Update on Effectiveness and Safety of Rotavirus Vaccines Umesh D. Parashar Lead, Viral Gastroenteritis Team Centers for Disease Control Prevention Atlanta, GA TM 1

2 Pentavalent Bovine-Human Reassortant Rotavirus Vaccine (RV5, RotaTeq) G1G3 G2G4 P[8] Bovine rotavirus with single human rotavirus gene substitution 3 oral doses

3 Monovalent Human Rotavirus Vaccine (RV1, Rotarix) G1P[8] Human rotavirus 2 oral doses

4 Both Vaccines Showed High Efficacy in Clinical Trials in Europe and Americas VaccineRegion Efficacy Against Severe Rotavirus AGE RV5 USA/ Finland 98% RV1Latin America85% RV1Europe96% Vesikari et al and Ruiz-Palacios et al, NEJM 2006 Vesikari T et al. Lancet 2007, 370;

5 Both Vaccines Showed Moderate Efficacy in Clinical Trials in Africa and Asia VaccineRegion Efficacy Against Severe Rotavirus AGE RV5Africa64% RV5Asia51% RV1Africa62% Armah et al. Lancet 2010 Zaman et al. Lancet 2010 Madhi et al NEJM 2010

Despite Lower Efficacy, RV1 Prevented More Severe Rotavirus AGE in Malawi Because of Higher Burden 2.5 episodes prevented 3.9 episodes prevented Efficac y 61.2%76.9%49.5% (44.0 – 73.2)(56.0 – 88.5)(19.2 – 68.3) South AfricaMalawi Severe rotavirus GE episodes per 100 Placebo Vaccine Madhi et al. NEJM Efficacy77%50%

WHO Recommended Global Use of Rotavirus Vaccines in

More than 30 Countries Have Implemented Rotavirus Vaccines 8 Europe: Austria Belgium Finland Luxembourg Africa: South Africa Sudan (North) GAVI-eligible Western Pacific: Australia Marshall Islands Micronesia Niue Palau Americas: Bolivia Brazil Cayman Islands Colombia Ecuador El Salvador Guatemala Guyana Honduras Mexico Nicaragua Panama Peru Paraguay United States Venezuela Middle East: Bahrain Morocco Qatar Not GAVI-eligible

9 Vaccine Effectiveness and Impact

10 Rotavirus Vaccines in USA Feb 2006 – RotaTeq recommended June 2008 – Rotarix recommended

Marked Decline in Rotavirus Hospitalization and ED Visit Rates in 3 US Counties, Payne D et al. CID 2011 and CDC unpublished data Vaccine

AgeRotavirus vaccine coverage in 2008 (≥1 dose) Decline in rotavirus hospitalization rate (2008 vs. 2006) < 1 year56%66% 1 to < 2 years44%95% 2 to < 3 years<1%85% Decline Seen in Older Unvaccinated US Children Herd immunity? Payne D et al. CID 2011

13 First Evidence of Vaccine Impact on Diarrhea Mortality, Mexico

14 Vaccine Introduced (May 2007) Richardson et al, NEJM 2010

15 Vaccine Safety

History: Rotashield Experience Rotashield licensed in US in 1998 Associated with increased risk of intussusception – Relative risk of > 30 in first week after dose 1 – Attributable risk: 1 in 10,000 vaccinees Withdrawn from US in 1999 * Sources: WHO Wkly Epi Record; 2006;2(13) Patel et al. Exp Rev Vacc; 2009; 8(11);

17 No Risk of Intussusception with Either RV5 or RV1 in Large Clinical Trials *Ruiz-Palacios et al. NEJM 2006;354(1) *Vesikari et al. NEJM 2006;354(1)

18 Why Continue to Monitor Intussusception? Pre-licensure trials powered to exclude large (~10-fold) increase in relative risk within days of any dose Further monitoring to evaluate lower risk in shorter time periods after vaccination

19 Post-Licensure Intussusception Data Mexico and Australia have identified a low-level risk of intussusception after dose 1 of rotavirus vaccines – ~1-2 cases per 100,000 vaccinated (5-10 times lower than Rotashield risk) Risk not documented in US to date – Insufficient data to exclude risk of magnitude seen in other countries

How do the benefits of vaccination compare with potential risks? 20

Real-world Benefits vs. Risk of Rotavirus Vaccination Hospitalizations (deaths) prevented Intussusception cases (deaths) caused Mexico 1 11,600 (663)41 (2) Brazil 1 69,600 (640)55 (3) Australia 2 7,000 (0)6 (0) US 3 53,000 (16)48 (0) 21 * 1: Patel, NEJM 2011;364(24); : TGA: 3: Cortese, US ACIP, October 2010

Conclusions Marked reductions in severe diarrhea in countries using vaccine Low intussusception risk in some settings Proven benefits of vaccination far outweigh potential short-term low-level risk 22