Polio

Polio

1. VIRUS

   • CHARACTERISTICS
     • Picornavirus
     • Strains
       • FMDV
       • Enterovirus
       • Rhinovirus
       • Hepatitis A
     • +ive sense ssRNA genome
     • 7400 bases
     • 33nm diameter
   • STRUCTURE
     • Icosahedron
       • VP1, VP2, VP3, VP4 (inside)
         • 60 copies
     • Maturational cleavage
       • VPO -> VP2+VP4
       • metastable state -> virion entry
     • Receptor
       • homo-dimer
       • adhesion molecule
       • Endocytosis
       • immunoglobulin
   • ENTRY: structural changes
     • 160s -> 135s -> 80s
     • Receptor: catalyst
     • Endocytosis -> directly release RNA
   • TRANSLATION
     • No: virion Pol, splicing, 5' cap
     • IRES
       • regulates whether replication/translation occurs
     • Monocistronic: no splicing - each translated mRNA codes for one protein
       • translation into one long polypeptide -> cleaved by internal proteases -> 10 individual protiens. e.g. vpg - binds viral RNA, synth +ive -ive strands. Uridylated -> primer. capsid proteins, VP1 VP3 VPO
   • RNA SYNTHESIS
     • polypeptide cleaved by internal proteases
       • -> 10 viral proteins
         • e.g. VPg : binds viral DNA, snth viral +ive -ive strand RNA, uridylated acts as primer
         • e.g. capsid proteins: VP0, VP1, VP3

2. VACCINES

   • Rationale
     • IgA
       • Locally secreted - prevents rep in GI tract
     • IgG, IgM
       • NTs: prevent spread to motor neurons
   • Made possible by...
     • 1. propogation in non-neuonal cells
     • 2. id of 3 serotypes
       • PV1, PV2, PV3
         • constrained variation
     • 3. viremia precedes paralysis
     • 4. protective efficacy of passive immunoglobulins
   • Inactive Polio Vaccine (IPV)
     • formalin inactivation of 3 virulent strains
   • Oral Polio Vaccine (OPV)
     • weakened strain of 3 serotypes
     • Live Attenuated
       • 1. Serial passage: monkey kidney epithelial cells
       • 2. Host range mutants: in viral IRES
         • altered stem loops + decreased efficiency of transcription initiation
       • 3. Passage at low temps
       • 4. Use naturally avirulent strain: in areas where non-path
   • OPV over IPV
     • 1. Easy administration
     • 2. Mass campaigns/administration
     • 3. Low cost
     • 4. Excretion over 3-4 weeks - expanding coverage
     • 5. Induction of intestinal/mucosal immunity (IgA)

3. ERADICATION

   • Principles
     • 'The Biologic Principles of Poliovirus Eradication' by Dowde & Birmingham
     • Proof: Cuba, 1962. Mass OPV vacination. Stopped all WT virus circulation within 1 year
     • 1. Absence of carrier state
     • 2. human-human transmission
     • 3. imm stops transmission
     • 4. no non-human host/reservoirs
     • 5. Finite virus environmental stability
   • Strategy
     • 1. Routine vaccinations
       • high coverage of OPV - 3 doses in 1st year of life At least 80% coverage needed (even 90% may not stop WT virus circulation) +Prevents pockets of non-imm children -> prevent spread + outbreak
     • 2. Supplementary vaccinations
       • NIDs - complement not replace routine vaccines 2 doses given to every child <5 yrs regardless of prev treatment Synchronised NIDs of neighbouring countries +catches non/partially imm children, boosts imm in those who already are +eradicates any fertile seedbed for virus
       • NIDs
     • 3. Surveillance
       • AFP surveillance
         • AFP = clinical manifestation of weakness/paralysis + reduced muscle tone without obvious cause
         • 1. Identify + report AFP cases
           • in all >15 yrs By health workers or community number cases reported per year indicates country's ability to detect polio
         • 2. Transport stool samples for analysis
           • in order to differentiate between FP forms All children must be reported and tested on within 58 hrs of symptom onset
         • 3. Isolate poliovirus
           • 1. distinguish between WT + vaccine-related 2. distinguish between the 2 types of WT (type 2 eradicated since 1999)
         • 4. Mapping virus
           • to id origin. Check reference bank and classify into genetic families -> appropriate imm strat to that area
     • 4. Mop-up campaigns
       • door-door immunisations in specific areas where virus known/suspected to be present. Priority areas: high pop density, high pop mobility, poor sanitation, low access to healthcare, polio present within last 3 years, low routine imm coverage
   • OPV over-use
     • Resolution
       • 1. Globally synchronised withdrawal of OPV 2-3 yrs after last WT virus
       • 2. No use of IPV
       • 3. AFP/virus surveillance for 3 yrs after last VDPV
       • 4. Containment of lab stocks
       • 5. Create global monovalent OPV stocks sufficient to deal with re-emergence
     • Vaccine Associated Paralytic Poliomyelitis VAPP
       • Clinically indistinguishable from WT polio Occurs from 1st dose 1/2.7 million cases Sporadic Can occur from household contact
     • Circulating Vaccine-Derived Poliovirus cVDPV
       • Can occur in under-immunised areas where there are enough susceptible children for excreted vaccine-derived Polio to circulate. The lower the pop immunity, the longer it will circulate as it replicates, changes and exchanges genetic material with other enterovirus strains.
     • Immunodeficient Vaccine-Derived Poliovirus iVDPV
       • Prolonged replication of vaccine-derived virus in immunodeficient -> do not clear intestinal infection -> excrete iVDPV for prolonged periods

4. PATHOGENESIS

   • Human pathogen
     • CD155 gene
       • D1: PV binding site
   • Enterovirus
     • faecal-oral route -> rep in GI tract -> shed in faeces
   • Levels
     • 1. Primary viremia
       • IN bloodstream
       • No symptoms
     • 2. Secondary viremia
       • other sites e.g. brown fat, muscle
       • minor symptoms
     • 3. Paralytic Poliomyelitis
       • CNS entry
         • across blood-brain barrier, idp of CD155
         • retrograde axonal transport
         • infected monocytes / macrophages
       • paralysis, respiratory arrest, death