31May06 KL Vadheim Lecture 8 1 Polio, Rotavirus, Rabies MedCh 401 Lecture 8
31May06 KL Vadheim Lecture 8 2
Polio
• Aka Poliomyelitis, Infantile paralysis
• 3 serotypes
• No cross-protection between serotypes
• Enteroviridae - Gastrointestinal disease
• Two types of virions– D particles; infective– C particles; non-infective
31May06 KL Vadheim Lecture 8 3
Polio Disease I
• ~95% - inapparent infections with no symptoms or only minor illness
• 4% - nonparalytic poliomyelitis; minor illness progresses to headache, vomiting, pain in limbs, back and neck; complete recovery.
31May06 KL Vadheim Lecture 8 4
Polio Disease II• <1% - paralytic poliomyelitis
– mild disease for several days– no symptoms for 1-3 days– rapid onset of flaccid paralysis with fever and
progression to maximum extent of paralysis within a few days
– paralysis of affected muscle is permanent– partial or total recovery of function within 6 months
by compensation from unaffected muscle groups
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Polio Disease III• Post-polio Syndrome
– late manifestation of acute paralytic polio– 25-40% of people who had paralytic polio 15-40
years previously– muscle pain, exacerbation of existing weakness or
new weakness/paralysis– failure of compensating muscle/nerves– NOT a consequence of persistent infection– NOT contagious
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Polio Transmission
• Fecal-oral
• Oral-oral
• Humans only known reservoir
• Requires a receptor for cell attachment and entry
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U.S. Incidence, paralytic polio• 1952 - peak incidence
– 21,000 cases
• 1980-1994– 127 cases
• 6 imported, wild poliovirus
• 2 indeterminate
• 119 Vaccine-associated paralytic polio (VAPP)
• 1995– 4 cases in unvaccinated Amish community
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Polio vaccines
• Inactivated Polio Virus - Salk
• Live, oral, attenuated Polio Virus - Sabin
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IPV v. OPV• Trivalent• Inactivated viruses• Highly effective vaccine• >90% immune after 2
doses• >99% immune after 3
doses• Duration unknown
• Trivalent• Live, attenuated viruses • Highly effective vaccine• ~50% immune after 1
dose• >95% immune after 3
doses• Immunity probably
lifelong
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Polio vaccine schedules• IPV - U.S., Europe, etc.
– 4 doses– 2, 4, 6-18 months and 4-6 years
• IPV/OPV– four doses, any combination, by age 6
• OPV, endemic countries– 4 doses within first 12 months– epidemic/endemic areas: >10 doses
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IPV Vaccine FormulationComponent,
per 0.5 ml doseIPV (IPOL)
Sanofi PasteurDTaP-HepB-IPV(Pediarix) GSK
Type 1 polio virus 40 D antigenUnits (DU)
40 DU
Type 2 8 DU 8 DUType 3 32 DU 32 DU2-Phenoxyethanol 0.5% 2.5 mgFormaldehyde <0.2% <100 gNeomycin < 5 ngStreptomycin 200 ngPolymyxin B 25 ng <0.05 ngDiphtheria toxoid 25 LfTetanus toxoid 10 LfPertussis toxin,inactivated
25 g
Filamentoushemagglutinin
25 g
Pertactin 8 gHBsAg 10 gAluminum adjuvant <0.85 mgTween 80 <100 gThimerosal <12.5ng
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IPV production• VERO cells established on microcarriers with MEM
and fetal calf serum• Cells infected with Polioviruses types 1, 2 or 3,
medium changed to serum-free M199• Viral suspensions clarified, filtered, concentrated• Purification: anion exchange, gel filtration, anion
exchange chromatography• Adjust titers and inactivate at 37C, 12 days with
formalin
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Cutter Incident
• April, 1955 - Six manufacturers licensed to sell IPV
• Massive immunization of U.S. population initiated
• Cases of paralytic polio began to appear– All from Cutter Lab’s IPV– ~260 cases of type 1 polio, 192 paralytic– Due to incomplete inactivation of virus
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IPV v. OPV in U.S.
• 1955 - IPV licensed
• 1961 - Switched to OPV– superior ability to induce intestinal immunity– prevent polio spread among close contacts
• 1999 to present - IPV used exclusively– eliminates risk of Vaccine-Acquired Paralytic
Polio (VAPP)
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Polio eradication by 2000• Adopted in 1988
– 350,000 cases paralytic polio/year– polio endemic in 125 countries
• 2003 status– 784 confirmed cases– 6 endemic countries
• 2005 status– 61,606 cases paralytic polio– polio endemic in 4 countries
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Rotavirus
• Reoviridae– segmented genome– prevalence of pathogenic serotypes varies
worldwide– serotypes continually changing
• Heterotypic protection– natural infection or immunization with one
serotype protected against another serotype
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Rotavirus Pathogenesis• Universal disease
– All children are exposed and acquire antibodies by age 5
• Leading cause of severe dehydrating diarrhea in infants and young children
• Sudden onset of watery diarrhea, fever and vomiting
• Recovery in 4-5 days
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Rotavirus Transmission
• Fecal-oral?– Improvements in water, sanitation, hygiene
have not decreased incidence
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Rotavirus Incidence• U.S.
– 500,000 physician visits– 50,000 hospitalizations– 20-40 deaths– Most common cause of severe diarrhea in
children in areas with high living standards
• Developing world– ~500,000 deaths in children– 1,600 - 2,400 deaths per day
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Rotavirus Disease BurdenU.S. Worldwide
ParameterTotal Risk
per childTotal Risk
per childBirths 3.9
million130 million
Rotavirusgastroenteritis
2.7million
1:1.4 100 million 1:1.3
Physician/ER visits 600,000 1:65
Hospitalizations 48,000 1:81
Deaths 20 1:200,000 600,000 –873,000
1:160
Medical costs $300mIndirect + direct costs $1.1b
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Rotavirus vaccines• Wyeth - Rotashield (Sept. 1998)
– Live, oral, tetravalent– human/simian reassortant viruses– withdrawn in 1999 due to increased incidence
of intussusception
• Merck - Rotateq (Feb. 2006)– Live, oral, pentavalent– Bovine/human reassortant viruses
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Rotavirus vaccines
• GSK - Rotarix; not yet available in U.S.– Live, oral, attenuated, human – Monovalent– Cross-protective, replicates well in GI
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Rabies Pathogenesis
• Acute viral encephalitis
• ~100% fatal– survivors are permanently brain damaged
• Incubation period 5 days - several years– usually 20-60 days
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Rabies Transmission• Saliva from bite of infected animal
– Aerosol (bat caves)– Direct implantation (transplantation of infected
tissue)
• Virus attaches to peripheral nerve endings and travels to the CNS
• Many wild animals serve as reservoirs– All mammals believed to be susceptible– Dogs, bats are primary carriers
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Rabies Treatment
• Immune globulin
• Vaccine
• No effective therapy once symptoms appear
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Rabies Vaccines
• Inactivated virus
• Human diploid cell vaccine (sanofi Pasteur)
• Purified Chick embryo culture vaccine (Chiron/Novartis)
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Rabies VaccinesRabies vaccinecomponents,per 1 ml dose
Rabavert (PCEC)Novartis (Chiron)
Imovax (HDCV)sanofi Pasteur
Rabies antigen NLT 2.5 IU NLT 2.5 IU
Bovine gelatin(stabilizer)
<12 mg
Human serumalbumin
<0.3 mg <100 mg
Potassiumglutamate
1 mg
Na EDTA 0.3 mg
Chicken ovalbumin <3 ngNeomycin < 1g <150 g
Amphotericin B <2 ngChlortetracycline <20 ngPhenol red indicator 20 g
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Pre- v. Post-exposure Treatment
• 3 doses vaccine– days 0, 7, 21 or 28
• Boosters– annual or biennial,
depending on risk
• Rabies immune globulin– day 0
• Vaccine– day 0, 3, 7, 14, 28 or 30
– IM in deltoid muscle
– much less effective if injected into gluteal area
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Rabies vaccine efficacy• PCEC (Chiron) and HDCV (sanofi Pasteur)
essentially equivalent
• No controlled clinical trials
• Vaccine + immune globulin– standard post-exposure treatment– 100% effective IF
• timely administration
• adequate dose
• appropriate administration