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Select Agents and Toxins
National Select Agent Registry
Established in 1996 after the OKC bombing
Antiterrorism and Effective Death Penalty Act of
1996
42 CFR 72.6
Responsibility of the Department of Health and
Human Services
2001 - USA PATRIOT Act (42 CFR 73)
Agents published
Federal Register on March 18, 2005
HHS - Human-related agents
USDA - Agricultural-related agents
http://edocket.access.gpo.gov/2005/pdf/055216.pdf
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Select Agents and Toxins
7 CFR Part 331, 9 CFR Part 121, and 42 CFR Part
73
Work with these agents require:
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FBI background investigation
Mental health assessment
Laboratory certification
Training certification(s)
Transfer and shipping documentation
CDC’s role
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Laboratory Registration and Select Agents
Tracking Program
Designated by the HHS
http://www.selectagents.gov/Select%20Agents%20and%20Toxins%20List.html
Select Agent Viruses
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Cercopithecine herpesvirus 1 (Herpes B virus)
Crimean-Congo haemorrhagic fever virus
Eastern Equine Encephalitis virus
Ebola virus
Lassa fever virus
Lujo virus
Marburg virus
Monkeypox virus
Reconstructed replication competent forms of the
1918 pandemic influenza virus containing any
portion of the coding regions of all eight gene
segments (Reconstructed1918 Influenza virus)
South American Haemorrhagic Fever viruses
Flexal
Guanarito
Junin
Machupo
Sabia
Chapare
Variola major virus (Smallpox virus)
Variola minor virus (Alastrim)
Tick-borne encephalitis complex (flavi) viruses
Central European Tick-borne encephalitis
Far Eastern Tick-borne encephalitis
Kyasanur Forest disease
Omsk Hemorrhagic Fever
Russian Spring and Summer encephalitis
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Hendra virusNipah virusRift Valley fever
virusVenezuelan Equine Encephalitis virus
USDA Select Agents AND TOXINSAfrican horse
sickness virusAfrican swine fever virusAkabane
virusAvian influenza virus (highly
pathogenic)Bluetongue virus (exotic)Bovine spongiform
encephalopathy agentCamel pox virusClassical swine
fever virusFoot-and-mouth disease virusGoat pox
virusJapanese encephalitis virusLumpy skin disease
virusMalignant catarrhal fever virus(Alcelaphine
herpesvirus type 1)Menangle virusPeste des petits
ruminants virusRinderpest virusSheep pox virusSwine
vesicular disease virusVesicular stomatitis virus Indiana
subtypes IN2, IN3Virulent Newcastle disease virus 1
Arthropod-Borne Viral
Diseases
Chapter 38
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Introduction
Arthropod-Borne viruses:
Arboviruses
Viruses transmitted by
arthropods
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Mosquitos
Ticks
Others
Hundreds known
Serious global health problem
Cause hundreds of millions of
infections each year
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Millions of deaths per year
Major impact on economies
Often follow changes in climate
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Hurricanes/tropical storms
Global warming
Heavy Rainfall
Zoonoses
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A zoonotic agent is one that normally persists in animals in a non- or
low-pathogenic state, but can cause disease in humans
In most instances, transmission to humans is incidental
It is also a dead-end for the virus
The diseases are termed zoonoses (sing: zoonosis)
Outbreaks of zoonoses are termed epizootic
Persistence of a disease agent in a particular environment is termed
endemic
An epidemic of animal infections is termed enzootic
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Togaviruses
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Family Togaviridae, genus Alphavirus
Plus-strand RNA
Can undergo recombination with other alphaviruses
More than 30 viruses
Enveloped
Notable members
Venezuelan equine encephalitis virus group
Eastern equine encephalitis virus group
Western equine encephalitis virus group
Chikungunya virus
O'nyong-nyong virus
Ross River virus
Semliki forest virus
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Flaviviruses
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Family Flaviviridae
Plus-strand RNA
Enveloped
Virus maturation on cytoplasmic membranes
Dozens of known species
Notable members
Dengue virus group
Japanese encephalitis virus group
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JE virus
West nile virus
St. Louis encephalitis virus
Tick-borne encephalitis virus group
Yellow fever virus group
Russian Spring-Summer encephalitis virus
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Bunyaviruses
Family Bunyaviridae
Negative-strand or ambisense RNA
Tripartite genomes
Three gene segments
S - small (nucleocapsid)
M - medium (glycoproteins G1 and G2)
L - large (RNA polymerase)
Enveloped
Dozens of known species
Five genera
Nairovirus
Orthobunyavirus
Phlebovirus
Hantavirus (rodent-borne)
Tospovirus (plant viruses)
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Bunyaviruses
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Notable members (arthropod-borne)
Phleboviruses
Toscana and Tehran viruses (Sandfly fever)
Punto Toro virus (hemorrhagic fever)
Rift Valley fever virus (hemorrhagic fever)
Coltivirus
Colorado tick fever
Orthobunyavirus
La Crosse virus (encephalitis)
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Venezuelan Equine Encephalitis
First recognized as South American equine disease (1930s)
Highly fatal
Subsequently identified as human disease (1950s)
Rarely fatal; instances of permanent neurological damage
Until 1995, sporadic epizootic outbreaks of human and equine
cases in SA
Sometimes hundreds of thousands
Mid 1990s outbreaks occurred in Central America and Mexico
Similar alphaviruses in the VEE group were found in Florida (e.g.
Everglades virus)
Ecology
Endemic vector: Culex species mosquitos
Amplification hosts: rodents
Epidemic vectors: Ochlerotatus and Psorophora spp.
mosquitos
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VEE Phylogenetics
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Dengue
Four serotypes: 1-4
Most important human arboviral pathogen
About 50 million infections each year
2.5 billion people at risk
Humans and other primates are amplifying hosts
Endemic in Texas
Peridomestic vectors
Aedes aegypti
Aedes albopictus
Pathogenesis: Immunopathology
Infection with first dengue virus results in dengue fever
Second infection with another serotype can result in dengue
hemorrhagic fever
Inflammatory immune response
Cytokine storm
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Dengue
Virus
Phylogenetic
s
West Nile Fever
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First isolated in the West Nile river district of Uganda (1937)
Until U. S. outbreak it was an Old World disease
Introduced to U. S. in 1999
Most likely from Israel by container ship
Ecology
Vector: Culex mosquitos
Amplifying hosts: birds
Virus is now endemic in the U. S.
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West Nile Fever
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Pathogenesis
Historically, only known to cause a febrile illness
1996 Romanian outbreak resulted in unusually higher mortality
and encephalitis
1998 Russian outbreak also had high incidence of neurological
manifestations
Arrival in U. S. resulted in tens of thousands of infections
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Naive population
Blood bank studies suggest only 1 in 5 show symptoms
Molecular mechanisms are largely unknown
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Animal studies suggest a chemokine response in the CNS may recruit
inflammatory cells
CTL infiltrates kill neurons in mice infected with WNV
West Nile Virus
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Clinical outcomes
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Completely asymptomatic (80%)
West Nile fever - headache, confusion, complete recovery
West Nile meningitis
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meningeal inflammation
photophobia
phonophobia
Kernig sign (inability to straighten leg without pain)
Brudzinski's sign (lift head and hips and knees flex)
West Nile encephalitis
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encephalopathy (altered level of consciousness, lethargy, personality change)
seizures
CNS inflammation
West Nile meningoencephalitis
Acute flaccid paralysis
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May have long-term or indefinite weakness
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Yellow Fever
Principally a disease of Africa and
South America
It is thought that YFV arrived in
the Americas during the slave
trade
Infected slaves, who had some
genetic resistance, carried the
virus, which then entered the
local ecosystem after mosquito
bites
Two forms
Urban Yellow Fever
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Mosquito-human transmission cycle
Aedes aegypti
Jungle Yellow Fever
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Mosquito-primate transmission cycle
with spillover to humans
Aedes spp. in Africa
Haemagogus and Sabethes spp. in
Yellow Fever Virus
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Genome
10.8 kb RNA
Single ORF of 10.2 kb
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Structural proteins
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nucleocapsid (C)
Premembrane/membrane (prM/M) - involved in membrane fusion
Envelope (E) - spike protein, HA activity, neutralizing antibody target
Nonstructural proteins
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NS1 - expressed on cell membranes, including surface; involved in RNA
synthesis
NS2A - Interacts with NS3 and NS5 to regulate viral gene expression
NS2B - Interacts with NS3 to form protease for viral polypeptide
NS3
NS4A - Involved with RNA synthesis
NS4B - Involved with RNA synthesis
NS5 - RNA polymerase and methyltransferase for 5’ Met-G cap formation
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Yellow Fever
Pathogenesis
Onset 3-6 days
Sometimes a brief (48 hr) recovery period occurs, followed by
jaundice
Primary replication in lymph nodes
Systemic infection
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Liver, spleen, kidneys, bone marrow, lymph nodes
Acute liver failure
Apoptosis of hepatocytes
Inflammation
Immune infiltrates (immunopathology?)
10% mortality
Control
Virus first isolated in 1928
YFV 17D live attenuated vaccine strain derived 1937
31 amino acid differences between vaccine strain and wild-type
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Yellow Fever Vaccine
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Rare adverse events following vaccination
Recent report of a death (Doblas et al. 2006. J Clin Virol. 36:156)
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26-year old Spanish woman planning to travel to Africa
Developed yellow fever a few days after vaccination
Died 10 days after vaccination
Genome of recovered virus sequenced
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Only two silent mutations were found
ChimeriVax Yellow Fever Vaccine Backbone
Proprietary (Acambis, Inc)
Reverse genetics system of 17D
Replace E gene with E gene of choice
Vaccine Candidates
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West Nile ChimeriVax candidate is in clinical trials
JEV Chimerivax
DENV four serotype Chimerivax