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Classifications

Harrison's Part

◆

Subtypes

2

Encephalitic (furious) rabies

The classical form, accounting for the majority of human cases: fluctuating agitation and hyperexcitability, hydrophobia and aerophobia, hypersalivation, and autonomic instability, progressing to coma and death. Hydrophobia and aerophobia are more characteristic of dog-acquired disease.

Show evidence (1 reference)

PMID:23723193 SUPPORT Human Clinical

"Encephalopathy, hydrophobia, and aerophobia were more common in dog-acquired rabies."

Associates the encephalitic phenotype with dog-acquired rabies in a 122-case series.

Paralytic (dumb) rabies

Ascending flaccid weakness with relatively preserved consciousness, frequently misdiagnosed as Guillain-Barre syndrome. Survival time is longer than in encephalitic rabies, but the outcome is the same.

Show evidence (1 reference)

PMID:23723193 SUPPORT Human Clinical

"Patients with paralytic rabies had longer survival times than those with encephalitic rabies, and also had shorter incubation periods if they had received postexposure prophylaxis."

Distinguishes the paralytic form by its longer survival time.

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Discussions and Knowledge Gaps

1

What is the molecular basis of the neuronal dysfunction that kills in rabies, given that infected neurons are structurally preserved and inflammation is minimal?

KNOWLEDGE GAP OPEN rabies_neuronal_dysfunction_basis

Attached to

pathophysiology#Neuronal Dysfunction Without Substantial Neuronal Death

This is the central unresolved question of the entry and the reason no post-symptomatic therapy has ever worked. Every candidate mechanism proposed so far - electrophysiological alterations, ion channel and neurotransmission effects, neurotoxicity, and more recently mitochondrial bioenergetic failure with mitophagy - remains a candidate rather than a demonstrated cause. Until the effector step is identified there is no rational target for therapy after symptom onset, which is precisely the window in which every attempted treatment, the Milwaukee protocol included, has failed.

Proposed experiments

Electrophysiological phenotyping of infected human-derived neurons

rabies_neuron_electrophysiology

Patch-clamp and multi-electrode-array characterisation of synaptic transmission, resting membrane potential, and ion channel behaviour in rabies-infected human iPSC-derived neurons, comparing street virus with laboratory-adapted strains, to establish whether a reproducible functional lesion precedes any structural change.

Supporting outcome

A consistent, strain-independent defect in synaptic transmission or excitability appearing before structural change would identify the effector step of neuronal dysfunction.

Refuting outcome

Normal electrophysiology in productively infected neurons would argue the fatal lesion lies outside cell-autonomous neuronal function, redirecting attention to network or systemic mechanisms.

Mitochondrial rescue in an infected neuronal model

rabies_mitochondrial_rescue

Test whether restoring mitochondrial membrane potential or blocking mitophagy preserves neuronal function in infected neurons, directly probing the bioenergetic hypothesis proposed from naturally infected human and canine brain.

Supporting outcome

Functional rescue without reducing viral replication would establish mitochondrial failure as the causal effector rather than a bystander correlate.

Refuting outcome

Preserved mitochondrial function with unchanged neuronal dysfunction would demote the bioenergetic account to an epiphenomenon.

Show evidence (1 reference)

PMID:15804968 SUPPORT Other

"The precise bases of this functional impairment are unknown, and current knowledge on electro-physiological alterations, effects on ion channels and neurotransmission, and neurotoxicity are reviewed."

States directly that the basis of the functional impairment is unknown, which is the gap this discussion records.

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Pathophysiology

11

Inoculation of Virus into Peripheral Tissue

A bite from an infected animal deposits saliva-borne lyssavirus into peripheral wound tissue. Virus may replicate locally in muscle or persist at the inoculation site before entering the nervous system, which accounts for the characteristically long and variable incubation period.

skeletal muscle fiber CL:0008002

skeletal muscle tissue UBERON:0001134

Downstream

Neuromuscular Junction Entry into Motor Neurons Virus deposited at the wound reaches motor nerve terminals at the neuromuscular junction, the principal portal of entry into the nervous system.

Selective Vulnerability of Dorsal Root Ganglion Neurons Virus at the inoculation site also reaches the sensory ganglion serving that dermatome, a separate branch from the motor-neuron route and the likely basis of the local sensory symptoms patients report at the healed bite.

Show evidence (1 reference)

PMID:12144896 SUPPORT Other

"Viral transmission occurs mainly via animal bite, and once the virus is deposited in peripheral wounds"

Establishes deposition of virus in peripheral wound tissue as the initiating event.

Neuromuscular Junction Entry into Motor Neurons

Virions concentrate at the neuromuscular junction, colocalising with nicotinic acetylcholine receptors, and are taken up into endosomal compartments of the motor nerve terminal. Rabies virus glycoprotein also binds the p75 neurotrophin receptor with high affinity, giving the virus more than one route into the neuron.

motor neuron CL:0000100

virion attachment to host cell GO:0019062 receptor-mediated endocytosis GO:0006898

Downstream

Retrograde Axonal Transport to the Central Nervous System Endocytosed virions in acidified compartments of the nerve terminal are carried centripetally along the axon toward the neuronal cell body.

Show evidence (3 references)

PMID:10797395 SUPPORT In Vitro

"Texas Red-labeled alpha-bungarotoxin, which binds to nicotinic acetylcholine receptors, colocalized precisely with virus at the densities identifying these regions as neuromuscular junctions."

Shows virus colocalising with nicotinic acetylcholine receptors at the neuromuscular junction.

PMID:25165859 SUPPORT In Vitro

"The p75 Nerve Growth Factor (NGF) receptor (p75NTR) binds RABV Glycoprotein (RABV-G) with high affinity."

Documents the high-affinity glycoprotein-p75NTR interaction used for neuronal entry.

PMID:29188797 SUPPORT Other

"The virus first infects peripheral motor neurons, and symptoms occur after the virus reaches the central nervous system."

Confirms peripheral motor neurons as the first infected cell population in human disease.

Retrograde Axonal Transport to the Central Nervous System

Rabies virus depends on long-distance retrograde axonal transport to reach the central nervous system. It travels within acidic compartments largely together with p75NTR, and moves faster and more directively than the receptor's endogenous cargo, indicating that the virus does not merely hitchhike on the transport machinery but manipulates it.

motor neuron CL:0000100

retrograde axonal transport GO:0008090

Downstream

Central Nervous System Neuronal Infection Arrival of virus at the neuronal cell body establishes infection in the spinal cord and brain, from which trans-synaptic spread disseminates the infection through the neuraxis.

Show evidence (3 references)

PMID:25165859 SUPPORT In Vitro

"Rabies virus (RABV) is a neurotropic virus that depends on long distance axonal transport in order to reach the central nervous system (CNS)."

States the dependence of CNS invasion on long-distance axonal transport.

PMID:25165859 SUPPORT In Vitro

"Hence, RABV may employ p75NTR-dependent transport as a fast mechanism to facilitate movement to the CNS."

Supports p75NTR-dependent transport as an accelerated route to the CNS.

PMID:12144896 SUPPORT Other

"once the virus is deposited in peripheral wounds, centripetal passage occurs towards the central nervous system."

Describes centripetal spread to the CNS in the clinical review literature.

Central Nervous System Neuronal Infection

Virus reaching the spinal cord and brain infects neurons and spreads trans-synaptically through the neuraxis, including brainstem, limbic, and hypothalamic structures. Symptoms begin only after the CNS is reached, which is why the disease is clinically silent throughout the incubation period.

neuron CL:0000540

central nervous system UBERON:0001017 brainstem UBERON:0002298 spinal cord UBERON:0002240

Downstream

Negri Body Formation and Viral Replication Infected neurons assemble cytoplasmic viral factories in which viral RNA synthesis takes place.

Mitochondrial Dysfunction and Mitophagy in Infected Neurons Infection of CNS neurons is accompanied by disrupted mitochondrial structure and altered bioenergetics in naturally infected human and canine brain.

Show evidence (2 references)

PMID:29188797 SUPPORT Other

"The virus first infects peripheral motor neurons, and symptoms occur after the virus reaches the central nervous system."

Establishes CNS arrival as the trigger for clinical disease.

PMID:18444083 SUPPORT Model Organism

"Abnormal hypersignal T2 changes were found at hippocampus, hypothalamus, brainstem, and spinal cord of paralytic dogs."

Naturally infected dogs show CNS involvement of hippocampus, hypothalamus, brainstem, and spinal cord.

Negri Body Formation and Viral Replication

Rabies virus nucleoprotein N and phosphoprotein P condense into spherical, liquid-like cytoplasmic inclusions, the Negri bodies, which act as viral factories. All viral RNA species (genome, antigenome, and mRNAs) are found inside them, and these are the sites where viral transcription and replication occur. Negri bodies are the classical histopathological hallmark of rabies.

neuron CL:0000540 hippocampal pyramidal neuron CL:0000598 cerebellar Purkinje cell CL:0000121

viral transcription GO:0019083 viral genome replication GO:0019079

Negri body GO:0016234

Downstream

Neuronal Dysfunction Without Substantial Neuronal Death Productive intraneuronal replication is followed by profound functional impairment of infected neurons, although the molecular steps linking replication to dysfunction remain incompletely defined.

Show evidence (3 references)

PMID:19494013 SUPPORT In Vitro

"Significantly, short-term RNA labeling in the presence of BrUTP strongly suggests that the NBLs are the sites where viral transcription and replication take place."

Direct experimental evidence that Negri body-like structures are the sites of viral RNA synthesis.

PMID:31317498 SUPPORT Other

"NBs are cytoplasmic inclusion bodies in which viral RNAs (mRNAs as well as genomic and antigenomic RNAs) are synthesized."

Characterises Negri bodies as the cytoplasmic compartments of viral RNA synthesis.

PMID:31317498 SUPPORT Other

"The co-expression of rabies virus nucleoprotein N and phosphoprotein P is sufficient to induce the formation of cytoplasmic inclusions recapitulating NBs properties."

Identifies N and P as the minimal viral components sufficient to build the replication compartment.

Mitochondrial Dysfunction and Mitophagy in Infected Neurons

In naturally infected human and canine brain, respiratory complex activities rise but ATP production does not, consistent with a fall in mitochondrial membrane potential. Disrupted cristae architecture and markers of mitophagy and autophagy accompany these changes, offering one candidate route from infection to neuronal dysfunction in the near absence of cell death.

neuron CL:0000540

mitophagy GO:0000423 autophagy GO:0006914

Downstream

Neuronal Dysfunction Without Substantial Neuronal Death Bioenergetic failure and mitophagy are proposed to converge on functional impairment of otherwise structurally preserved neurons.

Show evidence (1 reference)

PMID:35229271 SUPPORT Human Clinical

"We propose that altered mitochondrial bioenergetics and cristae architecture probably induce mitophagy, leading to autophagy and consequent neuronal dysfunction in rabies."

Proposes the mitochondrial-mitophagy route to neuronal dysfunction; framed as a proposal by the authors, hence PROVISIONAL confidence.

Selective Vulnerability of Dorsal Root Ganglion Neurons

In experimentally infected mice, sensory ganglion neurons show inflammatory infiltrates and degenerative change while CNS neurons remain comparatively spared. This selective peripheral sensory vulnerability is a plausible correlate of the pain, itch, and paresthesias patients report at the healed bite. Clinical review independently attributes those local symptoms to infection of the local peripheral sensory ganglia, so the human correlate is asserted in the clinical literature even though the cellular vulnerability itself is characterised only in mice.

sensory neuron CL:0000101

dorsal root ganglion UBERON:0000044

Show evidence (3 references)

PMID:19252919 SUPPORT Model Organism

"Light microscopy showed multifocal mononuclear inflammatory cell infiltrates in the sensory ganglia and a spectrum of degenerative neuronal changes."

Documents degenerative change in sensory ganglia in the mouse model.

PMID:19252919 SUPPORT Model Organism

"Hence, gangliocytes exhibit selective vulnerability in this animal model."

States the selective vulnerability finding, explicitly scoped to the animal model.

PMID:30747124 SUPPORT Human Clinical

"Local neurological symptoms are likely to be due to RABV infection in local peripheral sensory ganglia"

Human clinical review attributing bite-site sensory symptoms to local sensory ganglion infection.

Neuronal Dysfunction Without Substantial Neuronal Death

The defining paradox of rabies neuropathology: clinical disease is catastrophic while morphological changes in the brain are mild. Neurons are largely structurally preserved and inflammation is minimal, so the fatal outcome is attributed to functional impairment of infected neurons rather than to their destruction. The precise basis of that impairment remains unknown.

neuron CL:0000540

chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

Downstream

Acute Progressive Encephalomyelitis Widespread neuronal functional failure manifests as an acute, progressive encephalomyelitis that is nearly always fatal.

Show evidence (2 references)

PMID:15804968 SUPPORT Other

"Because morphologic changes in natural rabies are usually relatively mild, it is thought that the severe clinical disease with a fatal outcome must be due to neuronal dysfunction of rabies virus-infected neurons."

States the dysfunction-not-destruction principle directly.

PMID:35229271 SUPPORT Human Clinical

"The presence of minimal neuropathological changes observed in rabies indicates that neuronal dysfunction, rather than neuronal death contributes to the fatal outcome."

Independent confirmation in naturally infected human and canine brain.

Acute Progressive Encephalomyelitis

The clinical expression of CNS infection: an acute, relentlessly progressive encephalomyelitis passing through prodrome, an acute neurological phase, coma, and death. Once it begins it is essentially incurable.

brain UBERON:0000955

Downstream

Divergence into Encephalitic versus Paralytic Clinical Forms The encephalomyelitis expresses itself in two distinguishable clinical forms whose separation tracks with viral burden and host inflammatory response.

Centrifugal Spread to Salivary Glands and Extraneural Organs Once CNS infection is established, virus travels back out along nerves to peripheral organs.

Show evidence (2 references)

PMID:12144896 SUPPORT Other

"Rabies is an acute, progressive, incurable viral encephalitis."

The abstract defines rabies as an acute, progressive, incurable viral encephalitis.

PMID:29188797 SUPPORT Other

"Once clinical disease develops, it is almost certainly fatal."

Confirms near-universal fatality once clinical disease is established.

Divergence into Encephalitic versus Paralytic Clinical Forms

Rabies presents as either encephalitic (furious) disease, with agitation, hydrophobia, aerophobia, and autonomic instability, or paralytic (dumb) disease, with ascending flaccid weakness and relatively preserved consciousness. In naturally infected dogs, furious disease carries higher brain viral load with only moderate inflammation, whereas paralytic disease shows delayed neuroinvasion with more intense inflammation, suggesting the host inflammatory response shapes which form develops.

Show evidence (3 references)

PMID:18444083 SUPPORT Model Organism

"Larger quantities of rabies viral RNA were found in the brains of furious than in paralytic dogs."

Documents the higher brain viral burden of the furious form in the canine model.

PMID:18444083 SUPPORT Model Organism

"Paralytic rabies is characterized by delayed viral neuroinvasion and a more intense inflammation than furious rabies."

Contrasts the inflammatory and neuroinvasive profile of the paralytic form.

PMID:23723193 SUPPORT Human Clinical

"Patients with paralytic rabies had longer survival times than those with encephalitic rabies, and also had shorter incubation periods if they had received postexposure prophylaxis."

Human case-series evidence that the two forms differ in survival time.

Centrifugal Spread to Salivary Glands and Extraneural Organs

After CNS infection is established, virus moves outward along peripheral nerves and autonomic plexuses to reach salivary glands, skin, cornea, heart, tongue, larynx, adrenal medulla, and the gastrointestinal tract. Salivary gland involvement loads the saliva with virus and closes the transmission cycle; skin and corneal involvement is what makes antemortem nuchal skin biopsy diagnostically useful.

skin of body UBERON:0002097 cornea UBERON:0000964

Show evidence (4 references)

PMID:10462032 SUPPORT Human Clinical

"RVA was found in nerve plexuses in multiple organs, including the gastrointestinal tract."

Postmortem human series demonstrating rabies antigen in extraneural nerve plexuses.

PMID:10462032 SUPPORT Human Clinical

"Minor salivary glands of the tongue contained RVA and major salivary glands showed RVA in plexuses, but not in either acini or ducts."

Localises rabies antigen within salivary tissue, the anatomical basis of saliva-borne transmission.

PMID:10462032 SUPPORT Human Clinical

"RVA was observed in hair follicles of the skin and rarely in pancreatic islets."

Cutaneous nerve involvement underpins antemortem nuchal skin biopsy diagnosis.

+ 1 more reference

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Histopathology

2

Negri bodies

Eosinophilic cytoplasmic inclusion bodies in infected neurons, classically in hippocampal pyramidal cells and cerebellar Purkinje cells. They are the histological hallmark of rabies and are now understood to be liquid-like viral factories where viral RNA synthesis takes place, not inert debris.

Show evidence (2 references)

PMID:19494013 SUPPORT In Vitro

"Rabies virus infection induces the formation of cytoplasmic inclusion bodies that resemble Negri bodies found in the cytoplasm of some infected nerve cells."

Identifies Negri bodies as cytoplasmic inclusions in infected nerve cells.

PMID:31317498 SUPPORT Other

"For rabies virus, those viral factories are called Negri bodies (NBs)."

Establishes the modern interpretation of Negri bodies as viral factories.

Minimal inflammation with preserved neuronal structure

The neuropathology of rabies is famously underwhelming relative to the clinical devastation: little inflammatory infiltrate and largely preserved neuronal morphology, with mitochondrial disruption visible only on closer inspection.

Show evidence (1 reference)

PMID:35229271 SUPPORT Human Clinical

"Morphological analysis showed minimal inflammation with preserved neuronal and disrupted mitochondrial structure in both human and canine brains."

Documents the discordance between mild histopathology and fatal clinical disease.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

12

Digestive 1

Dysphagia HP:0002015

Show evidence (1 reference)

PMID:30747124 SUPPORT Human Clinical

"patients experience pain in the throat or difficulty swallowing"

Documents throat pain and dysphagia as the initial swallowing disturbance preceding hydrophobia.

Head and Neck 1

Excessive salivation HP:0003781

Show evidence (1 reference)

PMID:30747124 SUPPORT Human Clinical

"Autonomic dysfunction is common and includes hypersalivation, sweating, piloerection (goose bumps), and priapism (persistent and painful penile erection)."

Human clinical review documenting hypersalivation as a common autonomic manifestation of rabies.

Metabolism 1

Fever HP:0001945

Show evidence (1 reference)

PMID:28846292 SUPPORT Other

"Following an incubation period ranging from a few days to a few years, rabies presents with a vague, febrile illness, frequently with pain and paresthesias at the wound site."

Describes the febrile prodrome of clinical rabies.

Nervous System 7

Paresthesias at the wound site FREQUENT HP:0003401

Show evidence (2 references)

PMID:30747124 SUPPORT Human Clinical

"About half of patients develop pain, paraesthesia (abnormal sensation of tingling or pricking), and/or pruritus (itching), which usually occur close to the site of the bite"

About half of patients, supporting the FREQUENT band (30-79%).

PMID:28846292 SUPPORT Other

"Following an incubation period ranging from a few days to a few years, rabies presents with a vague, febrile illness, frequently with pain and paresthesias at the wound site."

Documents wound-site pain and paresthesias in the prodromal phase.

Autonomic instability Abnormal autonomic nervous system physiology HP:0012332

Show evidence (4 references)

PMID:30747124 SUPPORT Human Clinical

"Autonomic dysfunction is common and includes hypersalivation, sweating, piloerection (goose bumps), and priapism (persistent and painful penile erection)."

Human clinical review documenting autonomic dysfunction as a common feature and naming its manifestations.

PMID:30747124 SUPPORT Human Clinical

"Cardiopulmonary complications are very common and include sinus tachycardia (abnormally rapid heart rate originating in the sinus node), cardiac arrhythmias (abnormal heart rhythm), heart failure, hypotension (low blood pressure), hyperventilation, hypoxaemia"

Documents the cardiovascular manifestations of autonomic involvement in human patients.

PMID:30747124 SUPPORT Human Clinical

"This dysfunction may be caused by direct infection of autonomic nervous system centres or autonomic pathways involving the hypothalamus, spinal cord and/or autonomic ganglia."

Attributes the autonomic dysfunction to infection of hypothalamic, spinal, and autonomic-ganglion pathways.

+ 1 more reference

Paralysis HP:0003470

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:28846292 SUPPORT Other

"Within 2 weeks, the neurological phase typically progresses into encephalitic or paralytic rabies, followed by coma."

Establishes paralytic rabies as one of the two neurological presentations.

Myoclonus HP:0001336

Show evidence (1 reference)

PMID:23723193 SUPPORT Human Clinical

"tremor, myoclonus, local sensory symptoms, symptoms at the exposure site, and local symptoms in the absence of a bite or scratch were more common in patients with bat-acquired rabies"

Documents myoclonus and tremor as features, more common in bat-acquired cases.

Coma HP:0001259

Show evidence (1 reference)

PMID:28846292 SUPPORT Other

"Death typically occurs within 2 to 3 days of coma onset."

Documents coma as the terminal phase and its short interval to death.

Headache HP:0002315

Show evidence (1 reference)

PMID:30747124 SUPPORT Human Clinical

"These symptoms include fever, chills, malaise, fatigue, insomnia, anorexia, headache, anxiety and irritability"

Lists headache among the prodromal symptoms of human rabies.

Agitation HP:0000713

Temporal: RECURRENT

Show evidence (2 references)

PMID:30747124 SUPPORT Human Clinical

"Spells may occur with agitation, confusion, hallucinations and aggressive behaviour, typically lasting for periods of one to five minutes"

Documents agitation, hallucinations, and aggressive behaviour as episodic features of encephalitic rabies.

PMID:30747124 SUPPORT Human Clinical

"In the encephalitic form, patients have episodes of hyperexcitability or generalised arousal that are separated by lucid periods"

Establishes the episodic hyperexcitability with intervening lucid periods characteristic of the encephalitic form.

Other 2

Viral encephalitis OBLIGATE HP:0033993

Temporal: ACUTE Course: PROGRESSIVE

Show evidence (1 reference)

PMID:12144896 SUPPORT Other

"Rabies is an acute, progressive, incurable viral encephalitis."

Rabies is defined as an acute progressive viral encephalitis.

Hydrophobia VERY_FREQUENT HP:0032505

Show evidence (2 references)

PMID:30747124 SUPPORT Human Clinical

"The majority of patients with encephalitic rabies develop hydrophobia, which is a specific and characteristic feature of rabies."

Supports the VERY_FREQUENT band within the encephalitic subtype and the near-pathognomonic character of the sign.

PMID:23723193 SUPPORT Human Clinical

"Encephalopathy, hydrophobia, and aerophobia were more common in dog-acquired rabies."

Documents hydrophobia and aerophobia and their association with dog-acquired rabies.

💊

Medical Actions

7

Thorough wound cleansing

Action: wound care management Ontology label: Wound Care Management NCIT:C116681

Immediate and thorough washing of the wound is the first step of post-exposure prophylaxis and mechanically removes virus before it can reach nerve terminals. It is cheap, universally available, and frequently skipped.

Mechanism Target:

INHIBITS Inoculation of Virus into Peripheral Tissue — Removes or inactivates virus at the inoculation site before neuronal entry can occur.

Show evidence (1 reference)

PMID:18496505 SUPPORT Human Clinical

"ACIP recommends that prophylaxis for the prevention of rabies in humans exposed to rabies virus should include prompt and thorough wound cleansing followed by passive rabies immunization with human rabies immune globulin (HRIG) and vaccination with a cell culture rabies vaccine."

ACIP places prompt thorough wound cleansing first in the prophylaxis sequence.

Rabies immunoglobulin administration

Action: immunoglobulin therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Agent: human rabies immune globulin NCIT:C80831

Human rabies immune globulin infiltrated into and around the wound provides immediate passive neutralising antibody, covering the interval before the vaccine-induced response develops. It is given once, only to previously unvaccinated people.

Mechanism Target:

INHIBITS Neuromuscular Junction Entry into Motor Neurons — Neutralising antibody at the wound site blocks virions before they can engage receptors on the motor nerve terminal.

Show evidence (2 references)

PMID:12144896 SUPPORT Other

"Prophylaxis encompasses thorough wound treatment, vaccine administration, and inoculation of rabies immunoglobulin."

The abstract includes rabies immunoglobulin as part of prophylaxis.

PMID:18496505 SUPPORT Human Clinical

"HRIG is administered only once (i.e., at the beginning of antirabies prophylaxis) to previously unvaccinated persons to provide immediate, passive, rabies virus neutralizing antibody coverage until the patient responds to HDCV or PCECV by actively producing antibodies."

Specifies the timing, single administration, and bridging rationale for HRIG.

Rabies post-exposure vaccination

Action: vaccination Ontology label: Vaccination NCIT:C15346

Agent: rabies vaccine NCIT:C198514

A series of cell culture-derived rabies vaccine doses given after exposure. Together with wound care and immunoglobulin, post-exposure prophylaxis is highly effective at preventing progression to clinical disease, but only if given promptly.

Mechanism Target:

INHIBITS Retrograde Axonal Transport to the Central Nervous System — Active immunisation raises neutralising antibody during the long incubation period, clearing virus before it completes the journey to the central nervous system.

Show evidence (4 references)

PMID:12144896 SUPPORT Other

"Prophylaxis encompasses thorough wound treatment, vaccine administration, and inoculation of rabies immunoglobulin."

The abstract describes vaccine administration for prophylaxis.

PMID:29188797 SUPPORT Other

"If exposure occurs, timely post-exposure prophylaxis can prevent the progression to clinical disease and involves appropriate wound care, the administration of rabies immunoglobulin and vaccination."

States the three components of PEP and their preventive effect.

PMID:36535276 SUPPORT Human Clinical

"Post-exposure prophylaxis (PEP) for rabies is widely administered and highly effective."

Systematic review confirming PEP effectiveness.

+ 1 more reference

Rabies pre-exposure prophylaxis

Action: vaccination Ontology label: Vaccination NCIT:C15346

Agent: rabies vaccine NCIT:C198514

A vaccine series given before any exposure to people at elevated risk: veterinarians, laboratory workers, and long-term travellers to or residents of endemic areas. It does not remove the need for post-exposure prophylaxis but simplifies it, eliminating the immunoglobulin requirement and reducing the number of vaccine doses.

Show evidence (2 references)

PMID:35511716 SUPPORT Human Clinical

"PrEP does not eliminate the need for PEP; however, it does simplify the rabies PEP schedule (i.e., eliminates the need for rabies immunoglobulin and decreases the number of vaccine doses required for PEP)."

States the role and limits of pre-exposure prophylaxis.

PMID:28846292 SUPPORT Other

"Preexposure prophylaxis (PrEP) is available for individuals likely to be exposed to the RABV, such as veterinarians and long-term travelers or residents in endemic countries."

Identifies the target populations for PrEP.

Anti-rabies monoclonal antibody

Action: immunoglobulin therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Agent: anti-rabies monoclonal antibody NCIT:C20401

Monoclonal antibody preparations are replacing blood-derived rabies immune globulin for the passive-immunisation arm of post-exposure prophylaxis, which matters because RIG is chronically in short supply and carries the safety profile of a pooled human blood product. Because single antibodies select for escape at their own epitope, products are formulated as cocktails of non-competing antibodies binding separate epitopes on the viral glycoprotein.

Mechanism Target:

INHIBITS Neuromuscular Junction Entry into Motor Neurons — Like rabies immune globulin, neutralising monoclonal antibody at the wound site blocks virions before they engage receptors on the motor nerve terminal; it is the same mechanistic slot, filled by a recombinant product.

Show evidence (2 references)

PMID:39542064 SUPPORT In Vitro

"Currently, replacing traditional RIG with emerging mAb or mAb combinations is highly recommended due to the limited supply and potential safety risks of RIG."

States the rationale for displacing blood-derived RIG with monoclonal antibody products.

PMID:39542064 SUPPORT In Vitro

"RM02 and RM05 were non-competing and non-overlapping mAbs targeting epitopes I and III, respectively."

Documents the non-overlapping two-epitope cocktail design that guards against neutralisation escape.

Palliative and supportive care

Action: palliative care Ontology label: Palliative Care, Other Than Pain and Hospice NCIT:C15830

Once symptoms begin there is no established curative therapy, and management centres on relieving pain, agitation, and distress. In much of the world patients die at home without access to even this.

Show evidence (1 reference)

PMID:28846292 SUPPORT Other

"Preventing rabies is crucial, as treatment options after symptoms appear are mostly limited to palliative care."

States that post-symptomatic management is essentially palliative.

Milwaukee protocol

Action: Pharmacotherapy NCIT:C15986

Agent: ketamine CHEBI:6121 ribavirin CHEBI:63580 amantadine CHEBI:2618

An aggressive regimen of therapeutic (induced) coma with ketamine, ribavirin, and amantadine, promoted after a 2004 survival in Milwaukee. It is recorded here as a refuted intervention: two decades produced no documented evidence of efficacy and at least 64 failures, and the current recommendation is to abandon it. Any benefit historically attributed to the protocol is more plausibly explained by the intensive care that accompanied it.

Show evidence (3 references)

PMID:40139921 REFUTE Human Clinical

"Over the past 2 decades, no subsequent detailed reports have documented evidence of efficacy. There have been at least 64 cases with failure of the protocol."

Documents the absence of efficacy evidence and the accumulated failures.

PMID:40139921 REFUTE Human Clinical

"The time has now come to abandon the failed Milwaukee protocol for the therapy of rabies and consider new approaches based our current knowledge of rabies pathogenesis."

Explicit recommendation to abandon the protocol.

PMID:30747124 REFUTE Human Clinical

"The Milwaukee protocol, which included therapeutic coma and the administration of ketamine, ribavirin and amantadine, has proved to be ineffective and should no longer be used"

Independent review naming all three agents and stating the protocol is ineffective and should not be used.

🔬

Diagnosis

5

Direct fluorescent antibody test on postmortem brain tissue

Detection of rabies nucleoprotein antigen in brain touch impression smears using fluorescein-labelled antibody remains the reference standard for confirming rabies. The direct rapid immunohistochemical test is a light microscopy alternative for laboratories without fluorescence capability.

Show evidence (1 reference)

PMID:38376376 SUPPORT Other

"One of the earliest and most reliable techniques for post-mortem diagnosis of rabies is direct fluorescent antibody test (FAT). Even today, it remains the gold standard for confirming rabies in human and animal post-mortem samples"

Establishes brain FAT as the gold-standard confirmatory test.

Antemortem antigen detection on nuchal skin biopsy and corneal smear

Because virus reaches cutaneous nerves around hair follicles by centrifugal spread, antigen can be sought in a nuchal skin biopsy during life. Sensitivity and specificity are modest, and corneal smears are discouraged because of the risk of corneal scarification.

Show evidence (1 reference)

PMID:38376376 SUPPORT Other

"FAT can be employed for antigen detection in samples such as corneal smears and nuchal skin biopsies. However, the sensitivity and specificity of FAT are relatively low in these samples."

Supports the antemortem application while recording its limited accuracy.

Reverse transcription PCR for viral RNA

Conventional or real-time RT-PCR targeting the nucleoprotein gene is the most widely used laboratory confirmation, applicable to both antemortem and postmortem samples, and it also types the reservoir variant. Sensitivity is higher in pooled saliva and nuchal skin than in cerebrospinal fluid or urine.

Show evidence (2 references)

PMID:38376376 SUPPORT Other

"The most popular method for confirming the diagnosis of rabies in a laboratory, in both ante-mortem and post-mortem samples is conventional or real-time RT-PCR."

Establishes RT-PCR as the principal nucleic acid confirmation method.

PMID:38376376 SUPPORT Other

"PCR exhibits higher sensitivity in pooled saliva and nuchal skin samples but lower sensitivity in CSF, urine samples and extracted hair follicles"

Records the sample-type dependence of PCR sensitivity.

A negative antemortem test does not exclude rabies

The single most important interpretive caveat. Antemortem assays are insensitive enough that clinical suspicion, not a negative result, should drive management; series from a WHO reference laboratory confirmed only about 40 per cent of clinically suspected cases antemortem.

Show evidence (2 references)

PMID:38376376 SUPPORT Other

"A major limitation of ante-mortem tests for rabies is that negative results do not exclude a diagnosis of the disease"

States the interpretive caveat explicitly.

PMID:38376376 SUPPORT Other

"ante-mortem laboratory confirmation of rabies was achieved in 40.6 per cent (128 cases between 2012 and 2014) and 42.3 per cent (130 cases between 2015 and 2017) of clinically suspected rabies cases"

Quantifies real-world antemortem confirmation rates at a reference laboratory.

Underdiagnosis and the global burden estimate

The reported burden of rabies is an undercount, and the lack of sensitive laboratory methods is a direct cause rather than an incidental limitation.

Show evidence (1 reference)

PMID:24348170 SUPPORT Other

"The true disease burden and public health impact due to rabies remain underestimated due to lack of sensitive laboratory diagnostic methods."

Links diagnostic insensitivity to systematic underestimation of burden.

📈

Progression

4

Incubation

Clinically silent while virus travels from the inoculation site toward the central nervous system. Typically one to three months, but reported from a few days to a few years; bites to the head, neck, and hands, which are richly innervated and close to the CNS, tend to shorten it.

Show evidence (1 reference)

PMID:28846292 SUPPORT Other

"Following an incubation period ranging from a few days to a few years, rabies presents with a vague, febrile illness, frequently with pain and paresthesias at the wound site."

Gives the reported range of the incubation period.

Prodrome

A nonspecific febrile illness, often with pain, itch, or paresthesias at the healed wound. This is the window in which rabies is most often missed.

Show evidence (1 reference)

PMID:28846292 SUPPORT Other

"Clinicians often overlook the diagnosis of rabies at the initial presentation."

Documents the diagnostic difficulty of the prodromal phase.

Acute neurological phase

Duration: About 2 weeks from prodrome to coma

Progression into either encephalitic (furious) or paralytic (dumb) rabies, typically within two weeks of the prodrome.

Show evidence (1 reference)

PMID:28846292 SUPPORT Other

"Within 2 weeks, the neurological phase typically progresses into encephalitic or paralytic rabies, followed by coma."

Gives the timing and the two possible clinical trajectories.

Coma and death

Duration: 2 to 3 days from coma onset

Death typically follows within two to three days of coma onset. Well documented survival is exceptional, roughly 34 cases at six months after onset, many with serious neurological sequelae.

Show evidence (2 references)

PMID:28846292 SUPPORT Other

"Death typically occurs within 2 to 3 days of coma onset."

Gives the interval from coma to death.

PMID:40139921 SUPPORT Human Clinical

"Human rabies has a very high fatality rate and there have only been about 34 well-documented survivors, defined as survival at 6 months after onset of clinical rabies."

Quantifies documented survival as exceptional.

📊

Prevalence

1

Worldwide

Annual Incidence 0.74 per 100,000 (0.31–1.99) 1–9 per 1,000,000

Approximately 59,000 human deaths from dog-mediated rabies annually (95% CI 25,000 to 159,000), normalised against a world population of about 8 billion. Because clinical rabies is essentially always fatal, annual deaths approximate the annual incidence of clinical disease. The overwhelming majority of these deaths occur in Africa and Asia, and the figure is an undercount because antemortem diagnosis is insensitive and surveillance is weak.

Show evidence (1 reference)

PMID:25881058 SUPPORT Computational

"This study estimates that globally canine rabies causes approximately 59,000 (95% Confidence Intervals: 25-159,000) human deaths"

Source of both the central annual mortality estimate and the confidence interval behind rate_low and rate_high.

🦠

Infectious Agent

1

Rabies virus

Neurotropic, negative-sense single-stranded RNA lyssavirus (family Rhabdoviridae). Related lyssaviruses cause clinically indistinguishable disease.

Lyssavirus rabies NCBITaxon:11292

Show evidence (2 references)

PMID:12144896 SUPPORT Other

"The causative agents are neurotropic RNA viruses in the family Rhabdoviridae, genus Lyssavirus."

The abstract identifies lyssaviruses as the causative agents.

PMID:29188797 SUPPORT Other

"Rabies is a zoonotic disease that is caused by infection with viruses of the Lyssavirus genus, which are transmitted via the saliva of an infected animal."

Nature Reviews Disease Primers confirms Lyssavirus aetiology and saliva-borne transmission.

↔️

Transmission

2

Animal bite transmission

Rabies is transmitted mainly via the bite of an infected mammal, with virus-laden saliva deposited directly into the wound. Dogs are the dominant reservoir for human cases worldwide.

Show evidence (2 references)

PMID:12144896 SUPPORT Other

"Viral transmission occurs mainly via animal bite, and once the virus is deposited in peripheral wounds"

The abstract specifies bite transmission and peripheral wound deposition.

PMID:29188797 SUPPORT Other

"Dogs are the most important reservoir for rabies viruses, and dog bites account for >99% of human cases."

Quantifies the dominance of dog-mediated transmission in human rabies.

Non-bite and iatrogenic transmission

Less commonly, virus enters through contamination of open skin or mucous membranes, and rarely through organ or tissue transplantation from an undiagnosed donor. Bat-associated exposures are frequently unrecognised, so a bite history may be absent.

Show evidence (2 references)

PMID:28846292 SUPPORT Other

"The RABV is transmitted through the saliva of infected animals, contaminating bites, open skin, or mucous membrane, and, in rare cases, through organ transplantation."

Enumerates the non-bite and transplant-associated routes of transmission.

PMID:23723193 SUPPORT Human Clinical

"Bat-acquired cases of rabies were more often misdiagnosed and lacked a bite history."

Documents the frequently absent bite history in bat-acquired human rabies.

⚖️

Clinical Burden

High

Clinical rabies is nearly always fatal once symptoms begin, and it kills tens of thousands of people annually, disproportionately children in Africa and Asia. The entirely preventable nature of those deaths makes the burden a health-systems failure as much as a biological one.

Show evidence (1 reference)

PMID:35511716 SUPPORT Human Clinical

"Human rabies is an acute, progressive encephalomyelitis that is nearly always fatal once symptoms begin."

ACIP states the near-universal fatality of symptomatic rabies.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Rabies:

Guillain-Barre syndrome

Overlapping Features Paralytic rabies presents with ascending flaccid weakness and relatively preserved consciousness, and is frequently mistaken for Guillain-Barre syndrome; an exposure history and a compatible neurological trajectory should prompt reconsideration.

Distinguishing Features

A compatible animal exposure, which may be remote or unrecognised
Pain, itch, or paresthesia localised to the healed bite site
Inexorable progression to coma and death, without response to immunotherapy

Show evidence (2 references)

PMID:23723193 SUPPORT Human Clinical

"Bat-acquired cases of rabies were more often misdiagnosed and lacked a bite history."

Documents misdiagnosis as a recurring problem, especially where a bite history is absent.

PMID:30747124 SUPPORT Human Clinical

"Local symptoms at the site of the bite, piloerection, bladder dysfunction and fever are all features that favour a diagnosis of paralytic rabies."

Names the specific clinical features that discriminate paralytic rabies from Guillain-Barre syndrome.

📊

Related Datasets

2

Nanostring of 3D hiPSC-derived neurons infected with rabies virus-wild type-thai strain (WT-TH) and rabies virus-challenge virus standard 11 (CVS-11) against uninfected controls at 8 and 24 hours post-infection geo:GSE231664

This experiment is part of the project that primarily aims to utilize 3D hydrogel-based hiPSC-derived neuronal model to study rabies virus infection in the central nervous system. Having established the optimal 3D neuronal model, we then investigated the growth kinetics of two strains of rabies virus (TH and CVS-11) and comparatively analyzed the 2D and 3D culture models. We performed a gene expression analysis using NanoString to determine whether changes in gene expression could explain the differences in virus growth kinetics of two strains of rabies virus observed between the 2D and 3D neuronal culture models.

human MICROARRAY n=36

PMID:37692167

Identified by GEO DataSets index search for Rabies (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Recognition of copy-back defective interfering rabies virus genomes by RIG-I triggers efficient immune response against vaccine strains geo:GSE196051

Using next-generation sequencing (NGS) combined with bioinformatics tools, we characterized two major 5’copy-back defective interfering (5’cb DI) genomes generated during SAD replication. Furthermore, we identified a specific interaction of 5’cb DI genomes and RIG-I that correlated with a high stimulation of the type I IFN signaling

BULK RNA SEQ n=36

PMID:38461968

Identified by GEO DataSets index search for Rabies (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

🔬

Clinical Trials

2

NCT03961555 PHASE_II COMPLETED

Phase 2b randomised blinded comparison of the monoclonal antibody product SYN023 against licensed human rabies immune globulin in the post-exposure prophylaxis of adults with WHO Category III exposure. A placebo arm is ethically impossible here, so HRIG is necessarily the comparator.

Target Phenotypes: Viral encephalitis HP:0033993

Show evidence (1 reference)

clinicaltrials:NCT03961555 SUPPORT Human Clinical

"This is a Phase 2b, double blinded, randomized study of SYN023 compared to HyperRab"

Establishes the design and comparator of the phase 2b monoclonal antibody trial.

NCT04644484 PHASE_III COMPLETED

Phase III randomised blinded comparison of SYN023 against licensed human rabies immune globulin in post-exposure prophylaxis for WHO Category III exposure, intended to support licensure of a monoclonal alternative to blood-derived RIG.

Target Phenotypes: Viral encephalitis HP:0033993

Show evidence (1 reference)

clinicaltrials:NCT04644484 SUPPORT Human Clinical

"This trial is proposed to further the licensure of SYN023 to provide an effective PEP alternative available to those exposed persons who need such a product."

States the licensure intent for a monoclonal alternative to rabies immune globulin.

{ }

Source YAML

click to show

name: Rabies
creation_date: '2026-01-26T15:56:41Z'
category: Infectious Disease
description: >-
  Rabies is an acute, progressive, almost invariably fatal viral
  encephalomyelitis caused by rabies virus and other lyssaviruses, transmitted
  in the saliva of an infected mammal (dog bites account for the great majority
  of human cases). Virus deposited in a peripheral wound enters motor neurons at
  the neuromuscular junction, travels centripetally by retrograde axonal
  transport to the central nervous system, and replicates in cytoplasmic viral
  factories (Negri bodies). Fatal neurological disease follows from neuronal
  dysfunction rather than from extensive neuronal death: neuropathological
  changes are strikingly mild relative to the clinical picture. Virus then
  spreads centrifugally along nerves to the salivary glands and other extraneural
  organs, completing the transmission cycle. Post-exposure prophylaxis given
  before symptom onset is highly effective; once symptoms begin, care is
  essentially palliative.
disease_term:
  term:
    id: MONDO:0019173
    label: rabies
  preferred_term: Rabies
synonyms:
- Hydrophobia
- Human rabies
- Rabies encephalomyelitis
- Lyssa
parents:
- Viral Infection
- Neglected tropical disease
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:29188797
      reference_title: "Rabies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Rabies is a zoonotic disease that is caused by infection with viruses of the Lyssavirus genus, which are transmitted via the saliva of an infected animal."
      explanation: Rabies is a zoonotic viral infection, placing it in the infectious diseases part.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Clinical rabies is nearly always fatal once symptoms begin, and it kills tens
    of thousands of people annually, disproportionately children in Africa and
    Asia. The entirely preventable nature of those deaths makes the burden a
    health-systems failure as much as a biological one.
  evidence:
  - reference: PMID:35511716
    reference_title: "Use of a Modified Preexposure Prophylaxis Vaccination Schedule to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Human rabies is an acute, progressive encephalomyelitis that is nearly always fatal once symptoms begin."
    explanation: ACIP states the near-universal fatality of symptomatic rabies.
infectious_agent:
- name: Rabies virus
  infectious_agent_term:
    preferred_term: Lyssavirus rabies
    term:
      id: NCBITaxon:11292
      label: Lyssavirus rabies
  description: >-
    Neurotropic, negative-sense single-stranded RNA lyssavirus (family
    Rhabdoviridae). Related lyssaviruses cause clinically indistinguishable
    disease.
  evidence:
  - reference: PMID:12144896
    reference_title: "Rabies re-examined."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The causative agents are neurotropic RNA viruses in the family Rhabdoviridae, genus Lyssavirus."
    explanation: The abstract identifies lyssaviruses as the causative agents.
  - reference: PMID:29188797
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Rabies is a zoonotic disease that is caused by infection with viruses of the Lyssavirus genus, which are transmitted via the saliva of an infected animal."
    explanation: Nature Reviews Disease Primers confirms Lyssavirus aetiology and saliva-borne transmission.
transmission:
- name: Animal bite transmission
  description: >-
    Rabies is transmitted mainly via the bite of an infected mammal, with
    virus-laden saliva deposited directly into the wound. Dogs are the dominant
    reservoir for human cases worldwide.
  evidence:
  - reference: PMID:12144896
    reference_title: "Rabies re-examined."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Viral transmission occurs mainly via animal bite, and once the virus is deposited in peripheral wounds"
    explanation: The abstract specifies bite transmission and peripheral wound deposition.
  - reference: PMID:29188797
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dogs are the most important reservoir for rabies viruses, and dog bites account for >99% of human cases."
    explanation: Quantifies the dominance of dog-mediated transmission in human rabies.
- name: Non-bite and iatrogenic transmission
  description: >-
    Less commonly, virus enters through contamination of open skin or mucous
    membranes, and rarely through organ or tissue transplantation from an
    undiagnosed donor. Bat-associated exposures are frequently unrecognised, so a
    bite history may be absent.
  evidence:
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The RABV is transmitted through the saliva of infected animals, contaminating bites, open skin, or mucous membrane, and, in rare cases, through organ transplantation."
    explanation: Enumerates the non-bite and transplant-associated routes of transmission.
  - reference: PMID:23723193
    reference_title: "Clinical features of dog- and bat-acquired rabies in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bat-acquired cases of rabies were more often misdiagnosed and lacked a bite history."
    explanation: Documents the frequently absent bite history in bat-acquired human rabies.
pathophysiology:
- name: Inoculation of Virus into Peripheral Tissue
  description: >-
    A bite from an infected animal deposits saliva-borne lyssavirus into
    peripheral wound tissue. Virus may replicate locally in muscle or persist at
    the inoculation site before entering the nervous system, which accounts for
    the characteristically long and variable incubation period.
  role: trigger
  biological_scale: TISSUE
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:12144896
    reference_title: "Rabies re-examined."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Viral transmission occurs mainly via animal bite, and once the virus is deposited in peripheral wounds"
    explanation: Establishes deposition of virus in peripheral wound tissue as the initiating event.
  downstream:
  - target: Neuromuscular Junction Entry into Motor Neurons
    causal_link_type: DIRECT
    description: >-
      Virus deposited at the wound reaches motor nerve terminals at the
      neuromuscular junction, the principal portal of entry into the nervous
      system.
    evidence:
    - reference: PMID:10797395
      reference_title: "Rabies virus entry at the neuromuscular junction in nerve-muscle cocultures."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These findings show that in nerve-muscle cocultures, the neuromuscular junction is the major site of entry into neurons."
      explanation: Identifies the neuromuscular junction as the major neuronal entry site in a nerve-muscle coculture model.
  - target: Selective Vulnerability of Dorsal Root Ganglion Neurons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Virus at the inoculation site also reaches the sensory ganglion serving
      that dermatome, a separate branch from the motor-neuron route and the
      likely basis of the local sensory symptoms patients report at the healed
      bite.
    evidence:
    - reference: PMID:30747124
      reference_title: "Rabies: a medical perspective."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Local neurological symptoms are likely to be due to RABV infection in local peripheral sensory ganglia"
      explanation: Attributes the human bite-site sensory symptoms to infection of the local peripheral sensory ganglia.
- name: Neuromuscular Junction Entry into Motor Neurons
  description: >-
    Virions concentrate at the neuromuscular junction, colocalising with
    nicotinic acetylcholine receptors, and are taken up into endosomal
    compartments of the motor nerve terminal. Rabies virus glycoprotein also
    binds the p75 neurotrophin receptor with high affinity, giving the virus more
    than one route into the neuron.
  role: mediator
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: virion attachment to host cell
    term:
      id: GO:0019062
      label: virion attachment to host cell
  - preferred_term: receptor-mediated endocytosis
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
  evidence:
  - reference: PMID:10797395
    reference_title: "Rabies virus entry at the neuromuscular junction in nerve-muscle cocultures."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Texas Red-labeled alpha-bungarotoxin, which binds to nicotinic acetylcholine receptors, colocalized precisely with virus at the densities identifying these regions as neuromuscular junctions."
    explanation: Shows virus colocalising with nicotinic acetylcholine receptors at the neuromuscular junction.
  - reference: PMID:25165859
    reference_title: "Rabies Virus Hijacks and accelerates the p75NTR retrograde axonal transport machinery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The p75 Nerve Growth Factor (NGF) receptor (p75NTR) binds RABV Glycoprotein (RABV-G) with high affinity."
    explanation: Documents the high-affinity glycoprotein-p75NTR interaction used for neuronal entry.
  - reference: PMID:29188797
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The virus first infects peripheral motor neurons, and symptoms occur after the virus reaches the central nervous system."
    explanation: Confirms peripheral motor neurons as the first infected cell population in human disease.
  downstream:
  - target: Retrograde Axonal Transport to the Central Nervous System
    causal_link_type: DIRECT
    description: >-
      Endocytosed virions in acidified compartments of the nerve terminal are
      carried centripetally along the axon toward the neuronal cell body.
    evidence:
    - reference: PMID:10797395
      reference_title: "Rabies virus entry at the neuromuscular junction in nerve-muscle cocultures."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The progressive increase of virus and tracers in nerve fibers and nerve cell bodies over time is consistent with retrograde transport of endocytosed virus from the motor nerve terminal."
      explanation: Links endosomal uptake at the terminal to retrograde movement toward the cell body.
- name: Retrograde Axonal Transport to the Central Nervous System
  description: >-
    Rabies virus depends on long-distance retrograde axonal transport to reach
    the central nervous system. It travels within acidic compartments largely
    together with p75NTR, and moves faster and more directively than the
    receptor's endogenous cargo, indicating that the virus does not merely
    hitchhike on the transport machinery but manipulates it.
  role: central_effector
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: retrograde axonal transport
    term:
      id: GO:0008090
      label: retrograde axonal transport
  evidence:
  - reference: PMID:25165859
    reference_title: "Rabies Virus Hijacks and accelerates the p75NTR retrograde axonal transport machinery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Rabies virus (RABV) is a neurotropic virus that depends on long distance axonal transport in order to reach the central nervous system (CNS)."
    explanation: States the dependence of CNS invasion on long-distance axonal transport.
  - reference: PMID:25165859
    reference_title: "Rabies Virus Hijacks and accelerates the p75NTR retrograde axonal transport machinery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Hence, RABV may employ p75NTR-dependent transport as a fast mechanism to facilitate movement to the CNS."
    explanation: Supports p75NTR-dependent transport as an accelerated route to the CNS.
  - reference: PMID:12144896
    reference_title: "Rabies re-examined."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "once the virus is deposited in peripheral wounds, centripetal passage occurs towards the central nervous system."
    explanation: Describes centripetal spread to the CNS in the clinical review literature.
  downstream:
  - target: Central Nervous System Neuronal Infection
    causal_link_type: DIRECT
    description: >-
      Arrival of virus at the neuronal cell body establishes infection in the
      spinal cord and brain, from which trans-synaptic spread disseminates the
      infection through the neuraxis.
    evidence:
    - reference: PMID:29188797
      reference_title: "Rabies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The virus first infects peripheral motor neurons, and symptoms occur after the virus reaches the central nervous system."
      explanation: Links peripheral neuronal infection to subsequent CNS infection and symptom onset.
- name: Central Nervous System Neuronal Infection
  description: >-
    Virus reaching the spinal cord and brain infects neurons and spreads
    trans-synaptically through the neuraxis, including brainstem, limbic, and
    hypothalamic structures. Symptoms begin only after the CNS is reached, which
    is why the disease is clinically silent throughout the incubation period.
  role: central_effector
  biological_scale: TISSUE
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  - preferred_term: brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  evidence:
  - reference: PMID:29188797
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The virus first infects peripheral motor neurons, and symptoms occur after the virus reaches the central nervous system."
    explanation: Establishes CNS arrival as the trigger for clinical disease.
  - reference: PMID:18444083
    reference_title: "Furious and paralytic rabies of canine origin: neuroimaging with virological and cytokine studies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Abnormal hypersignal T2 changes were found at hippocampus, hypothalamus, brainstem, and spinal cord of paralytic dogs."
    explanation: Naturally infected dogs show CNS involvement of hippocampus, hypothalamus, brainstem, and spinal cord.
  downstream:
  - target: Negri Body Formation and Viral Replication
    causal_link_type: DIRECT
    description: >-
      Infected neurons assemble cytoplasmic viral factories in which viral RNA
      synthesis takes place.
    evidence:
    - reference: PMID:19494013
      reference_title: "Functional characterization of Negri bodies (NBs) in rabies virus-infected cells: Evidence that NBs are sites of viral transcription and replication."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Rabies virus infection induces the formation of cytoplasmic inclusion bodies that resemble Negri bodies found in the cytoplasm of some infected nerve cells."
      explanation: Links neuronal infection to formation of the cytoplasmic inclusions seen in nerve cells.
  - target: Mitochondrial Dysfunction and Mitophagy in Infected Neurons
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Infection of CNS neurons is accompanied by disrupted mitochondrial
      structure and altered bioenergetics in naturally infected human and canine
      brain.
    evidence:
    - reference: PMID:35229271
      reference_title: "Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Morphological analysis showed minimal inflammation with preserved neuronal and disrupted mitochondrial structure in both human and canine brains."
      explanation: Documents disrupted mitochondrial structure in infected human and canine brain tissue.
- name: Negri Body Formation and Viral Replication
  description: >-
    Rabies virus nucleoprotein N and phosphoprotein P condense into spherical,
    liquid-like cytoplasmic inclusions, the Negri bodies, which act as viral
    factories. All viral RNA species (genome, antigenome, and mRNAs) are found
    inside them, and these are the sites where viral transcription and replication
    occur. Negri bodies are the classical histopathological hallmark of rabies.
  role: mediator
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: hippocampal pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: viral transcription
    term:
      id: GO:0019083
      label: viral transcription
  - preferred_term: viral genome replication
    term:
      id: GO:0019079
      label: viral genome replication
  cellular_components:
  - preferred_term: Negri body
    term:
      id: GO:0016234
      label: inclusion body
  evidence:
  - reference: PMID:19494013
    reference_title: "Functional characterization of Negri bodies (NBs) in rabies virus-infected cells: Evidence that NBs are sites of viral transcription and replication."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Significantly, short-term RNA labeling in the presence of BrUTP strongly suggests that the NBLs are the sites where viral transcription and replication take place."
    explanation: Direct experimental evidence that Negri body-like structures are the sites of viral RNA synthesis.
  - reference: PMID:31317498
    reference_title: "Structure and Function of Negri Bodies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NBs are cytoplasmic inclusion bodies in which viral RNAs (mRNAs as well as genomic and antigenomic RNAs) are synthesized."
    explanation: Characterises Negri bodies as the cytoplasmic compartments of viral RNA synthesis.
  - reference: PMID:31317498
    reference_title: "Structure and Function of Negri Bodies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The co-expression of rabies virus nucleoprotein N and phosphoprotein P is sufficient to induce the formation of cytoplasmic inclusions recapitulating NBs properties."
    explanation: Identifies N and P as the minimal viral components sufficient to build the replication compartment.
  downstream:
  - target: Neuronal Dysfunction Without Substantial Neuronal Death
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Productive intraneuronal replication is followed by profound functional
      impairment of infected neurons, although the molecular steps linking
      replication to dysfunction remain incompletely defined.
    evidence:
    - reference: PMID:15804968
      reference_title: "Neuronal dysfunction and death in rabies virus infection."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The precise bases of this functional impairment are unknown, and current knowledge on electro-physiological alterations, effects on ion channels and neurotransmission, and neurotoxicity are reviewed."
      explanation: States explicitly that the mechanistic basis of the functional impairment is not established.
- name: Mitochondrial Dysfunction and Mitophagy in Infected Neurons
  description: >-
    In naturally infected human and canine brain, respiratory complex activities
    rise but ATP production does not, consistent with a fall in mitochondrial
    membrane potential. Disrupted cristae architecture and markers of mitophagy
    and autophagy accompany these changes, offering one candidate route from
    infection to neuronal dysfunction in the near absence of cell death.
  role: amplifier
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: mitophagy
    term:
      id: GO:0000423
      label: mitophagy
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: PMID:35229271
    reference_title: "Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that altered mitochondrial bioenergetics and cristae architecture probably induce mitophagy, leading to autophagy and consequent neuronal dysfunction in rabies."
    explanation: Proposes the mitochondrial-mitophagy route to neuronal dysfunction; framed as a proposal by the authors, hence PROVISIONAL confidence.
  downstream:
  - target: Neuronal Dysfunction Without Substantial Neuronal Death
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Bioenergetic failure and mitophagy are proposed to converge on functional
      impairment of otherwise structurally preserved neurons.
    evidence:
    - reference: PMID:35229271
      reference_title: "Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The presence of minimal neuropathological changes observed in rabies indicates that neuronal dysfunction, rather than neuronal death contributes to the fatal outcome."
      explanation: Ties minimal structural pathology to dysfunction rather than death as the fatal mechanism.
- name: Selective Vulnerability of Dorsal Root Ganglion Neurons
  description: >-
    In experimentally infected mice, sensory ganglion neurons show inflammatory
    infiltrates and degenerative change while CNS neurons remain comparatively
    spared. This selective peripheral sensory vulnerability is a plausible
    correlate of the pain, itch, and paresthesias patients report at the healed
    bite. Clinical review independently attributes those local symptoms to
    infection of the local peripheral sensory ganglia, so the human correlate is
    asserted in the clinical literature even though the cellular vulnerability
    itself is characterised only in mice.
  role: modifier
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  locations:
  - preferred_term: dorsal root ganglion
    term:
      id: UBERON:0000044
      label: dorsal root ganglion
  evidence:
  - reference: PMID:19252919
    reference_title: "Selective vulnerability of dorsal root ganglia neurons in experimental rabies after peripheral inoculation of CVS-11 in adult mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Light microscopy showed multifocal mononuclear inflammatory cell infiltrates in the sensory ganglia and a spectrum of degenerative neuronal changes."
    explanation: Documents degenerative change in sensory ganglia in the mouse model.
  - reference: PMID:19252919
    reference_title: "Selective vulnerability of dorsal root ganglia neurons in experimental rabies after peripheral inoculation of CVS-11 in adult mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Hence, gangliocytes exhibit selective vulnerability in this animal model."
    explanation: States the selective vulnerability finding, explicitly scoped to the animal model.
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Local neurological symptoms are likely to be due to RABV infection in local peripheral sensory ganglia"
    explanation: Human clinical review attributing bite-site sensory symptoms to local sensory ganglion infection.
  notes: >-
    The selective cellular vulnerability is characterised only in mice (CVS-11
    strain); the human clinical literature independently attributes bite-site
    sensory symptoms to sensory ganglion infection but does not describe the
    cellular pathology.
- name: Neuronal Dysfunction Without Substantial Neuronal Death
  description: >-
    The defining paradox of rabies neuropathology: clinical disease is
    catastrophic while morphological changes in the brain are mild. Neurons are
    largely structurally preserved and inflammation is minimal, so the fatal
    outcome is attributed to functional impairment of infected neurons rather
    than to their destruction. The precise basis of that impairment remains
    unknown.
  role: central_effector
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15804968
    reference_title: "Neuronal dysfunction and death in rabies virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Because morphologic changes in natural rabies are usually relatively mild, it is thought that the severe clinical disease with a fatal outcome must be due to neuronal dysfunction of rabies virus-infected neurons."
    explanation: States the dysfunction-not-destruction principle directly.
  - reference: PMID:35229271
    reference_title: "Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of minimal neuropathological changes observed in rabies indicates that neuronal dysfunction, rather than neuronal death contributes to the fatal outcome."
    explanation: Independent confirmation in naturally infected human and canine brain.
  downstream:
  - target: Acute Progressive Encephalomyelitis
    causal_link_type: DIRECT
    description: >-
      Widespread neuronal functional failure manifests as an acute, progressive
      encephalomyelitis that is nearly always fatal.
    evidence:
    - reference: PMID:35511716
      reference_title: "Use of a Modified Preexposure Prophylaxis Vaccination Schedule to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Human rabies is an acute, progressive encephalomyelitis that is nearly always fatal once symptoms begin."
      explanation: Names the resulting clinical syndrome and its outcome.
- name: Acute Progressive Encephalomyelitis
  description: >-
    The clinical expression of CNS infection: an acute, relentlessly progressive
    encephalomyelitis passing through prodrome, an acute neurological phase, coma,
    and death. Once it begins it is essentially incurable.
  role: outcome
  biological_scale: ORGANISM
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:12144896
    reference_title: "Rabies re-examined."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Rabies is an acute, progressive, incurable viral encephalitis."
    explanation: The abstract defines rabies as an acute, progressive, incurable viral encephalitis.
  - reference: PMID:29188797
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Once clinical disease develops, it is almost certainly fatal."
    explanation: Confirms near-universal fatality once clinical disease is established.
  downstream:
  - target: Divergence into Encephalitic versus Paralytic Clinical Forms
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The encephalomyelitis expresses itself in two distinguishable clinical
      forms whose separation tracks with viral burden and host inflammatory
      response.
    evidence:
    - reference: PMID:18444083
      reference_title: "Furious and paralytic rabies of canine origin: neuroimaging with virological and cytokine studies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furious and paralytic rabies differ in clinical manifestations and survival periods."
      explanation: Establishes the two clinical forms as mechanistically and prognostically distinct.
  - target: Centrifugal Spread to Salivary Glands and Extraneural Organs
    causal_link_type: DIRECT
    description: >-
      Once CNS infection is established, virus travels back out along nerves to
      peripheral organs.
    evidence:
    - reference: PMID:10462032
      reference_title: "Extraneural organ involvement in human rabies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "After the development of the central nervous system infection, there is centrifugal spread of the rabies virus to extraneural (systemic) organs."
      explanation: States the direction and timing of centrifugal spread relative to CNS infection.
- name: Divergence into Encephalitic versus Paralytic Clinical Forms
  description: >-
    Rabies presents as either encephalitic (furious) disease, with agitation,
    hydrophobia, aerophobia, and autonomic instability, or paralytic (dumb)
    disease, with ascending flaccid weakness and relatively preserved
    consciousness. In naturally infected dogs, furious disease carries higher
    brain viral load with only moderate inflammation, whereas paralytic disease
    shows delayed neuroinvasion with more intense inflammation, suggesting the
    host inflammatory response shapes which form develops.
  role: modifier
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:18444083
    reference_title: "Furious and paralytic rabies of canine origin: neuroimaging with virological and cytokine studies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Larger quantities of rabies viral RNA were found in the brains of furious than in paralytic dogs."
    explanation: Documents the higher brain viral burden of the furious form in the canine model.
  - reference: PMID:18444083
    reference_title: "Furious and paralytic rabies of canine origin: neuroimaging with virological and cytokine studies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Paralytic rabies is characterized by delayed viral neuroinvasion and a more intense inflammation than furious rabies."
    explanation: Contrasts the inflammatory and neuroinvasive profile of the paralytic form.
  - reference: PMID:23723193
    reference_title: "Clinical features of dog- and bat-acquired rabies in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with paralytic rabies had longer survival times than those with encephalitic rabies, and also had shorter incubation periods if they had received postexposure prophylaxis."
    explanation: Human case-series evidence that the two forms differ in survival time.
  notes: >-
    The viral-burden versus inflammation account comes from naturally infected
    dogs; the corresponding human mechanism has not been demonstrated as directly.
- name: Centrifugal Spread to Salivary Glands and Extraneural Organs
  description: >-
    After CNS infection is established, virus moves outward along peripheral
    nerves and autonomic plexuses to reach salivary glands, skin, cornea, heart,
    tongue, larynx, adrenal medulla, and the gastrointestinal tract. Salivary
    gland involvement loads the saliva with virus and closes the transmission
    cycle; skin and corneal involvement is what makes antemortem nuchal skin
    biopsy diagnostically useful.
  role: consequence
  biological_scale: ORGANISM
  locations:
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  evidence:
  - reference: PMID:10462032
    reference_title: "Extraneural organ involvement in human rabies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RVA was found in nerve plexuses in multiple organs, including the gastrointestinal tract."
    explanation: Postmortem human series demonstrating rabies antigen in extraneural nerve plexuses.
  - reference: PMID:10462032
    reference_title: "Extraneural organ involvement in human rabies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Minor salivary glands of the tongue contained RVA and major salivary glands showed RVA in plexuses, but not in either acini or ducts."
    explanation: Localises rabies antigen within salivary tissue, the anatomical basis of saliva-borne transmission.
  - reference: PMID:10462032
    reference_title: "Extraneural organ involvement in human rabies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RVA was observed in hair follicles of the skin and rarely in pancreatic islets."
    explanation: Cutaneous nerve involvement underpins antemortem nuchal skin biopsy diagnosis.
  - reference: PMID:10462032
    reference_title: "Extraneural organ involvement in human rabies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings indicate that centrifugal spread of rabies virus to extraneural organs occurs frequently in human rabies."
    explanation: Establishes that centrifugal extraneural spread is a frequent, not exceptional, feature.
has_subtypes:
- name: Encephalitic
  display_name: Encephalitic (furious) rabies
  description: >-
    The classical form, accounting for the majority of human cases: fluctuating
    agitation and hyperexcitability, hydrophobia and aerophobia, hypersalivation,
    and autonomic instability, progressing to coma and death. Hydrophobia and
    aerophobia are more characteristic of dog-acquired disease.
  evidence:
  - reference: PMID:23723193
    reference_title: "Clinical features of dog- and bat-acquired rabies in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Encephalopathy, hydrophobia, and aerophobia were more common in dog-acquired rabies."
    explanation: Associates the encephalitic phenotype with dog-acquired rabies in a 122-case series.
- name: Paralytic
  display_name: Paralytic (dumb) rabies
  description: >-
    Ascending flaccid weakness with relatively preserved consciousness,
    frequently misdiagnosed as Guillain-Barre syndrome. Survival time is longer
    than in encephalitic rabies, but the outcome is the same.
  evidence:
  - reference: PMID:23723193
    reference_title: "Clinical features of dog- and bat-acquired rabies in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with paralytic rabies had longer survival times than those with encephalitic rabies, and also had shorter incubation periods if they had received postexposure prophylaxis."
    explanation: Distinguishes the paralytic form by its longer survival time.
phenotypes:
- name: Viral encephalitis
  category: Neurologic
  frequency: OBLIGATE
  description: >-
    Acute progressive viral encephalomyelitis is the defining manifestation of
    clinical rabies.
  phenotype_term:
    preferred_term: Viral encephalitis
    term:
      id: HP:0033993
      label: Viral encephalitis
    temporality: ACUTE
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:12144896
    reference_title: "Rabies re-examined."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Rabies is an acute, progressive, incurable viral encephalitis."
    explanation: Rabies is defined as an acute progressive viral encephalitis.
- name: Fever
  category: Constitutional
  description: >-
    The prodrome is a vague febrile illness, easily mistaken for any number of
    common infections, which is why rabies is so often missed at first
    presentation.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Following an incubation period ranging from a few days to a few years, rabies presents with a vague, febrile illness, frequently with pain and paresthesias at the wound site."
    explanation: Describes the febrile prodrome of clinical rabies.
- name: Paresthesias at the wound site
  category: Neurologic
  description: >-
    Pain, itch, or paresthesia localised to the healed bite site is an early and
    relatively specific clue, and is thought to reflect infection of the sensory
    ganglion serving that dermatome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
  evidence:
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About half of patients develop pain, paraesthesia (abnormal sensation of tingling or pricking), and/or pruritus (itching), which usually occur close to the site of the bite"
    explanation: About half of patients, supporting the FREQUENT band (30-79%).
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Following an incubation period ranging from a few days to a few years, rabies presents with a vague, febrile illness, frequently with pain and paresthesias at the wound site."
    explanation: Documents wound-site pain and paresthesias in the prodromal phase.
- name: Hydrophobia
  category: Neurologic
  subtype: Encephalitic
  diagnostic: true
  description: >-
    Involuntary pharyngeal and inspiratory spasm provoked by attempts to drink,
    ultimately by the sight or thought of water. With aerophobia (the same
    response to a draught of air), it is close to pathognomonic and is more
    characteristic of dog-acquired disease. HPO has no aerophobia term, so the
    aerophobic component is captured in this description rather than as a
    separate coded phenotype.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hydrophobia
    term:
      id: HP:0032505
      label: Hydrophobia
  evidence:
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients with encephalitic rabies develop hydrophobia, which is a specific and characteristic feature of rabies."
    explanation: Supports the VERY_FREQUENT band within the encephalitic subtype and the near-pathognomonic character of the sign.
  - reference: PMID:23723193
    reference_title: "Clinical features of dog- and bat-acquired rabies in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Encephalopathy, hydrophobia, and aerophobia were more common in dog-acquired rabies."
    explanation: Documents hydrophobia and aerophobia and their association with dog-acquired rabies.
- name: Excessive salivation
  category: Autonomic
  subtype: Encephalitic
  description: >-
    Hypersalivation, combined with pharyngeal spasm that prevents swallowing,
    produces the frothing classically associated with rabies and also delivers
    virus-laden saliva to the next host.
  phenotype_term:
    preferred_term: Excessive salivation
    term:
      id: HP:0003781
      label: Excessive salivation
  evidence:
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autonomic dysfunction is common and includes hypersalivation, sweating, piloerection (goose bumps), and priapism (persistent and painful penile erection)."
    explanation: Human clinical review documenting hypersalivation as a common autonomic manifestation of rabies.
- name: Autonomic instability
  category: Autonomic
  description: >-
    Labile blood pressure and heart rate, hyperthermia, priapism, and cardiac
    arrhythmias accompany brainstem and hypothalamic involvement and contribute
    to death.
  phenotype_term:
    preferred_term: Autonomic instability
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autonomic dysfunction is common and includes hypersalivation, sweating, piloerection (goose bumps), and priapism (persistent and painful penile erection)."
    explanation: Human clinical review documenting autonomic dysfunction as a common feature and naming its manifestations.
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiopulmonary complications are very common and include sinus tachycardia (abnormally rapid heart rate originating in the sinus node), cardiac arrhythmias (abnormal heart rhythm), heart failure, hypotension (low blood pressure), hyperventilation, hypoxaemia"
    explanation: Documents the cardiovascular manifestations of autonomic involvement in human patients.
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This dysfunction may be caused by direct infection of autonomic nervous system centres or autonomic pathways involving the hypothalamus, spinal cord and/or autonomic ganglia."
    explanation: Attributes the autonomic dysfunction to infection of hypothalamic, spinal, and autonomic-ganglion pathways.
  - reference: PMID:18444083
    reference_title: "Furious and paralytic rabies of canine origin: neuroimaging with virological and cytokine studies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Abnormal hypersignal T2 changes were found at hippocampus, hypothalamus, brainstem, and spinal cord of paralytic dogs."
    explanation: Corroborating canine imaging showing involvement of the hypothalamic and brainstem structures named above; supporting, not sole, evidence.
- name: Paralysis
  category: Neurologic
  subtype: Paralytic
  description: >-
    Ascending flaccid weakness with relatively preserved consciousness defines
    paralytic rabies and is a frequent source of misdiagnosis as Guillain-Barre
    syndrome.
  phenotype_term:
    preferred_term: Paralysis
    term:
      id: HP:0003470
      label: Paralysis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Within 2 weeks, the neurological phase typically progresses into encephalitic or paralytic rabies, followed by coma."
    explanation: Establishes paralytic rabies as one of the two neurological presentations.
- name: Myoclonus
  category: Neurologic
  description: >-
    Myoclonus and tremor, along with abnormal cranial nerve, motor, and sensory
    findings, are reported particularly in bat-acquired rabies.
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: PMID:23723193
    reference_title: "Clinical features of dog- and bat-acquired rabies in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tremor, myoclonus, local sensory symptoms, symptoms at the exposure site, and local symptoms in the absence of a bite or scratch were more common in patients with bat-acquired rabies"
    explanation: Documents myoclonus and tremor as features, more common in bat-acquired cases.
- name: Coma
  category: Neurologic
  description: >-
    The neurological phase gives way to coma within about two weeks, and death
    follows within days of coma onset.
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Death typically occurs within 2 to 3 days of coma onset."
    explanation: Documents coma as the terminal phase and its short interval to death.
- name: Headache
  category: Neurologic
  description: >-
    One of the nonspecific prodromal symptoms, alongside fever, chills, malaise,
    insomnia, anorexia, anxiety, and irritability. Individually unremarkable,
    which is precisely why the prodrome is so often attributed to something else.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These symptoms include fever, chills, malaise, fatigue, insomnia, anorexia, headache, anxiety and irritability"
    explanation: Lists headache among the prodromal symptoms of human rabies.
- name: Agitation
  category: Neurologic
  subtype: Encephalitic
  description: >-
    Encephalitic rabies produces episodic hyperexcitability and generalised
    arousal separated by lucid intervals, with spells of agitation, confusion,
    hallucinations, and aggressive behaviour lasting one to five minutes, either
    spontaneous or triggered by sensory stimuli. The preserved lucid intervals
    between spells are part of what makes the picture distinctive.
  phenotype_term:
    preferred_term: Agitation
    term:
      id: HP:0000713
      label: Agitation
    temporality: RECURRENT
  evidence:
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spells may occur with agitation, confusion, hallucinations and aggressive behaviour, typically lasting for periods of one to five minutes"
    explanation: Documents agitation, hallucinations, and aggressive behaviour as episodic features of encephalitic rabies.
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the encephalitic form, patients have episodes of hyperexcitability or generalised arousal that are separated by lucid periods"
    explanation: Establishes the episodic hyperexcitability with intervening lucid periods characteristic of the encephalitic form.
- name: Dysphagia
  category: Gastrointestinal
  subtype: Encephalitic
  description: >-
    Throat pain and difficulty swallowing precede frank hydrophobia and are
    mechanistically distinct from it: dysphagia is the impairment, hydrophobia
    is the violent involuntary inspiratory and pharyngeal spasm that swallowing
    attempts then provoke. Together with hypersalivation, dysphagia is why saliva
    pools rather than being swallowed.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients experience pain in the throat or difficulty swallowing"
    explanation: Documents throat pain and dysphagia as the initial swallowing disturbance preceding hydrophobia.
progression:
- phase: Incubation
  notes: >-
    Clinically silent while virus travels from the inoculation site toward the
    central nervous system. Typically one to three months, but reported from a
    few days to a few years; bites to the head, neck, and hands, which are richly
    innervated and close to the CNS, tend to shorten it.
  evidence:
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Following an incubation period ranging from a few days to a few years, rabies presents with a vague, febrile illness, frequently with pain and paresthesias at the wound site."
    explanation: Gives the reported range of the incubation period.
- phase: Prodrome
  notes: >-
    A nonspecific febrile illness, often with pain, itch, or paresthesias at the
    healed wound. This is the window in which rabies is most often missed.
  evidence:
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinicians often overlook the diagnosis of rabies at the initial presentation."
    explanation: Documents the diagnostic difficulty of the prodromal phase.
- phase: Acute neurological phase
  duration: About 2 weeks from prodrome to coma
  notes: >-
    Progression into either encephalitic (furious) or paralytic (dumb) rabies,
    typically within two weeks of the prodrome.
  evidence:
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Within 2 weeks, the neurological phase typically progresses into encephalitic or paralytic rabies, followed by coma."
    explanation: Gives the timing and the two possible clinical trajectories.
- phase: Coma and death
  duration: 2 to 3 days from coma onset
  notes: >-
    Death typically follows within two to three days of coma onset. Well
    documented survival is exceptional, roughly 34 cases at six months after
    onset, many with serious neurological sequelae.
  evidence:
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Death typically occurs within 2 to 3 days of coma onset."
    explanation: Gives the interval from coma to death.
  - reference: PMID:40139921
    reference_title: "Demise of the Milwaukee Protocol for Rabies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Human rabies has a very high fatality rate and there have only been about 34 well-documented survivors, defined as survival at 6 months after onset of clinical rabies."
    explanation: Quantifies documented survival as exceptional.
histopathology:
- name: Negri bodies
  description: >-
    Eosinophilic cytoplasmic inclusion bodies in infected neurons, classically in
    hippocampal pyramidal cells and cerebellar Purkinje cells. They are the
    histological hallmark of rabies and are now understood to be liquid-like
    viral factories where viral RNA synthesis takes place, not inert debris.
  diagnostic: true
  finding_term:
    preferred_term: Negri body
    term:
      id: NCIT:C120945
      label: Inclusion Body
  evidence:
  - reference: PMID:19494013
    reference_title: "Functional characterization of Negri bodies (NBs) in rabies virus-infected cells: Evidence that NBs are sites of viral transcription and replication."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Rabies virus infection induces the formation of cytoplasmic inclusion bodies that resemble Negri bodies found in the cytoplasm of some infected nerve cells."
    explanation: Identifies Negri bodies as cytoplasmic inclusions in infected nerve cells.
  - reference: PMID:31317498
    reference_title: "Structure and Function of Negri Bodies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For rabies virus, those viral factories are called Negri bodies (NBs)."
    explanation: Establishes the modern interpretation of Negri bodies as viral factories.
- name: Minimal inflammation with preserved neuronal structure
  description: >-
    The neuropathology of rabies is famously underwhelming relative to the
    clinical devastation: little inflammatory infiltrate and largely preserved
    neuronal morphology, with mitochondrial disruption visible only on closer
    inspection.
  evidence:
  - reference: PMID:35229271
    reference_title: "Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morphological analysis showed minimal inflammation with preserved neuronal and disrupted mitochondrial structure in both human and canine brains."
    explanation: Documents the discordance between mild histopathology and fatal clinical disease.
diagnosis:
- name: Direct fluorescent antibody test on postmortem brain tissue
  description: >-
    Detection of rabies nucleoprotein antigen in brain touch impression smears
    using fluorescein-labelled antibody remains the reference standard for
    confirming rabies. The direct rapid immunohistochemical test is a light
    microscopy alternative for laboratories without fluorescence capability.
  evidence:
  - reference: PMID:38376376
    reference_title: "Recent updates on laboratory diagnosis of rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One of the earliest and most reliable techniques for post-mortem diagnosis of rabies is direct fluorescent antibody test (FAT). Even today, it remains the gold standard for confirming rabies in human and animal post-mortem samples"
    explanation: Establishes brain FAT as the gold-standard confirmatory test.
- name: Antemortem antigen detection on nuchal skin biopsy and corneal smear
  description: >-
    Because virus reaches cutaneous nerves around hair follicles by centrifugal
    spread, antigen can be sought in a nuchal skin biopsy during life. Sensitivity
    and specificity are modest, and corneal smears are discouraged because of the
    risk of corneal scarification.
  evidence:
  - reference: PMID:38376376
    reference_title: "Recent updates on laboratory diagnosis of rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FAT can be employed for antigen detection in samples such as corneal smears and nuchal skin biopsies. However, the sensitivity and specificity of FAT are relatively low in these samples."
    explanation: Supports the antemortem application while recording its limited accuracy.
- name: Reverse transcription PCR for viral RNA
  description: >-
    Conventional or real-time RT-PCR targeting the nucleoprotein gene is the most
    widely used laboratory confirmation, applicable to both antemortem and
    postmortem samples, and it also types the reservoir variant. Sensitivity is
    higher in pooled saliva and nuchal skin than in cerebrospinal fluid or urine.
  evidence:
  - reference: PMID:38376376
    reference_title: "Recent updates on laboratory diagnosis of rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most popular method for confirming the diagnosis of rabies in a laboratory, in both ante-mortem and post-mortem samples is conventional or real-time RT-PCR."
    explanation: Establishes RT-PCR as the principal nucleic acid confirmation method.
  - reference: PMID:38376376
    reference_title: "Recent updates on laboratory diagnosis of rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PCR exhibits higher sensitivity in pooled saliva and nuchal skin samples but lower sensitivity in CSF, urine samples and extracted hair follicles"
    explanation: Records the sample-type dependence of PCR sensitivity.
- name: A negative antemortem test does not exclude rabies
  description: >-
    The single most important interpretive caveat. Antemortem assays are
    insensitive enough that clinical suspicion, not a negative result, should
    drive management; series from a WHO reference laboratory confirmed only about
    40 per cent of clinically suspected cases antemortem.
  evidence:
  - reference: PMID:38376376
    reference_title: "Recent updates on laboratory diagnosis of rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A major limitation of ante-mortem tests for rabies is that negative results do not exclude a diagnosis of the disease"
    explanation: States the interpretive caveat explicitly.
  - reference: PMID:38376376
    reference_title: "Recent updates on laboratory diagnosis of rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ante-mortem laboratory confirmation of rabies was achieved in 40.6 per cent (128 cases between 2012 and 2014) and 42.3 per cent (130 cases between 2015 and 2017) of clinically suspected rabies cases"
    explanation: Quantifies real-world antemortem confirmation rates at a reference laboratory.
- name: Underdiagnosis and the global burden estimate
  description: >-
    The reported burden of rabies is an undercount, and the lack of sensitive
    laboratory methods is a direct cause rather than an incidental limitation.
  evidence:
  - reference: PMID:24348170
    reference_title: "Laboratory diagnosis of human rabies: recent advances."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The true disease burden and public health impact due to rabies remain underestimated due to lack of sensitive laboratory diagnostic methods."
    explanation: Links diagnostic insensitivity to systematic underestimation of burden.
differential_diagnoses:
- name: Guillain-Barre syndrome
  description: >-
    Paralytic rabies presents with ascending flaccid weakness and relatively
    preserved consciousness, and is frequently mistaken for Guillain-Barre
    syndrome; an exposure history and a compatible neurological trajectory should
    prompt reconsideration.
  distinguishing_features:
  - A compatible animal exposure, which may be remote or unrecognised
  - Pain, itch, or paresthesia localised to the healed bite site
  - Inexorable progression to coma and death, without response to immunotherapy
  evidence:
  - reference: PMID:23723193
    reference_title: "Clinical features of dog- and bat-acquired rabies in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bat-acquired cases of rabies were more often misdiagnosed and lacked a bite history."
    explanation: Documents misdiagnosis as a recurring problem, especially where a bite history is absent.
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Local symptoms at the site of the bite, piloerection, bladder dysfunction and fever are all features that favour a diagnosis of paralytic rabies."
    explanation: Names the specific clinical features that discriminate paralytic rabies from Guillain-Barre syndrome.
prevalence:
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.74
  rate_low: 0.31
  rate_high: 1.99
  notes: >-
    Approximately 59,000 human deaths from dog-mediated rabies annually (95% CI
    25,000 to 159,000), normalised against a world population of about 8 billion.
    Because clinical rabies is essentially always fatal, annual deaths approximate
    the annual incidence of clinical disease. The overwhelming majority of these
    deaths occur in Africa and Asia, and the figure is an undercount because
    antemortem diagnosis is insensitive and surveillance is weak.
  evidence:
  - reference: PMID:25881058
    reference_title: "Estimating the global burden of endemic canine rabies."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "This study estimates that globally canine rabies causes approximately 59,000 (95% Confidence Intervals: 25-159,000) human deaths"
    explanation: Source of both the central annual mortality estimate and the confidence interval behind rate_low and rate_high.
treatments:
- name: Thorough wound cleansing
  description: >-
    Immediate and thorough washing of the wound is the first step of
    post-exposure prophylaxis and mechanically removes virus before it can reach
    nerve terminals. It is cheap, universally available, and frequently skipped.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: wound care management
    term:
      id: NCIT:C116681
      label: Wound Care Management
  target_mechanisms:
  - target: Inoculation of Virus into Peripheral Tissue
    treatment_effect: INHIBITS
    description: >-
      Removes or inactivates virus at the inoculation site before neuronal entry
      can occur.
  evidence:
  - reference: PMID:18496505
    reference_title: "Human rabies prevention--United States, 2008: recommendations of the Advisory Committee on Immunization Practices."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACIP recommends that prophylaxis for the prevention of rabies in humans exposed to rabies virus should include prompt and thorough wound cleansing followed by passive rabies immunization with human rabies immune globulin (HRIG) and vaccination with a cell culture rabies vaccine."
    explanation: ACIP places prompt thorough wound cleansing first in the prophylaxis sequence.
- name: Rabies immunoglobulin administration
  description: >-
    Human rabies immune globulin infiltrated into and around the wound provides
    immediate passive neutralising antibody, covering the interval before the
    vaccine-induced response develops. It is given once, only to previously
    unvaccinated people.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: immunoglobulin therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: human rabies immune globulin
      term:
        id: NCIT:C80831
        label: Human Rabies Virus Immune Globulin
  target_mechanisms:
  - target: Neuromuscular Junction Entry into Motor Neurons
    treatment_effect: INHIBITS
    description: >-
      Neutralising antibody at the wound site blocks virions before they can
      engage receptors on the motor nerve terminal.
  evidence:
  - reference: PMID:12144896
    reference_title: "Rabies re-examined."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Prophylaxis encompasses thorough wound treatment, vaccine administration, and inoculation of rabies immunoglobulin."
    explanation: The abstract includes rabies immunoglobulin as part of prophylaxis.
  - reference: PMID:18496505
    reference_title: "Human rabies prevention--United States, 2008: recommendations of the Advisory Committee on Immunization Practices."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HRIG is administered only once (i.e., at the beginning of antirabies prophylaxis) to previously unvaccinated persons to provide immediate, passive, rabies virus neutralizing antibody coverage until the patient responds to HDCV or PCECV by actively producing antibodies."
    explanation: Specifies the timing, single administration, and bridging rationale for HRIG.
  notes: >-
    HRIG is a polyclonal human immune globulin rather than a monoclonal antibody,
    so therapeutic_modality is OTHER; monoclonal antibody products are now
    entering use as replacements and would be tagged MONOCLONAL_ANTIBODY.
- name: Rabies post-exposure vaccination
  description: >-
    A series of cell culture-derived rabies vaccine doses given after exposure.
    Together with wound care and immunoglobulin, post-exposure prophylaxis is
    highly effective at preventing progression to clinical disease, but only if
    given promptly.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
    therapeutic_agent:
    - preferred_term: rabies vaccine
      term:
        id: NCIT:C198514
        label: Rabies Vaccine
  target_mechanisms:
  - target: Retrograde Axonal Transport to the Central Nervous System
    treatment_effect: INHIBITS
    description: >-
      Active immunisation raises neutralising antibody during the long incubation
      period, clearing virus before it completes the journey to the central
      nervous system.
  evidence:
  - reference: PMID:12144896
    reference_title: "Rabies re-examined."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Prophylaxis encompasses thorough wound treatment, vaccine administration, and inoculation of rabies immunoglobulin."
    explanation: The abstract describes vaccine administration for prophylaxis.
  - reference: PMID:29188797
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "If exposure occurs, timely post-exposure prophylaxis can prevent the progression to clinical disease and involves appropriate wound care, the administration of rabies immunoglobulin and vaccination."
    explanation: States the three components of PEP and their preventive effect.
  - reference: PMID:36535276
    reference_title: "Human rabies despite post-exposure prophylaxis: a systematic review of fatal breakthrough infections after zoonotic exposures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Post-exposure prophylaxis (PEP) for rabies is widely administered and highly effective."
    explanation: Systematic review confirming PEP effectiveness.
  - reference: PMID:36535276
    reference_title: "Human rabies despite post-exposure prophylaxis: a systematic review of fatal breakthrough infections after zoonotic exposures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Timely and appropriate administration of PEP is crucial to prevent rabies, and although people with high-risk exposures or immunosuppression can develop rabies despite adherence to core practices, this occurrence remains exceedingly rare."
    explanation: Qualifies effectiveness; breakthrough infections occur but are exceedingly rare and usually follow deviations from core practice.
- name: Rabies pre-exposure prophylaxis
  description: >-
    A vaccine series given before any exposure to people at elevated risk:
    veterinarians, laboratory workers, and long-term travellers to or residents
    of endemic areas. It does not remove the need for post-exposure prophylaxis
    but simplifies it, eliminating the immunoglobulin requirement and reducing
    the number of vaccine doses.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
    therapeutic_agent:
    - preferred_term: rabies vaccine
      term:
        id: NCIT:C198514
        label: Rabies Vaccine
  evidence:
  - reference: PMID:35511716
    reference_title: "Use of a Modified Preexposure Prophylaxis Vaccination Schedule to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PrEP does not eliminate the need for PEP; however, it does simplify the rabies PEP schedule (i.e., eliminates the need for rabies immunoglobulin and decreases the number of vaccine doses required for PEP)."
    explanation: States the role and limits of pre-exposure prophylaxis.
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Preexposure prophylaxis (PrEP) is available for individuals likely to be exposed to the RABV, such as veterinarians and long-term travelers or residents in endemic countries."
    explanation: Identifies the target populations for PrEP.
- name: Anti-rabies monoclonal antibody
  description: >-
    Monoclonal antibody preparations are replacing blood-derived rabies immune
    globulin for the passive-immunisation arm of post-exposure prophylaxis, which
    matters because RIG is chronically in short supply and carries the safety
    profile of a pooled human blood product. Because single antibodies select for
    escape at their own epitope, products are formulated as cocktails of
    non-competing antibodies binding separate epitopes on the viral glycoprotein.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: immunoglobulin therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: anti-rabies monoclonal antibody
      term:
        id: NCIT:C20401
        label: Monoclonal Antibody
  target_mechanisms:
  - target: Neuromuscular Junction Entry into Motor Neurons
    treatment_effect: INHIBITS
    description: >-
      Like rabies immune globulin, neutralising monoclonal antibody at the wound
      site blocks virions before they engage receptors on the motor nerve
      terminal; it is the same mechanistic slot, filled by a recombinant product.
  evidence:
  - reference: PMID:39542064
    reference_title: "Developing a human monoclonal antibody combination CRM25 to prevent rabies after exposure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Currently, replacing traditional RIG with emerging mAb or mAb combinations is highly recommended due to the limited supply and potential safety risks of RIG."
    explanation: States the rationale for displacing blood-derived RIG with monoclonal antibody products.
  - reference: PMID:39542064
    reference_title: "Developing a human monoclonal antibody combination CRM25 to prevent rabies after exposure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RM02 and RM05 were non-competing and non-overlapping mAbs targeting epitopes I and III, respectively."
    explanation: Documents the non-overlapping two-epitope cocktail design that guards against neutralisation escape.
  notes: >-
    Evidence here is preclinical characterisation of one cocktail (CRM25);
    the clinical comparison against HRIG is captured in the clinical_trials
    block (SYN023, NCT03961555 and NCT04644484).
- name: Palliative and supportive care
  description: >-
    Once symptoms begin there is no established curative therapy, and management
    centres on relieving pain, agitation, and distress. In much of the world
    patients die at home without access to even this.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: palliative care
    term:
      id: NCIT:C15830
      label: "Palliative Care, Other Than Pain and Hospice"
  evidence:
  - reference: PMID:28846292
    reference_title: "Rabies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Preventing rabies is crucial, as treatment options after symptoms appear are mostly limited to palliative care."
    explanation: States that post-symptomatic management is essentially palliative.
- name: Milwaukee protocol
  description: >-
    An aggressive regimen of therapeutic (induced) coma with ketamine, ribavirin,
    and amantadine, promoted after a 2004 survival in Milwaukee. It is recorded
    here as a refuted intervention: two decades produced no documented evidence
    of efficacy and at least 64 failures, and the current recommendation is to
    abandon it. Any benefit historically attributed to the protocol is more
    plausibly explained by the intensive care that accompanied it.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ketamine
      term:
        id: CHEBI:6121
        label: ketamine
    - preferred_term: ribavirin
      term:
        id: CHEBI:63580
        label: ribavirin
    - preferred_term: amantadine
      term:
        id: CHEBI:2618
        label: amantadine
  evidence:
  - reference: PMID:40139921
    reference_title: "Demise of the Milwaukee Protocol for Rabies."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Over the past 2 decades, no subsequent detailed reports have documented evidence of efficacy. There have been at least 64 cases with failure of the protocol."
    explanation: Documents the absence of efficacy evidence and the accumulated failures.
  - reference: PMID:40139921
    reference_title: "Demise of the Milwaukee Protocol for Rabies."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The time has now come to abandon the failed Milwaukee protocol for the therapy of rabies and consider new approaches based our current knowledge of rabies pathogenesis."
    explanation: Explicit recommendation to abandon the protocol.
  - reference: PMID:30747124
    reference_title: "Rabies: a medical perspective."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The Milwaukee protocol, which included therapeutic coma and the administration of ketamine, ribavirin and amantadine, has proved to be ineffective and should no longer be used"
    explanation: Independent review naming all three agents and stating the protocol is ineffective and should not be used.
  notes: >-
    Retained deliberately as a negative entry so the knowledge base records what
    has been tried and refuted, not only what is recommended.
clinical_trials:
- name: NCT03961555
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Phase 2b randomised blinded comparison of the monoclonal antibody product
    SYN023 against licensed human rabies immune globulin in the post-exposure
    prophylaxis of adults with WHO Category III exposure. A placebo arm is
    ethically impossible here, so HRIG is necessarily the comparator.
  target_phenotypes:
  - preferred_term: Viral encephalitis
    term:
      id: HP:0033993
      label: Viral encephalitis
  evidence:
  - reference: clinicaltrials:NCT03961555
    reference_title: "A Phase 2b Randomized Blinded Study to Evaluate SYN023 Compared to Human Rabies Immune Globulin in Post Exposure Prophylaxis of Rabies in Adults With Different Rabies Exposure Risks"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a Phase 2b, double blinded, randomized study of SYN023 compared to HyperRab"
    explanation: Establishes the design and comparator of the phase 2b monoclonal antibody trial.
- name: NCT04644484
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Phase III randomised blinded comparison of SYN023 against licensed human
    rabies immune globulin in post-exposure prophylaxis for WHO Category III
    exposure, intended to support licensure of a monoclonal alternative to
    blood-derived RIG.
  target_phenotypes:
  - preferred_term: Viral encephalitis
    term:
      id: HP:0033993
      label: Viral encephalitis
  evidence:
  - reference: clinicaltrials:NCT04644484
    reference_title: "A Phase III Randomized Blinded Study to Evaluate SYN023 Compared to Human Rabies Immune Globulin in Post Exposure Prophylaxis of Rabies in Adults With Category III Rabies Exposure Risks"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This trial is proposed to further the licensure of SYN023 to provide an effective PEP alternative available to those exposed persons who need such a product."
    explanation: States the licensure intent for a monoclonal alternative to rabies immune globulin.
discussions:
- discussion_id: rabies_neuronal_dysfunction_basis
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Neuronal Dysfunction Without Substantial Neuronal Death
  prompt: >-
    What is the molecular basis of the neuronal dysfunction that kills in rabies,
    given that infected neurons are structurally preserved and inflammation is
    minimal?
  rationale: >-
    This is the central unresolved question of the entry and the reason no
    post-symptomatic therapy has ever worked. Every candidate mechanism proposed
    so far - electrophysiological alterations, ion channel and neurotransmission
    effects, neurotoxicity, and more recently mitochondrial bioenergetic failure
    with mitophagy - remains a candidate rather than a demonstrated cause. Until
    the effector step is identified there is no rational target for therapy after
    symptom onset, which is precisely the window in which every attempted
    treatment, the Milwaukee protocol included, has failed.
  proposed_experiments:
  - experiment_id: rabies_neuron_electrophysiology
    name: Electrophysiological phenotyping of infected human-derived neurons
    description: >-
      Patch-clamp and multi-electrode-array characterisation of synaptic
      transmission, resting membrane potential, and ion channel behaviour in
      rabies-infected human iPSC-derived neurons, comparing street virus with
      laboratory-adapted strains, to establish whether a reproducible functional
      lesion precedes any structural change.
    supporting_outcome:
    - >-
      A consistent, strain-independent defect in synaptic transmission or
      excitability appearing before structural change would identify the
      effector step of neuronal dysfunction.
    refuting_outcome:
    - >-
      Normal electrophysiology in productively infected neurons would argue the
      fatal lesion lies outside cell-autonomous neuronal function, redirecting
      attention to network or systemic mechanisms.
  - experiment_id: rabies_mitochondrial_rescue
    name: Mitochondrial rescue in an infected neuronal model
    description: >-
      Test whether restoring mitochondrial membrane potential or blocking
      mitophagy preserves neuronal function in infected neurons, directly probing
      the bioenergetic hypothesis proposed from naturally infected human and
      canine brain.
    supporting_outcome:
    - >-
      Functional rescue without reducing viral replication would establish
      mitochondrial failure as the causal effector rather than a bystander
      correlate.
    refuting_outcome:
    - >-
      Preserved mitochondrial function with unchanged neuronal dysfunction would
      demote the bioenergetic account to an epiphenomenon.
  evidence:
  - reference: PMID:15804968
    reference_title: "Neuronal dysfunction and death in rabies virus infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The precise bases of this functional impairment are unknown, and current knowledge on electro-physiological alterations, effects on ion channels and neurotransmission, and neurotoxicity are reviewed."
    explanation: States directly that the basis of the functional impairment is unknown, which is the gap this discussion records.
notes: >-
  Two features make rabies unusual among the encephalitides and are worth holding
  onto when reading this entry. First, the long clinically silent incubation is
  not latency but travel time: the virus is physically crawling up an axon, and
  that slow transit is exactly the window post-exposure prophylaxis exploits.
  Second, the neuropathology is mild while the disease is uniformly fatal.
  Neurons are functionally deranged rather than destroyed, and no one has yet
  established why. That gap is the most important open mechanistic question in
  the entry, and it is the reason no post-symptomatic therapy has worked; it is
  recorded as a structured KNOWLEDGE_GAP discussion
  (rabies_neuronal_dysfunction_basis) attached to the Neuronal Dysfunction
  Without Substantial Neuronal Death node rather than left as prose here.
references:
- reference: DOI:10.1093/cid/ciad098
  title: Fatal Human Rabies Infection With Suspected Host-Mediated Failure of Post-Exposure Prophylaxis Following a Recognized Zoonotic Exposure—Minnesota, 2021
  found_in:
  - Rabies-deep-research-falcon.md
  findings:
  - statement: No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture–based vaccines.
    supporting_text: No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture–based vaccines.
    evidence:
    - reference: DOI:10.1093/cid/ciad098
      reference_title: Fatal Human Rabies Infection With Suspected Host-Mediated Failure of Post-Exposure Prophylaxis Following a Recognized Zoonotic Exposure—Minnesota, 2021
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture–based vaccines.
      explanation: Deep research cited this publication as relevant literature for Rabies.
- reference: DOI:10.1101/2024.11.05.24316773
  title: 'Rabies Test Accuracy: Comprehensive Systematic Review and Meta-Analysis for Human and Canine Diagnostics'
  found_in:
  - Rabies-deep-research-falcon.md
  findings:
  - statement: Rabies is almost invariably fatal once clinical symptoms manifest.
    supporting_text: Rabies is almost invariably fatal once clinical symptoms manifest.
    evidence:
    - reference: DOI:10.1101/2024.11.05.24316773
      reference_title: 'Rabies Test Accuracy: Comprehensive Systematic Review and Meta-Analysis for Human and Canine Diagnostics'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Rabies is almost invariably fatal once clinical symptoms manifest.
      explanation: Deep research cited this publication as relevant literature for Rabies.
- reference: DOI:10.3389/fitd.2025.1662211
  title: Participatory approach in designing a One Health rabies surveillance form for integrated bite case management in Uganda
  found_in:
  - Rabies-deep-research-falcon.md
  findings:
  - statement: Rabies, a neglected viral zoonotic disease endemic in Uganda, is one of the country’s top seven priority zoonotic diseases.
    supporting_text: Rabies, a neglected viral zoonotic disease endemic in Uganda, is one of the country’s top seven priority zoonotic diseases.
    evidence:
    - reference: DOI:10.3389/fitd.2025.1662211
      reference_title: Participatory approach in designing a One Health rabies surveillance form for integrated bite case management in Uganda
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Rabies, a neglected viral zoonotic disease endemic in Uganda, is one of the country’s top seven priority zoonotic diseases.
      explanation: Deep research cited this publication as relevant literature for Rabies.
- reference: DOI:10.3389/fvets.2023.1147543
  title: Evaluation of country infrastructure as an indirect measure of dog-mediated human rabies deaths
  found_in:
  - Rabies-deep-research-falcon.md
  findings:
  - statement: Rabies is a neglected disease, primarily due to poor detection stemming from limited surveillance and diagnostic capabilities in most countries.
    supporting_text: Rabies is a neglected disease, primarily due to poor detection stemming from limited surveillance and diagnostic capabilities in most countries.
    evidence:
    - reference: DOI:10.3389/fvets.2023.1147543
      reference_title: Evaluation of country infrastructure as an indirect measure of dog-mediated human rabies deaths
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: Rabies is a neglected disease, primarily due to poor detection stemming from limited surveillance and diagnostic capabilities in most countries.
      explanation: Deep research cited this publication as relevant literature for Rabies.
- reference: DOI:10.3390/diagnostics15040412
  title: 'Evaluating Rabies Test Accuracy: A Systematic Review and Meta-Analysis of Human and Canine Diagnostic Methods'
  found_in:
  - Rabies-deep-research-falcon.md
  findings:
  - statement: Rabies is almost invariably fatal once clinical symptoms manifest.
    supporting_text: Rabies is almost invariably fatal once clinical symptoms manifest.
    evidence:
    - reference: DOI:10.3390/diagnostics15040412
      reference_title: 'Evaluating Rabies Test Accuracy: A Systematic Review and Meta-Analysis of Human and Canine Diagnostic Methods'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Rabies is almost invariably fatal once clinical symptoms manifest.
      explanation: Deep research cited this publication as relevant literature for Rabies.
- reference: DOI:10.3390/pathogens14060586
  title: 'The Challenge of Lyssavirus Infections in Domestic and Other Animals: A Mix of Virological Confusion, Consternation, Chagrin, and Curiosity'
  found_in:
  - Rabies-deep-research-falcon.md
  findings:
  - statement: Lyssaviruses are RNA viruses in the Family Rhabdoviridae, Genus Lyssavirus.
    supporting_text: Lyssaviruses are RNA viruses in the Family Rhabdoviridae, Genus Lyssavirus.
    evidence:
    - reference: DOI:10.3390/pathogens14060586
      reference_title: 'The Challenge of Lyssavirus Infections in Domestic and Other Animals: A Mix of Virological Confusion, Consternation, Chagrin, and Curiosity'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Lyssaviruses are RNA viruses in the Family Rhabdoviridae, Genus Lyssavirus.
      explanation: Deep research cited this publication as relevant literature for Rabies.
- reference: DOI:10.3390/pathogens14080728
  title: 'Global Perspectives on Rabies Control and Elimination: A Scoping Review of Dog Owners’ Knowledge, Attitudes, and Practices'
  found_in:
  - Rabies-deep-research-falcon.md
  findings:
  - statement: Rabies is a fatal but entirely vaccine-preventable disease, with the highest risk in areas where free-roaming domestic dogs are prevalent.
    supporting_text: Rabies is a fatal but entirely vaccine-preventable disease, with the highest risk in areas where free-roaming domestic dogs are prevalent.
    evidence:
    - reference: DOI:10.3390/pathogens14080728
      reference_title: 'Global Perspectives on Rabies Control and Elimination: A Scoping Review of Dog Owners’ Knowledge, Attitudes, and Practices'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Rabies is a fatal but entirely vaccine-preventable disease, with the highest risk in areas where free-roaming domestic dogs are prevalent.
      explanation: Deep research cited this publication as relevant literature for Rabies.
- reference: DOI:10.3390/vaccines13070775
  title: 'Circulating Antibody’s Role During Post-Exposure Prophylaxis, and Beyond for Rabies: A Review'
  found_in:
  - Rabies-deep-research-falcon.md
  findings:
  - statement: Since the introduction of Pasteur’s rabies vaccine in 1885, rabies prophylaxis and post-exposure prophylaxis (PEP) have been widely administered globally under the recommendation of the World Health Organization (WHO).
    supporting_text: Since the introduction of Pasteur’s rabies vaccine in 1885, rabies prophylaxis and post-exposure prophylaxis (PEP) have been widely administered globally under the recommendation of the World Health Organization (WHO).
    evidence:
    - reference: DOI:10.3390/vaccines13070775
      reference_title: 'Circulating Antibody’s Role During Post-Exposure Prophylaxis, and Beyond for Rabies: A Review'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Since the introduction of Pasteur’s rabies vaccine in 1885, rabies prophylaxis and post-exposure prophylaxis (PEP) have been widely administered globally under the recommendation of the World Health Organization (WHO).
      explanation: Deep research cited this publication as relevant literature for Rabies.
datasets:
- accession: geo:GSE231664
  title: Nanostring of 3D hiPSC-derived neurons infected with rabies virus-wild type-thai strain (WT-TH) and rabies virus-challenge virus standard 11 (CVS-11) against uninfected controls at 8 and 24 hours post-infection
  description: This experiment is part of the project that primarily aims to utilize 3D hydrogel-based hiPSC-derived neuronal model to study rabies virus infection in the central nervous system. Having established the optimal 3D neuronal model, we then investigated the growth kinetics of two strains of rabies virus (TH and CVS-11) and comparatively analyzed the 2D and 3D culture models. We performed a gene expression analysis using NanoString to determine whether changes in gene expression could explain the differences in virus growth kinetics of two strains of rabies virus observed between the 2D and 3D neuronal culture models.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 36
  publication: PMID:37692167
  notes: Identified by GEO DataSets index search for Rabies (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE196051
  title: Recognition of copy-back defective interfering rabies virus genomes by RIG-I triggers efficient immune response against vaccine strains
  description: Using next-generation sequencing (NGS) combined with bioinformatics tools, we characterized two major 5’copy-back defective interfering (5’cb DI) genomes generated during SAD replication. Furthermore, we identified a specific interaction of 5’cb DI genomes and RIG-I that correlated with a high stimulation of the type I IFN signaling
  data_type: BULK_RNA_SEQ
  sample_count: 36
  publication: PMID:38461968
  notes: Identified by GEO DataSets index search for Rabies (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

📚

References & Deep Research

References

8

DOI:10.1093/cid/ciad098

Fatal Human Rabies Infection With Suspected Host-Mediated Failure of Post-Exposure Prophylaxis Following a Recognized Zoonotic Exposure—Minnesota, 2021

1 finding

No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture–based vaccines.

"No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture–based vaccines."

Show evidence (1 reference)

DOI:10.1093/cid/ciad098 SUPPORT Human Clinical

"No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture–based vaccines."

Deep research cited this publication as relevant literature for Rabies.

DOI:10.1101/2024.11.05.24316773

Rabies Test Accuracy: Comprehensive Systematic Review and Meta-Analysis for Human and Canine Diagnostics

1 finding

Rabies is almost invariably fatal once clinical symptoms manifest.

"Rabies is almost invariably fatal once clinical symptoms manifest."

Show evidence (1 reference)

DOI:10.1101/2024.11.05.24316773 Preprint · not peer-reviewed SUPPORT Other

"Rabies is almost invariably fatal once clinical symptoms manifest."

Deep research cited this publication as relevant literature for Rabies.

DOI:10.3389/fitd.2025.1662211

Participatory approach in designing a One Health rabies surveillance form for integrated bite case management in Uganda

1 finding

Rabies, a neglected viral zoonotic disease endemic in Uganda, is one of the country’s top seven priority zoonotic diseases.

"Rabies, a neglected viral zoonotic disease endemic in Uganda, is one of the country’s top seven priority zoonotic diseases."

Show evidence (1 reference)

DOI:10.3389/fitd.2025.1662211 SUPPORT Other

"Rabies, a neglected viral zoonotic disease endemic in Uganda, is one of the country’s top seven priority zoonotic diseases."

Deep research cited this publication as relevant literature for Rabies.

DOI:10.3389/fvets.2023.1147543

Evaluation of country infrastructure as an indirect measure of dog-mediated human rabies deaths

1 finding

Rabies is a neglected disease, primarily due to poor detection stemming from limited surveillance and diagnostic capabilities in most countries.

"Rabies is a neglected disease, primarily due to poor detection stemming from limited surveillance and diagnostic capabilities in most countries."

Show evidence (1 reference)

DOI:10.3389/fvets.2023.1147543 SUPPORT Computational

"Rabies is a neglected disease, primarily due to poor detection stemming from limited surveillance and diagnostic capabilities in most countries."

Deep research cited this publication as relevant literature for Rabies.

DOI:10.3390/diagnostics15040412

Evaluating Rabies Test Accuracy: A Systematic Review and Meta-Analysis of Human and Canine Diagnostic Methods

1 finding

Rabies is almost invariably fatal once clinical symptoms manifest.

"Rabies is almost invariably fatal once clinical symptoms manifest."

Show evidence (1 reference)

DOI:10.3390/diagnostics15040412 SUPPORT Other

"Rabies is almost invariably fatal once clinical symptoms manifest."

Deep research cited this publication as relevant literature for Rabies.

DOI:10.3390/pathogens14060586

The Challenge of Lyssavirus Infections in Domestic and Other Animals: A Mix of Virological Confusion, Consternation, Chagrin, and Curiosity

1 finding

Lyssaviruses are RNA viruses in the Family Rhabdoviridae, Genus Lyssavirus.

"Lyssaviruses are RNA viruses in the Family Rhabdoviridae, Genus Lyssavirus."

Show evidence (1 reference)

DOI:10.3390/pathogens14060586 SUPPORT Other

"Lyssaviruses are RNA viruses in the Family Rhabdoviridae, Genus Lyssavirus."

Deep research cited this publication as relevant literature for Rabies.

DOI:10.3390/pathogens14080728

Global Perspectives on Rabies Control and Elimination: A Scoping Review of Dog Owners’ Knowledge, Attitudes, and Practices

1 finding

Rabies is a fatal but entirely vaccine-preventable disease, with the highest risk in areas where free-roaming domestic dogs are prevalent.

"Rabies is a fatal but entirely vaccine-preventable disease, with the highest risk in areas where free-roaming domestic dogs are prevalent."

Show evidence (1 reference)

DOI:10.3390/pathogens14080728 SUPPORT Human Clinical

"Rabies is a fatal but entirely vaccine-preventable disease, with the highest risk in areas where free-roaming domestic dogs are prevalent."

Deep research cited this publication as relevant literature for Rabies.

DOI:10.3390/vaccines13070775

Circulating Antibody’s Role During Post-Exposure Prophylaxis, and Beyond for Rabies: A Review

1 finding

Since the introduction of Pasteur’s rabies vaccine in 1885, rabies prophylaxis and post-exposure prophylaxis (PEP) have been widely administered globally under the recommendation of the World Health Organization (WHO).

"Since the introduction of Pasteur’s rabies vaccine in 1885, rabies prophylaxis and post-exposure prophylaxis (PEP) have been widely administered globally under the recommendation of the World Health Organization (WHO)."

Show evidence (1 reference)

DOI:10.3390/vaccines13070775 SUPPORT Human Clinical

"Since the introduction of Pasteur’s rabies vaccine in 1885, rabies prophylaxis and post-exposure prophylaxis (PEP) have been widely administered globally under the recommendation of the World Health Organization (WHO)."

Deep research cited this publication as relevant literature for Rabies.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 51 citations 2026-04-04T16:13:16.365315

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Rabies
MONDO ID: (if available)
Category: Infectious Disease

Research Objectives

Please provide a comprehensive research report on Rabies covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Rabies — Comprehensive Disease Characteristics Report (Infectious Disease)

Executive summary (current understanding)

Rabies is an acute, progressive encephalitis caused by a neurotropic, negative-sense single-stranded RNA virus in the family Rhabdoviridae (genus Lyssavirus), classically transmitted via bites/saliva exposure from infected mammals (especially dogs). Once clinical symptoms begin, rabies is almost invariably fatal; therefore, the public-health focus is on prevention through vaccination of reservoir animals and prompt human post-exposure prophylaxis (PEP). (kaye2024rabiesvaccinefor pages 1-2)

Recent work (2023–2024) emphasizes (i) narrowing data gaps in global mortality estimation and program capacity using infrastructure-based indices, (ii) implementation science around One Health approaches (mass dog vaccination, surveillance, and bite case management), (iii) improved characterization of long-term immunity after vaccine-sparing intradermal PEP regimens, and (iv) continued development of rabies monoclonal antibodies (mAbs) as alternatives to rabies immunoglobulin (RIG). (bonaparte2023evaluationofcountry pages 1-2, ghosh2024rabiescontrolin pages 1-2, ya2024evaluationofone pages 1-2, chen2025circulatingantibody’srole pages 12-13)

Aspect	Key recent finding/statistic	Source (first author, year)	Publication venue	DOI/URL	Evidence type
Global burden and dog-mediated fraction	Rabies causes ~59,000 human deaths annually worldwide; >99% of human rabies deaths/cases are linked to infected dogs, with highest burden in Asia and Africa (ghosh2024rabiescontrolin pages 1-2, mwanyalu2025documentingchallengesin pages 1-2, okech2025participatoryapproachin pages 1-2)	Ghosh, 2024	Lancet Regional Health – Southeast Asia	https://doi.org/10.1016/j.lansea.2024.100452	Epidemiologic analysis / One Health program study
STOP-R modeled deaths in endemic countries	STOP-R index estimated 40,111 human rabies deaths in 2022 (95% CI 25,854–74,344) across DMRVV-endemic countries; projected 32,349 by 2030 (bonaparte2023evaluationofcountry pages 1-2, bonaparte2023evaluationofcountry pages 6-7)	Bonaparte, 2023	Frontiers in Veterinary Science	https://doi.org/10.3389/fvets.2023.1147543	Modeling study
Bangladesh dog population and mass dog vaccination	Estimated dog population 1,668,140; density 12.83 dogs/km²; human:dog ratio 86.70; MDV vaccinated mean 21,295 dogs/district/year out of ~26,065 estimated dogs; 70% annual pulse coverage is the operational target for interruption of transmission (ghosh2024rabiescontrolin pages 1-2)	Ghosh, 2024	Lancet Regional Health – Southeast Asia	https://doi.org/10.1016/j.lansea.2024.100452	National program analysis / forecasting
Kenya (Lamu County) implementation barriers	From 2020–2022, 73% (11/16) of facilities had human rabies vaccine stock-outs; 19% (3/16) had both vaccine and RIG; only 25% of health workers said first action was wound washing; 86% did not know recommended vaccine/RIG dosage and schedule (mwanyalu2025documentingchallengesin pages 1-2)	Mwanyalu, 2025	One Health Outlook	https://doi.org/10.1186/s42522-024-00129-1	Mixed-methods implementation study
PEP immunogenicity durability	After IPC intradermal PEP, all but 2 participants seroconverted by day 14; 87.0% retained neutralizing antibody titers ≥0.5 IU/mL at 12 months; IL-4 and IFN-γ T-cell responses persisted up to 1 year (ya2024evaluationofone pages 1-2, ya2024evaluationofone pages 2-3, ya2024evaluationofone pages 3-4)	Ya, 2024	NPJ Vaccines	https://doi.org/10.1038/s41541-024-01030-8	Prospective human immunogenicity study
Fatal PEP breakthrough infections	Systematic review identified 122 fatal breakthrough infections despite receipt of cell-culture vaccine; median exposure-to-symptom onset 20 days (IQR 16–24); deviations from core PEP practices in 56% (68/122) of cases (whitehouse2023humanrabiesdespite pages 1-3, whitehouse2023humanrabiesdespite pages 4-6)	Whitehouse, 2023	The Lancet Infectious Diseases	https://doi.org/10.1016/S1473-3099(22)00641-7	Systematic review
Diagnostic accuracy: human tests	Meta-analysis: human ELISA median sensitivity 90.5%, specificity 95.0%; human RT-PCR median sensitivity 94.4%, specificity 97.7%; RT-PCR detects viral RNA from saliva, CSF, and tissue samples (candiapuma2025evaluatingrabiestest pages 8-9, candiapuma2025evaluatingrabiestest pages 2-4, candiapuma2025evaluatingrabiestest pages 14-16)	Candia-Puma, 2025	Diagnostics	https://doi.org/10.3390/diagnostics15040412	Systematic review and meta-analysis
Diagnostic accuracy: canine/postmortem comparator tests	DFAT on brain tissue remains traditional postmortem gold standard, but pooled canine DFAT performance was variable (median sensitivity 79.2%, specificity 95.0%); canine rapid immunochromatographic tests had median sensitivity 93.5% and specificity 99.1% (candiapuma2025evaluatingrabiestest pages 9-12, candiapuma2024rabiestestaccuracy pages 1-3, candiapuma2024rabiestestaccuracy pages 12-14)	Candia-Puma, 2025	Diagnostics	https://doi.org/10.3390/diagnostics15040412	Systematic review and meta-analysis
ACIP PrEP schedule update	U.S. ACIP 2022 recommends a 2-dose intramuscular rabies PrEP series on days 0 and 7 for risk categories 1–4, replacing the older 3-dose primary series for many at-risk groups (rao2022useofa media 7550c3e2)	Rao, 2022	MMWR	https://doi.org/10.15585/mmwr.mm7118a2	U.S. guideline / expert recommendation
Dog vaccination threshold for elimination	Achieving ~70% dog vaccination coverage is repeatedly cited as the key herd-immunity threshold for interrupting dog-mediated rabies transmission (blumberg2024eliminationofdogmediated pages 1-2, beron2024dogmediatedrabiesvirus pages 1-3, ghosh2024rabiescontrolin pages 1-2)	Blumberg, 2024	Revue Scientifique et Technique de l'OIE	https://doi.org/10.20506/rst.se.3560	Expert review / public health policy
Real-world One Health surveillance / IBCM relevance	Uganda reported 190 human deaths in 2021–2024 and identified weak surveillance/PEP scarcity as drivers of a “cycle of neglect,” supporting integrated bite case management as a practical One Health response (okech2025participatoryapproachin pages 1-2)	Okech, 2025	Frontiers in Tropical Diseases	https://doi.org/10.3389/fitd.2025.1662211	Surveillance systems / implementation research

Table: This table summarizes major recent rabies findings across burden, prevention, diagnostics, and implementation. It is useful as a compact evidence map for building a disease knowledge base entry.

1. Disease information

1.1 Concise overview

Rabies is a vaccine-preventable zoonotic viral disease causing acute, progressive encephalitis/encephalomyelitis. Infection is typically acquired when virus-containing saliva from a rabid animal contacts broken skin or mucosal surfaces, most often via a bite. (kaye2024rabiesvaccinefor pages 1-2)

1.2 Key identifiers (knowledge-base readiness)

MONDO ID: Not available from the currently retrieved primary sources; must be mapped from an ontology resource (e.g., MONDO, MeSH) outside the present evidence set.
MeSH / ICD-10 / ICD-11: Not directly retrievable from the currently retrieved texts; needs dedicated ontology/database lookup.

1.3 Synonyms / alternative names

“Rabies”
“Rabies encephalitis” / “rabies encephalomyelitis” (clinical description in reviews). (kaye2024rabiesvaccinefor pages 1-2)

1.4 Source of information

This report is based on aggregated disease-level resources (systematic reviews, national program analyses, modeling studies) and primary clinical/immunology studies rather than EHR-derived patient cohorts, except where specific case reports are included (e.g., a fatal PEP failure case report). (ghosh2024rabiescontrolin pages 1-2, holzbauer2023fatalhumanrabies pages 3-4)

2. Etiology

2.1 Disease causal factors

Infectious cause: Rabies virus (RABV), a bullet-shaped, negative-sense ssRNA virus in Rhabdoviridae; described as a “neurotropic RNA virus.” (kaye2024rabiesvaccinefor pages 1-2, kaye2024rabiesvaccinefor pages 4-7)

2.2 Transmission and exposure ecology

Primary transmission occurs via bites and exposure to infected saliva through mucosal membranes or broken skin. (kaye2024rabiesvaccinefor pages 1-2)
In endemic settings, dogs are the dominant reservoir and driver of human infection; multiple sources reiterate that dog bites account for >99% of human rabies deaths/cases. (das2025globalperspectiveson pages 1-2, okech2025participatoryapproachin pages 1-2, ghosh2024rabiescontrolin pages 1-2)

2.3 Risk factors

Exposure-related * Bite location and severity (head/neck/face; multiple wounds; highly innervated sites such as fingers/face) are repeatedly over-represented among fatal “breakthrough” infections despite PEP. (whitehouse2023humanrabiesdespite pages 1-3, whitehouse2023humanrabiesdespite pages 4-6)

Health-system related (implementation risk factors) * Inadequate wound washing knowledge/practice and vaccine/RIG stockouts are documented barriers in elimination programs and increase the likelihood of missed or incomplete PEP. For example, in a Kenya case study, 73% of facilities had human rabies vaccine stock-outs and only 19% had both vaccine and RIG. (mwanyalu2025documentingchallengesin pages 1-2)

Host-related * Immunocompromise may contribute to rare PEP failures. A U.S. case report of fatal rabies after prompt ACIP-recommended PEP described no neutralizing antibodies by RFFIT and possible underlying immunodeficiency (IgM MGUS with reduced IgA/IgG). (holzbauer2023fatalhumanrabies pages 3-4)

2.4 Protective factors

Prompt and correct PEP (wound cleansing + vaccine ± passive immunization for severe exposures) is highly protective at the population level and is the central preventive intervention described across public health and clinical sources. (kaye2024rabiesvaccinefor pages 1-2, mwanyalu2025documentingchallengesin pages 1-2)
Mass dog vaccination achieving high coverage is protective at the population level by interrupting dog-to-dog transmission and reducing human exposures. (ghosh2024rabiescontrolin pages 1-2)

2.5 Gene–environment interactions

Rabies is not primarily a genetic disease; gene–environment interactions are not well-defined in the retrieved evidence. Rare apparent PEP failures likely reflect a combination of exposure intensity/anatomy + host immune status + care delivery factors rather than a known host genetic predisposition. (whitehouse2023humanrabiesdespite pages 1-3, holzbauer2023fatalhumanrabies pages 3-4)

3. Phenotypes (clinical presentation)

3.1 Core clinical phenotypes

From a 2024 narrative review, typical clinical features include a prodrome (fever, headache, fatigue) progressing to encephalomyelitis with hydrophobia and aerophobia; the review reports hydrophobia in ~80% and paralytic rabies in ~20%. (kaye2024rabiesvaccinefor pages 1-2)

Suggested HPO terms (examples; require final confirmation against HPO): * Hydrophobia (HP term to be mapped) * Aerophobia (HP term to be mapped) * Fever (HP:0001945) * Headache (HP:0002315) * Encephalitis (HP:0002383) * Paralysis (HP:0003470) * Dysphagia (HP:0002015) * Agitation / behavioral change (HPO mapping required)

3.2 Natural history and temporal development

A 2024 review describes five stages: incubation (days to years), prodrome, acute neurologic illness, coma, death. (kaye2024rabiesvaccinefor pages 1-2)

Notable 2023 update (breakthrough cases): In fatal breakthrough infections after PEP, median time from exposure to symptom onset was 20 days (IQR 16–24), reflecting very short incubation in many high-risk exposures. (whitehouse2023humanrabiesdespite pages 1-3)

3.3 Quality of life impact

Rabies causes severe neuropsychiatric and neurologic symptoms culminating in coma and death; quality-of-life instruments are not reported in the retrieved sources. Impact is inferred as profound due to near-universal fatality after symptom onset. (kaye2024rabiesvaccinefor pages 1-2)

4. Genetic / molecular information

Rabies is caused by a viral pathogen rather than human germline variants.

4.1 “Causal genes” / variants (human)

Not applicable as a primary etiology in the retrieved evidence.

4.2 Viral molecular targets relevant to prevention/therapy

Rabies virus glycoprotein G is the major neutralization target, underpinning vaccine-induced and passive antibody protection, and is the target of mAbs discussed as RIG alternatives. (chen2025circulatingantibody’srole pages 12-13)

5. Environmental information

Key environmental/lifestyle contributors in the retrieved evidence relate primarily to: * Dog ecology and free-roaming dog density (relevant to sustained transmission and outbreaks). (beron2024dogmediatedrabiesvirus pages 1-3) * Resource limitations and conflict/poverty that influence vaccine access, surveillance, and program performance (e.g., stockouts, underreporting). (mwanyalu2025documentingchallengesin pages 1-2, bonaparte2023evaluationofcountry pages 1-2)

6. Mechanism / pathophysiology

6.1 Causal chain (high-level)

Exposure/inoculation via bite/saliva →
Local replication and entry into peripheral nerves →
Neuroinvasion and spread within the CNS →
Progressive encephalitis/encephalomyelitis →
Coma and death.

A 2024 narrative review attributes death to “a massive inflammatory response in the CNS.” (kaye2024rabiesvaccinefor pages 1-2)

6.2 Immune evasion / immune response (current themes)

The 2024 review frames a major research target as “preventing the virus from evading the host’s innate immune response.” (kaye2024rabiesvaccinefor pages 4-7)

6.3 Suggested ontology terms

GO Biological Process (examples; to be curated): * innate immune response (GO:0045087) * inflammatory response (GO:0006954) * response to virus (GO:0009615)

Cell Ontology (CL) likely involved: * neurons (CL:0000540) * microglia (CL:0000129) * astrocytes (CL:0000127)

UBERON anatomical structures: * brain (UBERON:0000955) * spinal cord (UBERON:0002240) * peripheral nerve (UBERON:0001021)

6.4 Advanced technologies / recent developments

A 2024 review discusses exploratory approaches (e.g., CRISPR/Cas9, iPSC-based strategies) and AAV delivery as research directions, but these are not yet established clinical interventions for rabies. (kaye2024rabiesvaccinefor pages 4-7)

7. Anatomical structures affected

Primary system: Central nervous system (encephalitis/encephalomyelitis). (kaye2024rabiesvaccinefor pages 1-2)
Anatomical correlates of risk: Exposures to highly innervated sites (e.g., face/fingers) are associated with short incubation and higher risk even with PEP. (whitehouse2023humanrabiesdespite pages 4-6)

8. Temporal development

Typical incubation is described as days to years (broad range) in a 2024 narrative review; in contrast, breakthrough infections after PEP show very short incubation with median 20 days. (kaye2024rabiesvaccinefor pages 1-2, whitehouse2023humanrabiesdespite pages 1-3)

9. Inheritance and population

9.1 Epidemiology (recent data)

Global * Bangladesh analysis provides a clear statement: “Rabies… kills an estimated 59,000 people each year worldwide” and notes that “over 29 million individuals worldwide receive post-exposure prophylaxis (PEP)… resulting… [in] economic loss of US$ 8.6 billion.” (Published Aug 2024; https://doi.org/10.1016/j.lansea.2024.100452) (ghosh2024rabiescontrolin pages 1-2)

Global estimates with uncertainty / program monitoring * A 2023 modeling study (STOP-R) estimated 40,111 deaths in 2022 (95% CI 25,854–74,344) in dog-mediated rabies virus variant endemic countries, projected to 32,349 by 2030 (95% CI 21,110–57,019). (Published 09 May 2023; https://doi.org/10.3389/fvets.2023.1147543) (bonaparte2023evaluationofcountry pages 1-2, bonaparte2023evaluationofcountry pages 6-7)

Regional distribution * Multiple sources emphasize highest burden in Asia and Africa. (blumberg2024eliminationofdogmediated pages 1-2, ghosh2024rabiescontrolin pages 1-2)

9.2 Population demographics

Many sources highlight disproportionate burden in children; however, quantitative child-specific fractions are not consistently available in the 2023–2024 sources retrieved here.

10. Diagnostics

10.1 Current diagnostic concepts

Postmortem diagnosis has historically relied on direct fluorescent antibody testing (DFAT) on brain tissue as a gold standard comparator, but performance varies across studies. (candiapuma2025evaluatingrabiestest pages 2-4, candiapuma2024rabiestestaccuracy pages 12-14)
Antemortem diagnosis can use RT-PCR detection of viral RNA from saliva, CSF, and tissue samples. (candiapuma2025evaluatingrabiestest pages 2-4)

10.2 Recent quantitative diagnostic accuracy synthesis (2025)

A 2025 systematic review/meta-analysis reported: * Human ELISA (8 studies; n=2,837): sensitivity range 85.9–99.9% (median 90.5%), specificity range 69.0–99.8% (median 95.0%). (https://doi.org/10.3390/diagnostics15040412; published Feb 2025) (candiapuma2025evaluatingrabiestest pages 8-9) * Human RT-PCR (5 studies; n=456): sensitivity range 87.5–95.5% (median 94.4%), specificity range 83.3–99.8% (median 97.7%). (candiapuma2025evaluatingrabiestest pages 9-12) * The same review documents use of specimen types including serum, saliva, CSF, skin, oral swab, hair, and cornea across studies, reflecting multi-specimen strategies for antemortem diagnosis. (candiapuma2025evaluatingrabiestest pages 8-9)

Important limitation: specimen-specific antemortem performance for nuchal skin biopsy vs saliva vs CSF is not fully extractable from the provided excerpts; individual-study review would be required for test-by-specimen operating characteristics. (candiapuma2025evaluatingrabiestest pages 8-9, candiapuma2025evaluatingrabiestest pages 2-4)

11. Outcome / prognosis

Once symptomatic, rabies has a near-100% case fatality, which is repeatedly emphasized in reviews and public-health analyses. (kaye2024rabiesvaccinefor pages 1-2, ghosh2024rabiescontrolin pages 1-2)

11.1 Breakthrough infections despite PEP (2023 systematic review)

A 2023 Lancet Infectious Diseases systematic review (published May 2023; https://doi.org/10.1016/S1473-3099(22)00641-7) identified 122 fatal breakthrough infections (1980–2022) after receipt of modern cell-culture vaccine before symptom onset. Deviations from core PEP practices were present in 56% of cases, severe wound patterns were common, and median incubation was 20 days. (whitehouse2023humanrabiesdespite pages 1-3)

12. Treatment

12.1 Standard of care (prevention-focused)

A 2024 narrative review states that PEP includes wound cleaning, human rabies immunoglobulin (HRIG), and inactivated rabies vaccines. (kaye2024rabiesvaccinefor pages 1-2)

12.2 ACIP (U.S.) PrEP schedule (guideline-based)

ACIP 2022 recommends a 2-dose IM pre-exposure series (days 0 and 7) for risk categories 1–4 (e.g., laboratory workers with live virus, frequent bat handlers, veterinarians, and certain travelers). (Published May 2022; https://doi.org/10.15585/mmwr.mm7118a2) (rao2022useofa media 7550c3e2)

12.3 Passive immunization: RIG and mAbs (latest research direction)

A 2025 review summarizes that modern mAb cocktails are designed to meet WHO expectations of binding two or more non-overlapping epitopes on glycoprotein G and reports markedly higher early circulating antibody levels than HRIG in referenced studies (e.g., “over 10 times higher than that of HRIG” by day 1 for a cited mAb combination). (Published Jul 2025; https://doi.org/10.3390/vaccines13070775) (chen2025circulatingantibody’srole pages 12-13)

Clinical trials (pipeline evidence): Multiple interventional trials exist evaluating rabies immune globulins and mAbs in simulated or real PEP contexts, including SYN023 programs and other candidates (e.g., NCT04644484; NCT03961555). (NCT04644484 chunk 1/2; NCT03961555 chunk 1/2/3)

12.4 Treatment outcomes: immunogenicity after PEP (2024 primary data)

A prospective immunology study in Cambodia assessed immunity for 12 months after a WHO-recommended, vaccine-sparing IPC intradermal PEP regimen: * At day 14, “all except two individuals seroconverted” for neutralizing antibodies ≥0.5 IU/mL, and 87% maintained ≥0.5 IU/mL at 12 months. (Published Nov 2024; https://doi.org/10.1038/s41541-024-01030-8) (ya2024evaluationofone pages 2-3) * Median neutralizing antibody titers were 0.05 IU/mL at day 7 and 3.38 IU/mL at day 14; titers remained near/above the protective threshold at month 6 and month 12. (ya2024evaluationofone pages 2-3)

MAXO suggestions (examples): * Rabies post-exposure prophylaxis (MAXO mapping required) * Rabies vaccination (MAXO mapping required) * Passive immunization (rabies immunoglobulin / monoclonal antibody) (MAXO mapping required)

13. Prevention

13.1 Primary prevention

Mass dog vaccination is repeatedly emphasized; achieving 70% coverage in annual pulse vaccination campaigns is expected to substantially reduce dog rabies and thereby human rabies. (ghosh2024rabiescontrolin pages 1-2)

13.2 Secondary prevention

PEP after exposure: prompt wound care and vaccination are central. Bangladesh’s national analysis reiterates massive PEP utilization globally: “over 29 million individuals worldwide receive post-exposure prophylaxis (PEP).” (ghosh2024rabiescontrolin pages 1-2)

13.3 Public health implementation (real-world)

Bangladesh: national One Health program analysis supports that increases in mass dog vaccination and anti-rabies vaccine (human) correlate with declining human rabies risk, suggesting feasibility of progress toward “Zero by 30.” (ghosh2024rabiescontrolin pages 1-2)
Kenya (Lamu): persistent stockouts and health worker knowledge gaps demonstrate operational constraints that directly undermine timely PEP and elimination targets. (mwanyalu2025documentingchallengesin pages 1-2)

14. Other species / natural disease

Rabies (lyssavirus infections) affects warm-blooded vertebrates; dogs are emphasized as the only domestic animal functioning as reservoir, vector, and victim, whereas other domestic species are spillover/bellwethers. (https://doi.org/10.3390/pathogens14060586; published Jun 2025) (candiapuma2025evaluatingrabiestest pages 17-19)

15. Model organisms

This report’s retrieved sources focus on clinical/public-health and do not comprehensively enumerate model systems. However, a 2024 narrative review describes multiple preclinical approaches including mouse studies of combination therapies and immunomodulation, and exploratory gene-therapy concepts (e.g., AAV-mediated RNAi). (kaye2024rabiesvaccinefor pages 4-4)

Expert interpretation and synthesis (authoritative analysis)

The primary scientific bottleneck is not vaccine efficacy but delivery fidelity. The 2023 systematic review of fatal breakthrough infections found that in 56% of reported deaths there were deviations from core PEP practices, and RIG administration errors (e.g., absent RIG, IM-only RIG without wound infiltration) were common. This supports the expert consensus that “failures” are frequently system/implementation failures rather than intrinsic biologic failure. (whitehouse2023humanrabiesdespite pages 1-3, whitehouse2023humanrabiesdespite pages 4-6)
Program evaluation is moving toward measurable capacity indices and implementation science. STOP-R (2023) illustrates an approach to infer rabies burden and elimination capacity from country-level infrastructure metrics, addressing surveillance gaps that limit direct measurement. (bonaparte2023evaluationofcountry pages 1-2)
Vaccine-sparing intradermal regimens can yield durable immunity, supporting scale-up in resource-limited settings. The NPJ Vaccines 2024 immunology study shows robust neutralizing antibody responses and persistence (87% ≥0.5 IU/mL at 12 months) under a shortened regimen, relevant where PEP cost/access limits completion. (ya2024evaluationofone pages 2-3)
Diagnostics are modernizing toward molecular/immunologic methods, but evidence heterogeneity remains. A 2025 meta-analysis supports high median performance for human RT-PCR and ELISA, while emphasizing variability and the need for protocol modernization and antemortem access. (candiapuma2025evaluatingrabiestest pages 8-9, candiapuma2025evaluatingrabiestest pages 14-16)

Evidence gaps / not fully resolved from retrieved sources

Ontology identifiers (MONDO, MeSH, ICD-10/11) could not be extracted from the current evidence set and require targeted database lookup.
Specimen-specific antemortem diagnostic accuracy (e.g., nuchal skin biopsy vs saliva vs CSF) is not fully extractable from the provided excerpts.
Comprehensive HPO/GO/CL/MAXO mappings require dedicated ontology queries; suggestions above are plausible but should be validated.

Key URLs and publication dates (from retrieved sources)

Ghosh et al., Lancet Regional Health – Southeast Asia (Aug 2024): https://doi.org/10.1016/j.lansea.2024.100452 (ghosh2024rabiescontrolin pages 1-2)
Ya et al., NPJ Vaccines (Nov 2024): https://doi.org/10.1038/s41541-024-01030-8 (ya2024evaluationofone pages 1-2)
Whitehouse et al., Lancet Infectious Diseases (May 2023): https://doi.org/10.1016/S1473-3099(22)00641-7 (whitehouse2023humanrabiesdespite pages 1-3)
Bonaparte et al., Frontiers in Veterinary Science (09 May 2023): https://doi.org/10.3389/fvets.2023.1147543 (bonaparte2023evaluationofcountry pages 1-2)
Rao et al., ACIP PrEP recommendations, MMWR (May 2022): https://doi.org/10.15585/mmwr.mm7118a2 (rao2022useofa media 7550c3e2)
Candia-Puma et al., Diagnostics (Feb 2025): https://doi.org/10.3390/diagnostics15040412 (candiapuma2025evaluatingrabiestest pages 9-12)

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(candiapuma2024rabiestestaccuracy pages 1-3): Mayron Antonio Candia-Puma, Leydi Pola-Romero, Haruna Luz Barazorda-Ccahuana, Luis Daniel Goyzueta-Mamani, Alexsandro Sobreira Galdino, Ricardo Andrez Machado-de-Ávila, Rodolfo Cordeiro Giunchetti, Eduardo Antonio Ferraz Coelho, and Miguel Angel Chávez-Fumagalli. Rabies test accuracy: comprehensive systematic review and meta-analysis for human and canine diagnostics. MedRxiv, Nov 2024. URL: https://doi.org/10.1101/2024.11.05.24316773, doi:10.1101/2024.11.05.24316773. This article has 1 citations.
(candiapuma2024rabiestestaccuracy pages 12-14): Mayron Antonio Candia-Puma, Leydi Pola-Romero, Haruna Luz Barazorda-Ccahuana, Luis Daniel Goyzueta-Mamani, Alexsandro Sobreira Galdino, Ricardo Andrez Machado-de-Ávila, Rodolfo Cordeiro Giunchetti, Eduardo Antonio Ferraz Coelho, and Miguel Angel Chávez-Fumagalli. Rabies test accuracy: comprehensive systematic review and meta-analysis for human and canine diagnostics. MedRxiv, Nov 2024. URL: https://doi.org/10.1101/2024.11.05.24316773, doi:10.1101/2024.11.05.24316773. This article has 1 citations.
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(kaye2024rabiesvaccinefor pages 4-4): Alan D Kaye, Dominique M Perilloux, Elizabeth Field, Cody A Orvin, Spencer C Zaheri, William C Upshaw, Raju Behara, Tomasina Q Parker-Actlis, Adam M Kaye, Shahab Ahmadzadeh, Sahar Shekoohi, and Giustino Varrassi. Rabies vaccine for prophylaxis and treatment of rabies: a narrative review. Cureus, Jun 2024. URL: https://doi.org/10.7759/cureus.62429, doi:10.7759/cureus.62429. This article has 20 citations.

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OpenScientist Report

Classifications

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Medical Actions

Diagnosis

Progression

Prevalence

Infectious Agent

Transmission

Clinical Burden

Differential Diagnoses

Related Datasets

Clinical Trials

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Rabies — Comprehensive Disease Characteristics Report (Infectious Disease)

Executive summary (current understanding)

1. Disease information

1.1 Concise overview

1.2 Key identifiers (knowledge-base readiness)

1.3 Synonyms / alternative names

1.4 Source of information

2. Etiology

2.1 Disease causal factors

2.2 Transmission and exposure ecology

2.3 Risk factors

2.4 Protective factors

2.5 Gene–environment interactions

3. Phenotypes (clinical presentation)

3.1 Core clinical phenotypes

3.2 Natural history and temporal development

3.3 Quality of life impact

4. Genetic / molecular information

4.1 “Causal genes” / variants (human)

4.2 Viral molecular targets relevant to prevention/therapy

5. Environmental information

6. Mechanism / pathophysiology

6.1 Causal chain (high-level)

6.2 Immune evasion / immune response (current themes)

6.3 Suggested ontology terms

6.4 Advanced technologies / recent developments

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

9.1 Epidemiology (recent data)

9.2 Population demographics

10. Diagnostics

10.1 Current diagnostic concepts

10.2 Recent quantitative diagnostic accuracy synthesis (2025)

11. Outcome / prognosis

11.1 Breakthrough infections despite PEP (2023 systematic review)

12. Treatment