Rabies: Scientific Basis of the Disease and Its Management

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RABIES
Scientific Basis of the Disease
and Its Management
Copyright
Contributors
Foreword
Preface
1
A history of rabies-The foundation for global canine rabies elimination
	Introduction
	Asia
		A seat of canine domestication?
		Dogs, deaths, and divinities
		The disease and perceived remedies
		Postcolonial occurrence
		Semple's antirabic vaccine
		Additional progress throughout the 20th century
		Current status
	Europe
		Early incursions
		Recognition and control measures
		Wildlife rabies appreciation
		Oral vaccination applications
		Reintroductions
		Europe as rabies-free?!
	Africa
		Indigenous roots or regional translocations?
		Wildlife involvement
		Molecular insights
		Control measures
		Other lyssaviruses
		Toward 2030?
	South America, Central America, and the Caribbean
		Colonization impacts
		Centuries absent-canine rabies?
		The ``spillover´´ phenomenon
		From initial evidence to the successful vaccinations
		Regional efforts: Large-scale vaccination and laboratory-based surveillance
		Setbacks
		The emerging challenges of bat rabies
		Future perspectives
	North America
	Australia
		RABV
		ABLV
	References
2
Rabies virus
	Introduction
	Lyssaviruses
	Rabies virus architecture
	Virus structure and composition
	Morphology and core structure of standard and defective virus particles
	Viral proteins
		Nucleoprotein (N)
		Phosphoprotein (P)
		Virion-associated RNA polymerase or large protein (L)
		Matrix protein (M)
		Glycoprotein (G)
	Viral lipids and carbohydrate
	Genome and RNP structures
	Genome primary structure
	Lyssavirus genes
	Transcription of genes
	Replication of RABV N-vRNA genomes
	Regulation of transcription and replication
	Structural aspects of RABV RNA synthesis
	Life cycle of rabies virus infection
	Early-phase events: Role of the RABV receptor, endocytosis, and G-mediated fusion
	Middle-phase events: Transcription, replication, and nascent protein synthesis
		Viral RNP release, initiation of genome RNA transcription, replication, and protein synthesis
	Late phase: Assembly and budding of progeny virus
	Cell-to-cell spread (transport) of progeny virus
	References
	Further reading
3
Evolution of rabies virus
	Introduction
	Microevolutionary dynamics of rabies in stable host virus associations
	Macroevolutionary dynamics of rabies
	Reconciling strains of evidence for the role of adaptive evolution in cross-species transmission
	Applications of evolutionary data for rabies prevention and control-genetics as a tag on transmission
	Conclusions
	References
4
Epidemiology
	Introduction
	Global rabies epidemiology
		Asia
		Africa
		Middle East
		Europe
		North America
		Caribbean islands
		South America
		Oceania
	RABV transmission
		Typical routes of transmission
		Atypical routes of transmission
		Incubation period
		Viral shedding
		Enzootic cycles
		Cross-species transmission
		Host shift events
		Translocation events
	Surveillance general
		Principles of rabies surveillance
		Global limitations in surveillance capacity
		Rationale for implementing rabies surveillance systems
		Critical components of functional surveillance systems
		Laboratory diagnostic methods for effective surveillance system
		Future of integrated surveillance approaches
	Human rabies: Public health measures
	Animal rabies: Epidemiology and control
		Bats
		Terrestrial carnivores
		Domestic dogs
		Wildlife species of special concern
	References
5
Molecular epidemiology
	Introduction
	Key aspects of Lyssavirus biology
	Methods of viral typing
		Genetic characterization of lyssaviruses
		Application of high-throughput sequencing (HTS) methods
		Principles of phylogenetic analysis
	Lyssavirus taxonomy
		Lyssavirus species
		Molecular epidemiology of rabies-related lyssaviruses
			Australian bat lyssavirus
			European bat lyssaviruses
			Asian bat lyssaviruses
			Lyssaviruses of Africa
				Duvenhage lyssavirus
				Lagos bat lyssavirus
				Shimoni bat lyssavirus
				Mokola lyssavirus
				Ikoma lyssavirus
			Future issues
		Molecular epidemiology of rabies lyssaviruses
			Cosmopolitan lineage
			Africa 2
			Africa 3
			Arctic/Arctic-like
			Indian subcontinent
			Asian
			American indigenous
	Emerging trends
		The importance of viral typing
		Understanding the factors impacting viral spread
		Role of the host
		What controls host shift events?
		Impact of climate change
	Concluding remarks
	Acknowledgments
	References
6
Rabies in terrestrial animals
	Introduction
		General pathogenesis
		Incubation period
		Clinical signs
	Lyssavirus infections in reservoir species
		Basic concepts of reservoir host ecology for terrestrial rabies
		Reservoir hosts for terrestrial rabies
			Canidae
			Domestic dogs
			Foxes
				Red foxes
				Arctic foxes
				Other foxes
			Raccoon dog
			Jackals and coyotes
			Raccoons
			Skunks
			Mongooses
			Ferret badgers
			Marmosets
	Spillover (dead-end) hosts for terrestrial rabies
		Cats
		Cattle
		Kudu
		Wolves, African wild dogs, and other carnivores
		Rodents, opossums, and marsupials
	Acknowledgments
	References
7
Bat rabies
	Introduction
	Bat rabies in the New World
	Vampire bat rabies: Historical perspectives
	Rabies and insectivorous bats in the Americas
	Bat rabies in the Old World
	Eurasian lyssaviruses
		European bat-1 lyssavirus
		European bat-2 lyssavirus
		Aravan bat lyssavirus
		Khujand bat lyssavirus
		West Caucasian bat lyssavirus
		Irkut bat lyssavirus
		Bokeloh bat lyssavirus
		Lleida bat lyssavirus
		Unclassified viruses
	African lyssaviruses
	Lagos bat virus
	Duvenhage virus
	Shimoni bat lyssavirus
	African lyssaviruses not associated with bats
	Asian and Australian lyssaviruses
	Australian bat lyssavirus
	Gannoruwa bat lyssavirus
	Unclassified Australasian viruses
	Experimental studies with lyssaviruses in bats
	New World lyssavirus studies in bats
		Insectivorous bat RABV
		Hematophagous bat RABV
	Old World lyssavirus studies in bats
		EBLV-1
		EBLV-2
		ABLV
		ARAV, KHUV, IRKV, WCBV
		LBV
	Important knowledge gaps and challenges to lyssavirus research
	Aerosol transmission
	The role of torpor in potential maintenance of bat lyssavirus infections
	Inoculation route and dose
	Lyssavirus excretion
	The caveats of using wild caught bats in laboratory studies
	Complexities of bat surveillance initiatives
	Abortive infection and carrier state in bats
	Future experimental approaches
	Future prospects for controlling lyssaviruses in bats
	Conclusions
	Acknowledgments
	References
8
Human disease
	Introduction
	Exposures, incubation period, and prodromal symptoms
	Clinical forms of disease
		Encephalitic rabies
		Paralytic rabies
	Investigations
		Imaging studies
		Laboratory studies
			Detection of RABV RNA
			Brain tissues
	Differential diagnosis
	Rabies due to other Lyssavirus species
		Duvenhage virus
		Mokola virus
		European bat lyssavirus 1
		European bat lyssavirus 2
		Australian bat lyssavirus
		Irkut virus
	Conclusions
	References
9
Pathogenesis
	Introduction
	Virus entry into the nervous system
		Earliest events
		Superficial and nonbite exposures
	RABV receptors
		Nicotinic acetylcholine receptor
		Neural cell adhesion molecule (NCAM) receptor
		Low-affinity p75 neurotrophin receptor
		Metabotropic glutamate receptor subtype 2
	Spread to the CNS
	Spread within the CNS
	Spread from the CNS
	Animal models of RABV neurovirulence
	Structural damage caused by RABV infection in the CNS
		Innate immune responses
		Apoptosis
		Degeneration of neuronal processes
		Blood-brain-barrier (BBB)
	Brain dysfunction in rabies
		Neuropeptide synthesis during rabies
		Defective neurotransmission
			Acetylcholine
			Serotonin
			γ-Amino-n-butyric acid
		Electrophysiological alterations
		Ion channels
		Nitric oxide
		Excitotoxicity
		Oxidative stress
		Mitochondrial dysfunction
		Bases for behavioral changes
	Recovery from rabies and chronic RABV infection
	Conclusions
	References
10
Pathology
	Introduction
	Macroscopic findings
	Pathology in the central nervous system
	Overview
	Inflammation
	Cell injury and cell death
	Negri and lyssa bodies
	Degeneration of neuronal processes
	Distribution of rabies virus antigen
	Pathology in the peripheral nervous system
	Changes in sensory and autonomic ganglia
	Changes in spinal nerve roots and peripheral nerves
	Pathology involving the inoculation site, eye, and extraneural organs
		Changes at inoculation site
		Ocular pathology
		Changes in extraneural organs
	Summary and conclusions
	References
11
Immunology
	Introduction
	RABV innate immune response
		RABV triggering of host innate immune response and virus evasive mechanisms
		Innate immune response in the periphery
		Innate immune response in the NS
			RABV evasion of the IFN response in infected neurons
			RABV limits the inflammatory response in the NS
	RABV adaptive immune response
		RABV specific immune response in the periphery
		RABV provokes the killing of migratory T cells
			Entry of lymphocytes in the RABV-infected NS
			Destruction of T cells in the RABV-infected NS
	RABV infection triggers a CNS-mediated immune unresponsiveness
	Paradoxical role of IFN in RABV virulence
	Conclusions
	References
12
Laboratory diagnosis of rabies
	Laboratory-based rabies diagnostic testing
		Indications for rabies testing
		Biosafety and shipment of diagnostic specimens
		Quality assurance
		Optimal sampling for rabies diagnosis
		Laboratory reporting practices
	History of rabies diagnostic tests
	Detection of viral antigen
		The direct fluorescent antibody test
			Fluorescent conjugate selection, preparation, and evaluation
			Immunofluorescence test protocol
		Direct rapid immunohistochemical test
		Lateral flow assays
		Immunohistochemistry on formalin-fixed paraffin embedded tissues
		Enzyme-linked immunosorbent assay
	Molecular methods of viral RNA detection
		Advantages and disadvantages of molecular methods
		RNA extraction
		Reverse transcription-polymerase chain reaction methods
			Primer design
			Reverse transcription
			Polymerase chain reaction
			PCR product detection
		Real-time RT-PCRs for lyssavirus detection
			The 5 nuclease assay
			Assays using intercalating dyes
			Choice of assay
			Required controls
				Mock extraction control
				Positive and negative PCR controls
				Control for template integrity
		Application of molecular methods to fixed tissues
		Application of RT-PCR in research
		Other molecular methods for rabies virus detection
	Detection of live virus
	Antemortem diagnosis of rabies
	Conclusions
	Acknowledgments
	References
13
Measures of rabies immunity
	Introduction
	Rabies serology methods
		Serum neutralization assays
		ELISA, IFA, and immunochromatographic assays
	Assay selection
	Assuring quality results
	Defining ``adequate´´ or ``minimum´´ response to rabies vaccination
	Regulatory compliance
	Conclusions
	References
14
Human and animal vaccines
	Introduction
	History of rabies vaccines
	Pre-exposure prophylaxis
	Post-exposure prophylaxis
	Rabies virus strains for vaccine production
	Production of rabies vaccines
	Cell substrates for rabies virus propagation
	Primary cells
	Diploid cells
	Continuous cell lines
	Production systems
	Viral inactivation
	Downstream processing
	RABV purification
	Formulation
	Potency testing
	Safety issues and mitigation strategies
	Oral rabies vaccination
	Wildlife
	Domestic animals
	Monitoring oral rabies vaccination
	Future directions
	References
15
Next generation of rabies vaccines
	Introduction
	Current rabies vaccine regimens
	Incidence and risk for rabies and vaccine failures
	Correlates of protection
	Novel vaccines to rabies
		Live attenuated rabies virus vaccines
		Inactivated genetically modified rabies vaccine
		Inactivated adjuvanted traditional rabies vaccines
		Peptide vaccines
		Protein vaccines
		Genetic vaccines
		DNA vaccines
		RNA vaccines
		Viral vector vaccines
		Recombinant poxviruses
		Recombinant adenoviruses
	The ``ideal´´ rabies vaccine
	Summary
	References
16
Public health management of humans at risk
	Introduction
	Obstacles to preventing rabies in humans
	Exposure
	Vaccination protocols to prevent rabies
		Preexposure vaccination
		Postexposure vaccination
			Before vaccination begins
			Rabies immune globulin
			PEP vaccination regimens
		Previously vaccinated individuals and booster vaccinations
	Special populations
		Pregnancy
		Immunocompromised patients
		Travelers
	Adverse reactions to cell culture vaccines
	Interchangeability and coadministration of vaccines
	Educational initiatives
	Reducing vaccination regimens
	Conclusions and future
	References
	Further reading
17
Therapy of human rabies
	Human cases with recovery from rabies
		Milwaukee protocol
	Future prospects for the aggressive management of rabies in humans
		Critical care unit
		Combination therapy
		Antiviral therapy
		Immunotherapy
		Neuroprotective therapy
		Specific therapies to avoid
	Importance of palliation in the management of rabies
	References
18
Dog rabies and its control
	Introduction
		Historical perspectives and the current situation
		The burden of domestic dog-mediated rabies
	The influence of epidemiological and socioeconomic frameworks on dog rabies control
		Key epidemiological parameters
		Epidemiological factors influencing the effectiveness of control efforts
		Beyond ``effectiveness´´: Exploring social dimensions of rabies control
		Dog population management
			Culling
			Sterilization programs
	Practical aspects of dog rabies control
		Planning phase
		Implementation of mass dog vaccination campaigns
		Measuring the impact of mass dog vaccination campaigns
			Vaccination coverage
			Surveillance
		Maintaining rabies-free status
		Economics of dog vaccination for rabies control
		Extended benefits of dog rabies control
	Conclusions
	References
19
Rabies control in wild carnivores
	Introduction
	Historical aspects, milestones, and epizootiology
		Europe
		North America
		Asia
		Africa
		Central America, South America, and the Caribbean
	Conceptual foundations and principles
	Structure and operation of control programs
		Communication and collaboration
		Enhanced surveillance
		Management actions
			Population reduction
			Trap-vaccinate-release
			Oral rabies vaccination
		Contingency actions
		Translocation
		Program monitoring and evaluation
	Bait and vaccine principles, research and developments
		Vaccines
		Baits
	Conclusions
	Acknowledgments
	References
20
Modeling canine rabies virus transmission dynamics
	Introduction
		History of modeling rabies virus transmission dynamics
		The modeling backbone for canine rabies
		How to model rabies virus transmission?
	Existing modeling studies
		Insights and limitations
	The gap between models and data
		Bite data
		Laboratory-confirmed case data
		Sequence data
		Dog population and vaccination data
	Conclusions
	Data and code availability
	References
21
Strategies for the elimination of dog-mediated human rabies by 2030
	Introduction
	Sustainability requires government ownership and commitment
		Tools to support sustainable rabies elimination programs
			Global disease elimination/eradication strategies
			Disease prioritization
			Organization and planning for rabies elimination
			Financing
	International guidelines/recommendations
		Declaration of freedom
	Networks
	Monitoring and surveillance
		Monitoring of vaccination events
	Conclusions
	References
22
Future developments and challenges
	Introduction
	Pathogenesis
	Therapy of human rabies
	Epidemiology
	Prevention of human rabies
	Control of animal rabies
	Health impact and economic burden of canine rabies
	Conclusions
	References
Index
	A
	B
	C
	D
	E
	F
	G
	H
	I
	J
	K
	L
	M
	N
	O
	P
	Q
	R
	S
	T
	V
	W
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