Rotavirus Vaccines. Gagandeep Kang Christian Medical College Vellore

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1 Rotavirus Vaccines Gagandeep Kang Christian Medical College Vellore

2 Rotavirus disease burden Rotavirus vaccines and candidates Performance of vaccines in developed and developing countries Longitudinal studies of natural infections Implications for public health Outline

3 Group A rotaviruses are the most common cause of dehydrating gastroenteritis in children

4 Rotavirus mortality estimates for 2008 Tate et al, Lancet Infect Dis 2012

5 Rotavirus Surveillance WHO Network or Other (non-who Network) Surveillance Activities by WHO regions Data collected from regions and partners. Reference laboratories

6 WPR SEAR EUR EMR AMR AFR Papua New Guinea China Mongolia Fiji Laos Viet Nam Sri Lanka Nepal Myanmar Indonesia Azerbaijan Republic of Armenia Georgia Tajikistan Ukraine Sudan Tunisia Pakistan Egypt Morocco Jordan Iraq Syria Libya Yemen Afghanistan Oman Iran St.Vincent&Grena Ecuador Nicaragua Panama Colombia Venezuela Surinam El Salvador Chile Paraguay Bolivia Guatemala Honduras Guyana Ethiopia Cameroon Guinea Bissau Uganda Senegal Zambia Tanzania Kenya Togo Ghana Zimbabwe DRC % positive for rotavirus among children enrolled with acute gastroenteritis who had stool specimens tested, by country and WHO region, % positive for rotavirus World Health Organization Surveillance for rotaviral gastroenteritis

7 Annual incidence of rotavirus diarrhoea is 0.24 ( ) up to the age of 2 years Bilcke J et al. PloSOne 2009.

8 Rotavirus vaccine history Vaccine candidates developed since the early 1980s bovine strains human strains rhesus strains Essential requirements ability to replicate, safety Immune response Protective efficacy

9 The first licensed vaccine Tetravalent human-rhesus reassortant rotavirus vaccine (RRV-TV) developed at NIH Manufactured by Wyeth, licensed in 1998 as Rotashield 1.5 million doses given Vaccine Adverse Events Reporting System identified possible association with intussusception Withdrawn by the company in 1999

10 Licensed oral rotavirus vaccines Rotarix (GSK) live, oral, monovalent, human P[8]G1, attenuated by serial passage in cell culture Two dose schedule along with EPI/routine childhood vaccinations 85% efficacy against severe rotavirus disease and hospitalizations (two dose Ruiz-Palacios et al, NEJM, 2006 schedule, 6 and 10 weeks)

11 Licensed oral rotavirus vaccines Rotateq (Merck) live, oral, human-bovine reassortant (P[8], G1, G2, G3, G4) Three dose schedule with EPI/routine childhood vaccinations 74% and 98% efficacy against all and severe rotavirus disease Vesikari et al, NEJM, 2006

12 Comparison of Rotarix and Rotateq Angel et al, Nat Rev Microbiol, 2007

13 Other licensed rotavirus vaccines Lamb rotavirus strain (LLR), group A, G10P[12], attenuated by passage in cell culture, licensed in China Rotavin M1 G1P[8] in Vietnam, monovalent human strain, just licensed based on phase II studies

14 Other live oral vaccine candidates India Natural human bovine reassortants Bharat Biotech Intl Ltd 116E, G9P[11], monovalent human neonatal strain PHASE III ongoing I321 G10P[11], monovalent, human neonatal strain (poorly immunogenic, now dropped) UK bovine-human reassortants G6P[5] backbone with G1-G4 Shantha Biotechnics Ltd PHASE II completed G6P[5] backbone with G1-G4 and G9, Serum Institute of India PHASE II completed Australia/Indonesia Human neonatal strain RV3 G3P[6] PHASE II Bhandari et al, Vaccine, 2006

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16 What s driving the rapid roll out of rotavirus vaccines?

17 Number of Diarrhea-Related Deaths among Children 59 Months of Age or Younger from July 2002 through May 2009 in Mexico, According to Age Group Richardson et al, NEJM, % rate reduction in diarrhoea mortality; 95% confidence interval [CI], 29 to 39; P<0.001 with 74% 1 dose vaccine coverage

18 Vaccine coverage and rotavirus disease in 6 countries Who, Global NUVI Surveillance Report, 2012

19 Impact on hospitalizations and costs In the USA, nationally, for the period, there was an estimated reduction of 64,855 hospitalizations, saving approximately $278 million in treatment costs Cortes et al, NEJM, 2011

20 But are the current vaccines going to work as well everywhere?

21 Summary of the Immunogenicity Data (Mean Geometric Mean Concentration [GMC] and Seroconversion) for Rotarix by World Bank Income Group Patel et al, J Infect Dis. 2009

22 Africa Rotarix 4417 infants in per-protocol efficacy analysis Pooled vaccine efficacy, 61.2%; 95% CI, 44.0 to 73.2% Vaccine efficacy lower in Malawi than in South Africa (49.4% vs. 76.9%) Number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Rotateq 5468 infants Pooled vaccine efficacy, 39.3%; 95% CI, 19.1 to 754.7% Vaccine efficacy lower in Mali than in Ghana or Kenya Vaccine efficacy lower in second season than first IgA seroresponses 73-82% Armah et al, Lancet, 2010 Madhi et al NEJM, 2010

23 Asia Rotarix Cluster randomized effectiveness trial About 4000 infants Effectiveness about 40% Rotateq 2036 infants Vaccine efficacy 48.3% (95% CI ) against severe disease Zaman et al, unpublished, 2012 Zaman et al, Lancet, 2010

24 What can be inferred from studies on natural infection? Key data on protective immunity from Mexico studying natural infections 33 (22-42) 2 Subsequent infections are less severe 1 Complete protection from moderate to severe gastroenteritis after 2 infections 3 Second infections were more likely to be caused by another G type (P ) Velazquez et al, NEJM 1996

25 Protection against rotavirus diarrhoea Outcome and no. of previous infections No. of episodes Incidence per 100 child months Unadjusted relative risk (95% CI) Adjusted efficacy (95% CI) Any infection Mild diarrhoea Moderate to severe diarrhoea ( ) 0.49 ( ) 0.34 ( ) 0.56 ( ) 0.29 ( ) 0.23 ( ) 0.83 ( ) 0.45 ( ) 0.22 ( ) 39 (29 47) 52 (43 59) 67 (59 74) 44 (23 59) 72 (58 81) 79 (64 88) 18 (-57 57) 57 (6-80) 79 (29-94)

26 Comparison of severity between orders of rotaviral infection

27 Vaccine impact (1-relative incidence) Modeling the impact of vaccination given current data >>High income incidence >>Middle income incidence >>Mid/high income natural protection >>High income immunogenicity >>Middle income immunogenicity >>90% coverage Baseline (Low income, 70% coverge) Years since start of vaccination program Lopman et al, PloSOne 2012

28 Country level vaccine efficacy against severe rotavirus diarrhea incidence and 2009 under five mortality Fischer Walker and Black, BMC Public Health, 2011

29 Public health implications Fischer Walker and Black, BMC Public Health, 2011

30 Public health impact Rotavirus vaccine prevented severe rotavirus episodes in all regions 81% of episodes in Latin America 42.7% of episodes in high-mortality Asia 50% of episodes in sub-saharan Africa 88% of episodes low-mortality Asia and North Africa 91% of episodes in developed countries Although vaccine efficacy is lower, impact on severe disease and mortality is high because of the high incidence Higher vaccine efficacy is desirable but should not delay use of an effective public health tool

31 Thank you

32 Key questions Which vaccine is better?

33 Type specific protection in developing countries Study Vaccine G1 protective efficacy P Value Non-G1 protective efficacy P Value Ref Africa Rotarix Africa Rotateq Asia Rotateq 64.1 ( ) 32.3 ( ) 46.2 ( ) ( ) <0.001 Madhi et al, NEJM Armah et al, Lancet Zaman et al, Lancet 2010

34 Serum neutralizing antibodies with Serum neutrailizing antibody to Rotateq in Asia Vaccinee Placebo Vaccinee GMT Placebo GMT G G G G P Serum IgA responses were seen in 87.8% of vaccinees and 18.2% of controls Zaman et al, Lancet, 2010

35 What is the risk of intussusception?

36 Intussusception in vaccine trials Rotashield was calculated to have a risk of one excess intussusception per 10,000 vaccinees The Rotateq and Rotarix trials had nearly 70,000 children each in the safety studies No increased risk found, but companies asked to report intussusception for the first 3 years after licensure by the Federal Drug Administration in the US

37 Post-marketing surveillance Mexico , attributable risk of 3 to 4 additional cases of intussusception per 100,000 vaccinated infants (Velazquez et al, Ped Infect Dis J, 2012) US , Compared with , the rate was greater in 2007 (rate ratio [RR], 1.10), similar in 2008 (RR, 0.95), and lower in 2009 (RR, 0.93) (Yen et al, J Infect Dis, 2012) US , no increased risk (Shui et al, JAMA, 2012) US , no increased risk (Zickafoose et al, Arch Pediatr Adolesc Med, 2012) US , no increased risk (Loughlin et al, Ped Infect Dis J, 2012) Mexico and Brazil, short-term risk of intussusception in approximately 1 of every 51,000 to 68,000 vaccinated infants (Patel et al, NEJM, 2011) Australia, no overall increase in intussusception following receipt of rotavirus vaccine, there was some evidence of an elevated risk following the first dose of both vaccines (Buttery et al, Vaccine 2011) US, , no increased risk (Belongia et al, Ped Infect Dis J 2010)

38 Will strain replacement take place?

39 Strain replacement Two reports of disappearance of G1 strains and replacement with G2P4 strains in Brazil after introduction of nationwide introduction of rotavirus vaccine Gurgel et al, Emerg Infect Dis 2007, Nakagomi et al, Arch Virol 2008

40 Strain reassortment Vaccine or vaccine-reassortant rotavirus strains detected in 5 (4.7%) of 106 immunocompetent children who required treatment for rotavirus gastroenteritis at a large pediatric hospital in Texas in Four strains were related to pentavalent rotavirus vaccine while one was related to monovalent rotavirus vaccine. Boom et al, J Infect Dis 2012