Vincent Racaniello

Transcription

1 Vincent Racaniello

2 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.

3 Picornaviridae Genus Antigenic types Enterovirus Poliovirus 3 Coxsackieviruses, group A 23 Coxsackieviruses, group B 5 Echoviruses of humans 28 Enteroviruses of humans 4 Enteroviruses, nonhuman ~31 Hepatovirus Hepatitis A virus Parechovirus Human parechovirus 2 Rhinovirus Human rhinoviruses ~103 Bovine rhinoviruses ~3 Cardiovirus EMCV (mengovirus), TMEV 2 Aphthovirus Foot & mouth disease virus ~7 Erbovirus Equine rhinitis B virus Kobuvirus Aichi virus Teschovirus Porcine teschovirus 1

4 Poliovirus Structure

5 Poliovirus Genome Structure

6 Egyptian stele, Eighteenth Dynasty ( 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

7 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)

8 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.

9 1954 Francis clinical trial of Salk's formalin-killed poliovirus (IPV): 1,800,000 children. >50% protection; IPV licensed 12 April Paralytic poliomyelitis fell from 20,000 cases/ yr. to 2,500/yr.

10 1961 Sabin's live, attenuated strains are licensed in the U.S. and replace IPV Last case of poliomyelitis (wild type virus) in U.S IPV replaces OPV in U.S.

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12 Pathogenesis of Poliomyelitis Pathogenesis of Poliomyelitis OPV IPV

13 Poliovirus replication in spinal cord

14 Poliovirus vaccines Inactivated poliovirus vaccine, IPV must be injected when properly prepared does not cause disease does not produce intestinal immunity used and 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 in U.S.

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18 Determinants of attenuation in the Sabin vaccine strains Virus P1/Sabin P2/Sabin P3/Sabin Attenuation determinant 5 -UTR (480) VP4 (4065) VP3 (3225) VP1 (1106) VP1 (1134) 5 -UTR (481) VP1 (1143) 5 -UTR (472) VP3 (3091)

19 Internal initiation

20 CD155 Transgenic Mice

21 Viral growth in mouse brain PD C 9 x 10 3 pfu 472U >2 x 10 7 pfu Viral growth in HeLa cells

22 Reversion of P3/Sabin Virus Base at 472 Time of isolation after vaccination Histological lesion score Sabin vaccine U 0.36 DM1 U 24 h ND DM2 U 31 h 1.58 DM3 U/C 35 h ND DM4 C 47 h 2.48 DM38 C 18 da ND P3/119 C 3-4 weeks 3.34 from Evans et al., Nature 314: 548 (1985)

23 Polio Eradication Timeline 1988 WHA Resolution 2000 Stop poliovirus transmission 2005 Certify Global Eradication Stop polio immunization

24 Polio Eradication Progress Global cases of poliovirus: 2006: : : 333

25 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

26 Circulating vaccine-derived polioviruses

27 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

28 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

29 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

30 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

31 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

32 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

33 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

34 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 R x 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

35 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

36 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