Rotavirus & Rotavirus Vaccine

ByDr. Asad Ramlawi

DGPHC & PH Beithlehem / Palestine

Rotavirus

• First identified as cause of diarrhea in 1973

• Most common cause of severe diarrhea in infants and children

• Nearly universal infection by 5 years of age

• Responsible for up to 500,000 diarrheal deaths each year worldwide

Lengthy (~5 days on average) and severe purging causes electrolyte depletion/ dehydration/ complications

Rotavirus often spreads beyond the intestines into the blood stream

Rotavirus can replicate in most organs

Rotavirus – Diarrhea/Vomiting/Fever plus viremia in 90% of infected children

Blutt et al. Rotavirus antigenemia in children is associated with viremia. PLoS Med 2007;4:e121.

Acute gastroenteritis• Virtually all children infected by age 3-5 years• “Democratic” virus• Highest rates of disease between 6-24 months• First infections are most severe

Natural infection confers immunity against subsequent severe re-infections• Vaccines mimic the protective first infection without

causing the severe illness

Worldwide distribution• accounts for ~5% of all deaths among children <5

years old

Epidemiology of rotavirus

Electron micrograph of rotavirusElectron micrograph of rotavirus

• Reovirus (RNA)• VP7 and VP4 antigens define virus serotype

and induce neutralizing antibody• 5 predominant strains in U.S. (G1-G4, G9)

and account for 90% of isolates• G1 strain accounts for 75% of infections• Very stable and may remain viable for weeks

or months if not disinfected

Rotavirus

Rotavirus Pathogenesis

• Entry through mouth

• Replication in epithelium of small intestine

• Replication outside intestine and viremia uncommon

• Infection leads to isotonic diarrhea

0

100

200

300

400

500

600

700

800

900Total N Tests Total N Positive

2001 2002 2003 2004 2005 2006 2007 20082000

Rotavirus seasonality (onset and peak) was very consistent during the pre-licensure period

“Winter gastroenteritis”

0

100

200

300

400

500

600

700

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900Total N Tests Total N Positive

2001 2002 2003 2004 2005 2006 2007 20082000

Seasonality of rotavirus hospitalization rates, NVSN 2006-2008

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120

140

160

January February March April May June

Month

Rot

avir

us h

ospi

tali

zati

on ra

te p

er 1

0,00

0 ch

ildr

en <

3 ye

ars

2006

2007

2008

Total AGE and Rotavirus AGE cases in NVSN, Jan-April, 2006-2008

405

481

283

207259

180

100

200

300

400

500

600

2006 2007 2008

Num

ber o

f cas

es

Total AGE Rotavirus

51 % EIA+

54 % EIA+

6 % EIA+

Centers for Disease Control and Prevention. Delayed onset and diminished magnitude of rotavirus activity – United States, November 2007-May 2008. MMWR 2008; 57:697–700.

Rotavirus hospitalization and ED rates, NVSN 2006-2008

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5

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30

2006 2007 2008

Year

Hos

pita

liza

tion

rat

e pe

r 10

,000

ch

ildr

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3 yr

s

0

50

100

150

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350

ED

rate per 10,000 children <3 yrs

Hospitalization ED

6 Independent US Hospital-based Studies Reported 85-95% Reduction in Rotavirus Cases

2008 vs Previous Years

1. Clark F et al. 2. Daskalaki I et al. 3. Patel JA et al. 4. Harrison CJ et al. 5. Hatch S et al. 48th ICAAC / 46th IDSA Washington DC October 25-28, 2008; 6. Chang H et al. ACIP Atlanta October 22-23, 2008

Philadelphia, PA1

87% reduction in Community acquired cases (Children's Hospital of Philadelphia)

Kansas City, MO4

88% reductionHospitalization

Galveston, TX3

94% reductionHospitalization or ED

Philadelphia, PA2

94% reductionHospitalization (St Chris)

New York State6

85% reductionHospitalization/ED

Worcester, MA5

95% reductionHospitalization, ED , Outpatient

Epidemiological Implications

Monitoring for age redistribution:

Will severe rotavirus infections be deferred to older ages?

Varicella

Rotavirus Epidemiology

• Reservoir Human-GI tract

• Transmission Fecal-oral, fomites

• Temporal Fall and winter pattern (temperate areas)

• Communicability 2 days before to 10days after onset

Rotavirus Disease in the United States

• Annually* responsible for:– More than 400,000 physician visits

– More than 200,000 emergency dept visits

– 55,000-70,000 hospitalizations

– 20-60 deaths

• Annual direct and indirect costs are estimated at approximately $1 billion

*prevaccine era*prevaccine era

Rotavirus hospitalization and ED rates, NVSN 2006-2008

0

5

10

15

20

25

30

2006 2007 2008

Year

Hos

pita

liza

tion

rat

e pe

r 10

,000

ch

ildr

en <

3 yr

s

0

50

100

150

200

250

300

350

ED

rate per 10,000 children <3 yrs

Hospitalization ED

<1% coverage with >=1

dose

56% coverage with >=1

dose

31% coverage with >=1

dose

Estimates of annual rotavirus infection burden for U.S. children <3 years old, 2006

Payne DC, et al. Active, population-based surveillance for severe rotavirus gastroenteritis in children in the United States. Pediatrics 2008; 122:1235-43.

Risk Groups for Rotavirus Diarrhea

• Groups with increased exposure to virus– Children in child care centers

– Children in hospital wards (nosocomial rotavirus)

– Caretakers, parents of these children

– Children, adults with immuno- deficiency related diseases (e.g. SCID, HIV, bone marrow transplant)

Rotavirus Clinical Features

• Short incubation period (usually less than 48 hours)

• First infection after age 3 months generally most severe

• May be asymptomatic or result in severe dehydrating diarrhea with fever and vomiting

• Gastrointestinal symptoms generally resolve in 3 to 7 days

Rotavirus Complications

• Severe diarrhea

• Dehydration

• Electrolyte imbalance

• Metabolic acidosis

• Immunodeficient children may have more severe or persistent disease

Rotavirus Immunity

• Antibody against VP7 and VP4 probably important for protection

• First infection usually does not lead to permanent immunity

• Reinfection can occur at any age

• Subsequent infections generally less severe

Rotavirus Vaccines

• RV5 (RotaTeq®)– Contains five reassortant rotaviruses

developed from human and bovine parent rotavirus strains

– Vaccine viruses suspended in a buffer solution

– Contains no preservatives or thimerosal

Rotavirus Vaccines

• RV1 (Rotarix®)– Contains one strain of live attenuated

human rotavirus (type G1P[8])– provided as a lyophilized powder that is

reconstituted before administration

– Contains no preservatives or thimerosal

Rotavirus Vaccine Effectiveness

Condition

Any rotavirus diarrhea

Severe diarrhea

Effectiveness74%-87%

95%-98%

Both vaccines significantly reduced physician visits for diarrhea, and reduced rotavirus-related hospitalization

Rotavirus VaccineRecommendations

• Routine immunization of all infants without a contraindication

• 2 (RV1) or 3 (RV5) oral doses beginning at 2 months of age

• Subsequent doses in the series should be separated from the previous dose by 1 to 2 months

MMWRMMWR 2009;58:(RR-2) 2009;58:(RR-2)

• For both rotavirus vaccines– maximum age for first dose is 14 weeks 6

days– minimum interval between doses is 4 weeks– maximum age for any dose is 8 months 0

days

Rotavirus VaccineRecommendations

MMWRMMWR 2009;58:(RR-2) 2009;58:(RR-2)

Rotavirus VaccineRecommendations

• Routine immunization of all infants without a contraindication

• 2 (RV1) or 3 (RV5) oral doses beginning at 2 months of age

• Subsequent doses in the series should be separated from the previous dose by 1 to 2 months

MMWRMMWR 2009;58:(RR-2) 2009;58:(RR-2)

• For both rotavirus vaccines– maximum age for first dose is 14 weeks 6

days– minimum interval between doses is 4 weeks– maximum age for any dose is 8 months 0

days

Rotavirus VaccineRecommendations

MMWRMMWR 2009;58:(RR-2) 2009;58:(RR-2)

• ACIP did not define a maximum interval between doses

• If the interval between doses is prolonged, the child can still receive the vaccine as long as it can be given on or before the child’s 8 month birthday

• It is not necessary to restart the series or add doses because of a prolonged interval between doses

Rotavirus VaccineRecommendations

MMWRMMWR 2009;58:(RR-2) 2009;58:(RR-2)

• Completed the series with the same product whenever possible

• If the product used for a prior dose or doses is not available or is not known continue or complete the series with the product that is available

• If any dose in the series was RV5 (RotaTeq) or the vaccine brand used for any prior dose in the series is not known, a total of three doses of rotavirus vaccine should be administered

Rotavirus VaccineRecommendations

MMWRMMWR 2009;58:(RR-2) 2009;58:(RR-2)

Rotavirus VaccineContraindications

• Severe allergic reaction to a vaccine component or following a prior dose of vaccine

Rotavirus VaccinePrecautions*

• Altered immunocompetence

• Acute, moderate or severe gastroenteritis or other acute illness

• History of intussusception

*the decision to vaccinate if a precaution is present should be made on a case-by-case risk and benefit basis

Vaccine Effectiveness

RotaTeq® & Rotarix® Clinical Trials Very large, multi-national clinical trials 90-100% effective in preventing severe rotavirus

gastroenteritis 74-85% effective against rotavirus of any severity

Post-licensure (RotaTeq®) case/control studies in US Texas Children’s Hospital (Houston) * New York * New Vaccine Surveillance Network (NVSN)

* presented to ACIP, Oct. 2008

Immunosuppressed Household Contacts of Rotavirus Vaccine Recipients

• Infants living in households with persons who have or are suspected of having an immunodeficiency disorder or impaired immune status can be vaccinated

• Protection provided by vaccinating the infant outweighs the small risk for transmitting vaccine virus

Pregnant Household Contacts of Rotavirus Vaccine Recipients

• Infants living in households with pregnant women should be vaccinated– majority of women of childbearing age have

pre-existing immunity to rotavirus– risk for infection by vaccine virus is

considered to be very low

Rotavirus VaccineAdverse Reactions

Vomiting 15%-18%Diarrhea 9%-24%Irritability 13%-62%Fever 40%-43%Serious adverse Nonereactions

Rotavirus Vaccine Storage and Handling

• Store at 36-46o F (2-8o C) and protect from light

• RV1 diluent may be stored at room temperature

• Do not freeze vaccines or diluent• Administer RV5 as soon as possible

after being removed from refrigeration • RV1 should be administered within 24

hours of reconstitution

THANK YOU !