Poliovirus 2005

1
Poliovirus 2005

• J Barklie Clements
• b.clements_at_vir.gla.ac.uk
• tel [phone]

2
Poliovirus-2005

• classification
• pathogenesis epidemiology
• molecular biology
• prevention eradication

3
Classification
4
Picornaviruses

• pico (Latin very small)
• oldest described viruses
• (Egypt 1400 BC)
• foot and mouth first recognized in 1898
• poliomyelitis disease recognized in 1909, virus
  isolated in 1930

5
Picornaviruses

• Group IV ()sense RNA Viruses
• Family Picornaviridae
• Hosts Vertebrates
• Genus
  Species
• Enterovirus Poliovirus
  
• Rhinovirus Human rhinovirus A
  
• Hepatovirus Hepatitis A
  
• Cardiovirus
  Encephalomyocarditis
• Aphthovirus Foot and-mouth disease
  
• Parechovirus
• Erbovirus
  
  
• Kobuvirus
  
• Teschovirus
  

6
Poliovirus

• enterovirus
• three serotypes 1, 2, 3
• minimal immune cross reaction between serotypes
• rapidly inactivated by heat, formaldehyde,
  chlorine, ultraviolet light

7
Iron lung

• Extensively used in
• 1950s in US to assist
• breathing of polio cases

8
Pathogenesis Epidemiology
9
Transmission-1

• cases rarer in ancient times as poor
  sanitation
• with improvements in waste disposal
  plumbing, epidemics began in cities as sewage was
  dumped away from drinking water, babies were
  much less likely to be infected gain protective
  immunity.
• older children playing, swimming, at school,
  were more likely to be exposed to virus with more
  chance of paralytic poliomyelitis

10
Transmission-2

• reservoir human
• transmission fecal-oral
  oral-oral
• communicability 7-10 days before onset
  virus in stool for 3-6 weeks

11
Infection route-1

• entry into mouth
• replication in pharynx, GI tract, local
  lymphatics
• via blood to central nervous system (CNS)
• viral spread along nerve fibers
• destruction of motor neurons

12
Infection route-2

• Primary site is lymphoid tissue of oropharynx
  gut. Virus production at then leads to a
  viraemia. Virus
• may infect the CNS as the receptor is on
  lymphoid/ epithelial cells in the gut and on CNS
  neurons
• In CNS, replication is in motor neurones
• in the anterior horns of the spinal cord
• and brain stem. Distinctive plaques are
• due to lytic replication, and inflammation
• caused by an immune response

13

• Infection outcomes

14
Molecular biology
15
Virions

• non enveloped icosahedron of 60 subunits each
  of 4 polypeptides (VP1, 2, 3, 4) derived from
  cleavage of a polyprotein
• particle 27-30nm diameter genome length is
  2,500nm, therefore RNA is tightly packed with
  sodium or potassium ions to counteract the
  negative charges on its phosphate groups

16
RNA genome-1

• ()sense RNA molecule 7.2-8.5kb
• genomic RNA is infectious but much less so
  than intact particles
• 600-1200 base untranslated region at the 5'
  end (5 UTR) important in translation a shorter
  3' UTR important in (-)strand synthesis

17
RNA genome-2

• 5' UTR contains clover leaf secondary
  structure, the internal ribosome entry site
  (IRES)
• 5' end modified by covalently attached viral
  protein VPg (23 aa) the 3' end is
  polyadenylated as in eukaryotic mRNAs
• encodes a single polyprotein of 2100-2400 aa

18
()sense RNA genome
19
IRES function

• IRES is a landing pad for ribosomes.
  Normally, translation initiates when ribosomes
  bind the 5' m7G cap then scan the mRNA to the
  first AUG initiation codon
• the IRES binds ribosomes, delivers them
  directly to the polyprotein initiation AUG
  without any scanning -ie cap independent
  translation

20
Replication events

• Time Event
• 1-2h sharp fall in host
  macromolecular synthesis
• 2.5-3h start viral protein synthesis
• 3-4h start viral RNA synthesis
• 4-6h virus assembly in cytoplasm
  (crystals)
• 6-10h cell lysis release of new
  viruses

21
virus RNA polymerase (3D) copies ()RNA to
(-)sense for new ()strands, some of which are
translated others become virion RNA
RNA replication
22
Polyprotein cleaved by P2A protease to P1,P2 P3
further cleavages by protease 3CD
Maturation of viral proteins
23
Host shutoff

• due to cleavage of protein eIF-4G, a component
  of cell cap binding complex (CBC), by viral
  protease
• CBC binds m7G cap at the 5' end of cell mRNAs
  then binds the small ribosomal subunit during
  initiation of translation. The initiation complex
  formed scans the 5' UTR until the first AUG
• cleavage of eIF-4G stops formation of this
  complex, preventing translation of cell RNAs
• viral mRNAs, not m7G capped, are unaffected

24
P1 polyprotein cleaved into VP0, 3 and 1 which
join together enclosing the RNA. Final maturation
is via VP0 internal autocatalytic cleavage into
VP2 VP4
Assembly
25
Replication-overview
26
Prevention Eradication
27
Killed vaccine (IPV)
Jonas Salk believed that inactivated
virus would yield a safe and effective vaccine
Large scale trials began in 1954. The initial
vaccine was 70 effective against paralysis, and
94 effective against bulbar poliomyelitis that
affects breathing-it was immediately put into
widespread use
28
IPV

• highly effective in producing immunity to
  poliovirus
• gt90 immune after 2 doses
• gt99 immune after 3 doses
• duration of immunity unknown

29
IPV

• contains 3 serotypes of vaccine virus
• grown on monkey kidney (Vero) cells
• inactivated with formaldehyde
• contains 2-phenoxyethanol, neomycin,
  streptomycin, polymyxin B

30
Live vaccine (OPV)
Albert Sabin developed a live, attenuated
vaccine that went into widespread use in 1960
by then incidence of polio in the US had
dropped from 135 per million in 1955 to 26 per
million in 1961, and paralytic polio had fallen
by 90 the live vaccine gives better immunity,
but there are some problems...
31
OPV

• contains 3 serotypes of vaccine virus
• grown on monkey kidney cells
• contains neomycin and streptomycin
• shed in stool for some 6 weeks following
  vaccination

32
OPV

• highly effective in producing immunity
• 50 immune after 1 dose
• gt95 immune after 3 doses
• immunity probably lifelong

33
Vaccine associated paralytic polio (VAPP)

• 5-10 cases per year in US only with OPV
• increased risk in persons gt18 years
• increased risk in persons with immunodeficiency
• no procedure available for identifying persons at
  risk of paralytic disease
• mostly in healthy children their household
  contacts

34
VAPP US cases, 1980-1998

• healthy recipients of OPV 41
• healthy contacts of OPV recipients
  31
• community acquired 5
• immunodeficient 24

35
Vaccination schedules may include OPV IPV

• only IPV now available in US
• schedules begun with OPV should be completed with
  IPV
• any combination of 4 doses of IPV
• OPV by 5 years constitutes a complete series

36
US vaccination recommendations

• 2000, exclusive use of IPV recommended in US
• OPV no longer routinely available in the US

37
Eradication by 2005?

• last US case in 1979
• Western hemisphere
• certified free in 1994
• only affects humans - no animal reservoir
• effective, inexpensive vaccines
• life-long immunity -no long term carriers
• virus survives a short time outside humans

38
Progress in eradication
39
Last cases
Polio Eradication
40
Poliovirus-2005

• classification
• pathogenesis epidemiology
• molecular biology
• prevention eradication

41
Treatment
42

• Polio US, 1950-2002

43
Polio US, 1980-2002
44
Vaccination of adults

• routine vaccination of U.S. residents gt18 years
  of age not necessary or recommended
• may consider vaccination of travelers to
  polio-endemic countries and selected laboratory
  workers

45
Vaccination of unvaccinated adults

• IPV
• use standard IPV schedule if possible (0, 1-2
  months, 6-12 months)
• may separate doses by 4 weeks if accelerated
  schedule needed

46
(No Transcript)
47
Poliovirus-new vaccine protocol
1997, the U.S. Advisory Committee recommended a
change to reduce vaccine associated paralytic
polio Associated (VAPP) with OPV 2 doses of
IPV (2 and 4 month) followed by 2 doses of OPV
(12 month and 5 years) sequential schedule
provides the advantages of both vaccines,no risk
of VAPP with the critical first doses, and
gastrointestinal protection from the OPV
48
Vaccine-contraindications precautions

• severe allergic reaction to a component or
  following a prior dose of vaccine
• moderate or severe acute illness

49
Vaccine adverse reactions

• rare local reactions (IPV)
• no serious reactions to IPV documented
• paralytic poliomyelitis (OPV)

50
Poliovirus-which vaccine?
Live Vaccine (OPV) produces long-lasting
secretory immune reaction in lymphatic tissue of
small intestine which acts as a barrier to polio
passing through the gut. frequency of
vaccine-associated poliomyelitis is 1 per
5 million doses, the greatest risk following the
first dose. risk of paralytic disease is
extremely low approximately 1 case per 100
million doses. risk for paralytic disease in
contacts of vaccinees is one case per million
recipient first doses, and one case per 22
million for subsequent doses Inactivated
Vaccine (IPV) produces a strong humoral
immunity risk of polio due to incomplete virus
inactivation does not produce immunity in the
intestine, persons who receive only IPV may be
infected and transmit but not develop paralytic
disease
51
Vaccines

• 1955 inactivated vaccine (IPV)
• 1961 types 1 and 2 monovalent OPV
• 1962 type 3 monovalent OPV
• 1963 trivalent OPV
• 1987 enhanced potency IPV

52
Poliovirus-eradication
In 1988, WHO resolved to eradicate polio by
2000! Polio is one of only a limited number of
diseases (eg measles and smallpox) that can be
completely eradicated because only affects
humans - there is no animal reservoir
effective, inexpensive vaccines immunity is
life-long no long-term carriers virus
survives for a very short time outside human host

53
Eradication requires
54

• Wild Poliovirus 1988

55
Wild Poliovirus 2003

56
Wild Poliovirus 2004
57
Cellular receptors for picornaviruses
Virus Serotypes Receptor
Description Human Rhinovirus
91 ICAM-1 (Intracellular Adhesion Molecule

Immunoglobulin-like molecule) Human Rhinovirus
10 LDLR (Low Density Lipoprotein
Receptor) Poliovirus 3 CD155
Immunoglobulin-like molecule) Coxsackie A
3 ICAM-1 Echo 2
VLA-2 Integrin-like molecule Echo
6 DAF (Decay
Accelerating Factor, CD55)
Regulation of
complement activation EMCV 1
VCAM-1 (Vascular Cell Adhesion
Molecule)

58
Poliomyelitis

• first described by Michael Underwood in 1789
• first outbreak described in US in 1843
• 21,000 paralytic cases in the US in 1952
• global eradication in near future