31may06kl vadheim lecture 81 polio, rotavirus, rabies medch 401 lecture 8

31May06 KL Vadheim Lecture 8 1

Polio, Rotavirus, Rabies

MedCh 401

Lecture 8


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


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.


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


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


Polio Transmission

• Fecal-oral

• Oral-oral

• Humans only known reservoir

• Requires a receptor for cell attachment and entry


Christina’s World, A. Wyeth, 1949


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


Polio vaccines

• Inactivated Polio Virus - Salk

• Live, oral, attenuated Polio Virus - Sabin


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


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


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


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


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


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)


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


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


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


Rotavirus Transmission

• Fecal-oral?– Improvements in water, sanitation, hygiene

have not decreased incidence


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


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


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


Rotavirus vaccines

• GSK - Rotarix; not yet available in U.S.– Live, oral, attenuated, human – Monovalent– Cross-protective, replicates well in GI


Rabies Pathogenesis

• Acute viral encephalitis

• ~100% fatal– survivors are permanently brain damaged

• Incubation period 5 days - several years– usually 20-60 days


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


Rabies Treatment

• Immune globulin

• Vaccine

• No effective therapy once symptoms appear


Rabies Vaccines

• Inactivated virus

• Human diploid cell vaccine (sanofi Pasteur)

• Purified Chick embryo culture vaccine (Chiron/Novartis)


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


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


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

31may06kl vadheim lecture 81 polio, rotavirus, rabies medch 401 lecture 8

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