv injection of neutralising antibody, if the blood brain barrier can be bypassed by intraventricular administration [ 41 ], or breached pharmacologically [ 44 , 45 ]. Such apparently drastic therapy would be ethical for some sufferers of this fatal infection, but should be undertaken only when there is evidence of effectiveness in animals, and in an ethical and specialised research setting.…”

Section: Antiviral Therapy?mentioning

confidence: 99%

The Imperative of Palliation in the Management of Rabies Encephalomyelitis

Warrell

Tarantola

2017

TropicalMed

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The aim of this review is to guide clinicians in the practical management of patients suffering from rabies encephalomyelitis. This condition is eminently preventable by modern post-exposure vaccination, but is virtually always fatal in unvaccinated people. In the absence of any proven effective antiviral or other treatment, palliative care is an imperative to minimise suffering. Suspicion of rabies encephalomyelitis depends on recognising the classic symptomatology and eliciting a history of exposure to a possibly rabid mammal. Potentially treatable differential diagnoses must be eliminated, notably other infective encephalopathies. Laboratory confirmation of suspected rabies is not usually possible in many endemic areas, but is essential for public health surveillance. In a disease as agonising and terrifying as rabies encephalomyelitis, alleviation of distressing symptoms is the primary concern and overriding responsibility of medical staff. Calm, quiet conditions should be created, allowing relatives to communicate with the dying patient in safety and privacy. Palliative management must address thirst and dehydration, fever, anxiety, fear, restlessness, agitation, seizures, hypersecretion, and pain. As the infection progresses, coma and respiratory, cardiovascular, neurological, endocrine, or gastrointestinal complications will eventually ensue. When the facilities exist, the possibility of intensive care may arise, but although some patients may survive, they will be left with severe neurological sequelae. Recovery from rabies is extremely rare, and heroic measures with intensive care should be considered only in patients who have been previously vaccinated, develop rabies antibody within the first week of illness, or were infected by an American bat rabies virus. However, in most cases, clinicians must have the courage to offer compassionate palliation whenever the diagnosis of rabies encephalomyelitis is inescapable.

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“…This section ends with a brief description of potential future advances in the field of antirabies drug discovery. Indeed, although promising results were obtained in a preliminary experiment in dogs, in which three symptomatic animals (of 12) treated intrathecally with a live attenuated ERAderived rabies vaccine appeared to recover, a second experiment based on the same treatment resulted only in the probable prolongation of the survival period, with all the symptomatic dogs eventually dying [134]. In another study conducted in monkeys, a live attenuated Flury LEP-derived rabies vaccine was also administrated intrathecally at the clinical stage, but without success, as all symptomatic animals (n=2) succumbed with no detectable prolongation of the survival period [136].…”

Section: Future Developmentsmentioning

confidence: 99%

Human Rabies Encephalitis Prevention and Treatment: Progress Since Pasteurs Discovery

Dacheux¹,

Delmas²,

Bourhy

2011

IDDT

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Rabies remains one of the most ancient and deadly of human infectious diseases. This viral zoonosis is transmitted principally by the saliva of infected dogs, inducing a form of encephalomyelitis that is almost invariably fatal. Since the first implementation, by Louis Pasteur in 1885, of an efficient preventive post-exposure treatment, more effective protocols and safer products have been developed, providing almost 100% protection if administered early enough. However, this disease still represents a major, but neglected public health problem, with an estimated 55,000 human deaths due to rabies reported each year, mostly in Africa and Asia. Once the first clinical signs appear, there is no effective treatment. A ray of hope emerged in 2004, with the report of a patient recovering from rabies after aggressive, innovative treatment. However, this case was not clearly reproduced and the identification of targets for antiviral treatment in cases of rabies infection remains a major challenge. In this context, this review presents the state-of-the art in the prevention and curative treatment of human rabies. We begin by describing the viral etiological agent and the disease it causes, to provide an essential background to rabies. An overview of the post-exposure prophylaxis of rabies in humans is then given, from its initial implementation to possible future developments. Finally, an analysis of the various antiviral compounds tested in rabies in vitro, in animal models or in humans is presented, focusing in particular on potential new strategies.

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Prolonging morbidity in rabid dogs by intrathecal injection of attenuated rabies vaccine

Cited by 16 publications

References 10 publications

Differential Host Immune Responses after Infection with Wild-Type or Lab-Attenuated Rabies Viruses in Dogs

Differential Host Immune Responses after Infection with Wild-Type or Lab-Attenuated Rabies Viruses in Dogs

The Imperative of Palliation in the Management of Rabies Encephalomyelitis

Human Rabies Encephalitis Prevention and Treatment: Progress Since Pasteurs Discovery

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