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Vincent Racaniello
[email protected]
www.virology.ws
Poliomyelitis
Polio (grey), myelon (marrow) = Greek
itis (inflammation of) = Latin
“A common, acute viral disease characterized
clinically by a brief febrile illness with sore throat,
headache and vomiting, and often with stiffness of
the neck and back. In many cases a lower neuron
paralysis develops in the early days of illness”
—J.R. Paul, “Poliomyelitis (Infantile Paralysis)”, in A
Textbook of Medicine, 1959.
Genus
Picornaviridae
Enterovirus
Poliovirus
Coxsackieviruses, group A
Coxsackieviruses, group B
Echoviruses of humans
Enteroviruses of humans
Enteroviruses, nonhuman
Hepatovirus
Hepatitis A virus
Parechovirus
Human parechovirus
Rhinovirus
Human rhinoviruses
Bovine rhinoviruses
Cardiovirus
EMCV (mengovirus), TMEV
Aphthovirus
Foot & mouth disease virus
Erbovirus
Equine rhinitis B virus
Kobuvirus
Aichi virus
Teschovirus
Porcine teschovirus 1
Antigenic types
3
23
5
28
4
~31
2
~103
~3
2
~7
Poliovirus Structure
Poliovirus Genome Structure
• Egyptian stele,
Eighteenth Dynasty
(1580-1350 B.C.)
• Withered and
shortened left leg, foot
held in position
characteristic of
flaccid paralysis
• Danish physician Ove
Hamburger (1911)
concluded deformity
was due to infantile
paralysis
Epidemic poliomyelitis
• •First epidemics of poliomyelitis occurred in
Sweden: 1868 (14 cases), 1881 (13 cases).
• •Rutland, Vermont, 1894 (132 cases)
• •New York City, 1907 (750 cases)
Polio Research
1908
• Karl Landsteiner isolates poliovirus in monkeys after
injection with sterile filtrate from the spinal
cord of a boy who had died of polio
1949
• Enders, Weller, Robbins grow poliovirus in cultures
of human cells from non-nervous tissue.
Replaces the monkey for detecting and studying
poliovirus. Nobel Prize, 1954.
1954
Francis clinical trial of
Salk's formalin-killed
poliovirus (IPV):
1,800,000 children.
>50% protection; IPV
licensed 12 April
1955.
1955-1960
Paralytic poliomyelitis
fell from 20,000 cases/
yr. to 2,500/yr.
1961
Sabin's live, attenuated strains are licensed in the U.S. and
replace IPV.
1979
Last case of poliomyelitis (wild type virus) in U.S.
2000
IPV replaces OPV in U.S.
Pathogenesis of Poliomyelitis
Pathogenesis of Poliomyelitis
OPV
IPV
Poliovirus replication in spinal cord
Poliovirus vaccines
• Inactivated poliovirus vaccine, IPV
–
–
–
–
must be injected
when properly prepared does not cause disease
does not produce intestinal immunity
used 1955 - 1961 and 2000 - present in U.S.
• Oral poliovirus vaccine, OPV
–
–
–
–
–
easy to administer
produces intestinal immunity
mutant viruses empirically derived from virulent strains
usually reverts during intestinal replication
used 1961 - 2000 in U.S.
Determinants of attenuation in the
Sabin vaccine strains
Virus
Attenuation determinant
P1/Sabin
5’-UTR (480)
VP4 (4065)
VP3 (3225)
VP1 (1106)
VP1 (1134)
P2/Sabin
5’-UTR (481)
VP1 (1143)
P3/Sabin
5’-UTR (472)
VP3 (3091)
Internal initiation
CD155 Transgenic Mice
Viral growth in mouse brain
Viral growth in HeLa cells
PD50
472C
9 x 103 pfu
472U
>2 x 107 pfu
Reversion of P3/Sabin
Virus
Base at 472
Time of isolation
after vaccination
Sabin vaccine
DM1
DM2
DM3
DM4
DM38
P3/119
U
U
U
U/C
C
C
C
24 h
31 h
35 h
47 h
18 da
3-4 weeks
from Evans et al., Nature 314: 548 (1985)
Histological lesion
score
0.36
ND
1.58
ND
2.48
ND
3.34
Polio Eradication Timeline
1988
WHA Resolution
2000
Stop poliovirus transmission
2005
Certify Global Eradication
2005-2010
Stop polio immunization
Polio Eradication Progress
1988
2003
Global cases of
poliovirus:
2006: 2001
2007: 1307
2008: 333
Polio eradication
• In countries using OPV, only source of polio
is the vaccine
• Therefore OPV use will cease in posteradication period
• The plan to stop vaccination is based on
the assumption that there are no nonhuman reservoirs of poliovirus, and
circulation of attenuated strains and their
derivatives (VDPV) is limited
Circulating vaccine-derived polioviruses
Problems associated with VDPV
•
Recent outbreaks of poliomyelitis in Egypt, Dominican Republic/
Haiti, Philippines, Madagascar caused by VDPV
•
These VDPV strains regained virulence and spread in human
populations
•
Long-term persistence and excretion of VDPVs in
immunocompromised persons
•
These recent outbreaks demonstrate that neurovirulent
revertants of OPV can circulate for years (even in immune
populations) and cause poliomyelitis
Minnesota, October 2005
• Poliovirus type 1 isolated from an unvaccinated,
immunocompromised child (7 months old) in an
Amish community in Long Prairie, MN
• Spread to four other children
• No paralytic disease associated with infections
• Isolates are VDPVs
OPV transmission
• Polio outbreaks caused by VAPP strains
demonstrate that neurovirulent revertants of
OPV can circulate for years (even in immune
populations) and cause poliomyelitis
• These outbreaks mimic the situation that will
occur when OPV usage is halted: circulation of
neurovirulent revertants when vaccination
coverage drops
• In light of this information, we cannot simply stop
vaccinating
Vaccination against the vaccine
• After eradication, immunize globally with IPV
(not infectious)
– Higher cost than OPV
– Not effective in tropical, underdeveloped countries
• Careful monitoring of environmental samples
for poliovirus
Why poliovaccine must be stockpiled
after immunization ceases
• Virus in research laboratories (mislabeled?)
• Stored clinical and environmental samples
• Bioterrorism: Synthesis of infectious DNA readily
done
• Elimination of all sources of poliovirus is
impossible; assume an outbreak will occur
Which vaccine should be stockpiled?
• IPV: noninfectious, no reintroduction of virus
into the environment
• However, IPV is produced from virulent strains
• Poliovirus has escaped from vaccinemanufacturing plants at least twice
• mOPV
Rhinovirus
•
•
•
Typical picornaviruses
Cell receptor is either
ICAM-1 (91
serotypes) or LDLR
(10 serotypes)
Cause half of all
common colds, the
most common
infection of humans
Why do we care about the common cold?
•Adults get 2-4 colds/yr; children 6-8/yr
•Yearly costs in US > $20 billion: OTC and Rx
medicine, doctor visits, lost work days
•Complications include otitis media, sinusitis, serious lower tract
infection, particularly in young children, elderly,
immunocompromised, and with chronic disorders such as cystic
fibrosis
•50-80% of all asthma attacks occur with respiratory
infections, the majority being RVs; associated with asthma-induced
mortality
•Upper respiratory tract infections are the most common cause
of inappropriate antibiotic use, leading to resistant bacteria
•No effective treatments available
•
•
Infection spread by handnose, hand-eye contact
and aerosol
Virus replicates in
respiratory epithelium
• Unlike influenza infection,
RV infection of epithelial
cells does not cause cell
damage
• Infection leads to
production of many proinflammatory and immune
mediators
• Cytokines and
chemokines may be
responsible for cold
symptoms and asthma
exacerbations
Prevention of rhinovirus
infections
• Vaccines are not practical due to large
number of viral serotypes
• Capsid-binding antiviral drugs (e.g.
Pleconaril)
• Antiviral drugs against other viral targets
(proteinases, RNA polymerase)
• Early diagnosis is essential for antiviral
therapy - acute infections