Rotavirus Vaccines and Their Impacts in the United States Daniel C. Payne, PhD, MSPH

US Centers for Disease Control and Prevention National Immunization Conference September 29, 2014

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Today’s presentation • Trends in rotavirus disease burden among US children • Vaccine effectiveness during the post-licensure period

• Unexpected benefits from rotavirus vaccines

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Rotavirus infections • Gastroenteritis (often severe diarrhea and vomiting, lasting 1-2 weeks) + viremia in 90% of infected children • First infections are most severe

• Natural infection confers immunity against subsequent severe infections

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2 rotavirus vaccines approved by ACIP RotaTeq™ (Merck): Bovine-human pentavalent (G1, G2, G3, G4, P[8]) 3 doses @ 2, 4, 6 months

Rotarix® (GlaxoSmithKline):

Live, attenuated oral vaccines Heterotypic immunity against other strains

Human monvalent (G1, P[8]) 2 doses @ 2, 4 months DEPARTMENT OF HEALTH AND HUMAN SERVICES

Percentage of children receiving full course of rotavirus vaccines National Immunization Survey, 2009-2013 US children 19-35 months old 90 80 70 Percentage

60 50

Rotavirus Vaccine HP2020 Goal

40 30 20 10 0 2009

2010

Centers for Disease Control and Prevention, MMWR 2014

2011

2012

2013

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Trends in rotavirus disease burden among US children

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New Vaccine Surveillance Network (NVSN) SEATTLE Children’s Hospital KANSAS CITY Children’s Mercy Hospital OAKLAND Children’s Hospital Research Center

CINCINNATI Children’s Hospital Medical Center

NASHVILLE Vanderbilt University Medical Center

HOUSTON Texas Children’s Hospital

ROCHESTER University Medical Center

NVSN: Proportion of childhood acute gastroenteritis hospitalizations testing rotavirus positive, active surveillance Proportion of AGE hospitalizations rotavirus +

60% 51%

52%

50%

40%

30% 26%

26%

20%

20%

10% 6%

4%

1%

0% 2006

2007

2008

2009

2010

2011

2012

2013

RV+ %

Payne DC, et al. Clin Infect Dis 2011 and unpublished

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National Respiratory and Enteric Virus Surveillance System (NREVSS) • Passive lab surveillance • Real-time data for several viruses • Weekly passive reporting by consistently reporting laboratories: • # specimens tested by EIA • # positive for rotavirus

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Vaccine introduction

Tate et al. PIDJ 2013

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Estimated Cumulative Number of Rotavirus Hospitalizations Prevented Nationally Among Children under 5 Years of Age: Marketscan data

Number of Rotavirus Hospitalizations

600,000

567,781

500,000

Now, ~50K hospitalizations averted per year

400,000

300,000

243,169 200,000

176,586 124,113

100,000

64,855 36,890

0 2007-2008 2008-2009 2009-2010 2010-2011 2011-2012 2017-2018

Leshem et al., Pediatrics 2014 and unpublished

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US Vaccine Effectiveness Results

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RotaTeq

Rotarix

Vazquez M. Curr Opinion Pediatr 2014

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New Vaccine Surveillance Network Full course VE and 95% CI by Rotavirus Genotype for RotaTeq and Rotarix 100 Vaccine Effectiveness (%)

90 80 70 60 50 40 30 20 10 0

89%

87%

87%

74%

83%

G1P[8]

G2P[4]

G3P[8]

G3P[8]

G12P[8]

RotaTeq

RotaTeq

RotaTeq

DEPARTMENT OF HEALTH AND HUMAN SERVICES Rotarix RotaTeq

Unexpected benefits from rotavirus vaccines

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Indirect benefits (i.e. “herd immunity”) from rotavirus vaccine Clinical vaccine trials did not evaluate herd immunity Large reductions in rotavirus gastroenteritis medical visits were seen even among children who were too young to have been vaccinated Not just among older children, but also adults (parents/caretakers)

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Age-specific rotavirus hospitalization rate reduction and age-specific vaccine coverage by year Age

Decline in rotavirus AGE hospitalization rate (2008 vs. 2006)

Rotavirus vaccine coverage (>=1 dose)

< 1 year

66%

2006 <1%

1 -< 2 years

95%

0%

<1%

44%

2 -< 3 years

85%

0%

<1%

<1%

This age cohort was age-ineligible to receive rotavirus vaccine

2007 31%

2008 56%

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Rotavirus vaccination associated with ~20% reduction in risk of seizures requiring hospitalization or ED care compared with unvaccinated children during the year following vaccination

Payne DC, et al. Clin Infect Dis 2013

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Post-Licensure Intussusception Data  Mexico, Brazil, Australia, and US have identified a low-level risk of intussusception after both vaccines: ~1-6 cases per 100,000 children vaccinated

(no significant association was observed in the large clinical trials)  Estimated 43 intussusception cases (no deaths) vs. 53,000 averted diarrheal hospitalizations (16 deaths) in US children

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Conclusions The following results are consistent across surveillance platforms and methodologies:

Dramatic post-licensure decreases in rotavirus

High vaccine effectiveness A range of expected and unexpected benefits  Continued positive benefit : risk profile

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Acknowledgements • NVSN & EIP surveillance staff • • • • • • • • • • • • • • • • •

Umesh Parashar Margaret Cortese Jackie Tate Mary Wikswo Aaron Curns Idris Sulemana Jessica Moore Benjamin Lopman Aron Hall Manish Patel Catherine Yen Becky Moritz Michael Bowen Jon Gentsch Mathew Esona Jamie Lewis Slavica Rustempasic

• • • •

Eyal Lesham Brian Rha Paul Gastanaduy Kimmie Pringle

• Marietta Vazquez • Lilly Cheng Immergluck • • • • • • • • • •

Mary Allen Staat David Bernstein Peter Szilagyi Kathryn Edwards Natasha Halasa Julie Boom Raj Selvarangan Eileen Klein Janet Englund Parvin Azimi DEPARTMENT OF HEALTH AND HUMAN SERVICES

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25

90

80 20

70 60

15 50 40 10 30 20

5

Vaccine coverage (%)

Rotavirus hospitalization rarte per 10,000

NVSN (observed vs. expected) hospitalization rates

10 0

0 2006

2007

Observed Rate

Payne DC, et al. Clin Infect Dis 2011

2008

2009

Expected Rate

2010

2011

Vaccine Coverage

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Percent of rotavirus tests with a positive result, by week and rotavirus season, NREVSS laboratories, United States, 2000-2013

Tate et al. PIDJ 2013

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Number of childhood acute gastroenteritis hospitalizations testing rotavirus positive, NVSN 250 211 194

200 Hospitalizations

168 147

150

115

107

101

104

101

100 79 44

50

27 9

4

23 1

0 2006

2007

2008

2009

All-cause AGE

Payne DC, et al. Clin Infect Dis 2011

2010

2011

2012

2013

Rotavirus

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Comparison of Clinical Trial Efficacy to PostLicensure Vaccine Effectiveness (VE) Industrialized Countries

Developing Countries

 Vaccine efficacy against severe AGE = 72-100%

 Vaccine efficacy against severe AGE = 49-72%

 Rotavirus VE: 79-100%

Rotavirus VE: 43-92%

Messages:  Within a given population, Vaccine Efficacy closely reflects Vaccine Effectiveness  Vaccine performance varies by a population’s socioeconomic status  Why? DEPARTMENT OF HEALTH AND HUMAN SERVICES

Possible reasons for variability in rotavirus VE between high and low SES countries: • factors that can result in interference of uptake of a live, oral vaccine (such as breast milk, stomach acid, maternal antibodies) • co-administration of other live vaccines

• factors that may cause an impaired immune response to vaccine (concurrent enteric infections, malnutrition, and other infections {e.g., malaria})

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New Vaccine Surveillance Network VE and 95% CI by Age for a full course of Rotarix 100% 90% 80% 70% 60%

86%

50%

40%

56%

30% 20% 10% 0%

1 Not statistically significant

Payne DC, et al. Clin Infect Dis 2013

2

3

4

Age (years) DEPARTMENT OF HEALTH AND HUMAN SERVICES

New Vaccine Surveillance Network Full course VE and 95% CI by Age for RotaTeq 100% 90% 80%

89%

70% 60%

83%

85%

79%

50% 40% 30% 20% 10% 0%

1 Payne DC, et al. Clin Infect Dis 2013

2

Age (years)

3

4 Blue box indicates 95% CI bounds for RotaTeq VE DEPARTMENT OF HEALTH AND HUMAN SERVICES