Global Impact of Enteric Disease Deaths in young children

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2 Global Impact of Enteric Disease Deaths in young children 2 Average of 2.2 million deaths per year worldwide Typhoid Cholera ETEC Rotavirus Shigella WHO, 2000

3 3 Viral Agents Causing Gastroenteritis Rotavirus Enteric Adenovirus Astrovirus Norwalk like particles Human Calicivirus

4 4 Morbidity and mortality from diarrhea have decreased worldwide, Burden of severe disease remains high In 2002, 1,055,393 cases of diarrhea 1/3 : children < 5 years of age 12% required hospitalization MOPH 2002

5 5 Rotavirus double-stranded RNA envelop : structural proteins : VP 7 glycoprotein (G) G1-4, 9 : VP4 protease-cleaved hemagglutinin (P) Natural infection : first - protection 40% : second - protection 75%

6 6 The Virus- Classification Rotavirus has 7 major groups (A-G). Only groups A-C infect humans 1 Group A responsible for majority of childhood infections 1 Group B has been associated with extensive epidemics of diarrhoea illnesses in adults in China and Bangladesh 2,3 1Linhares and Breese, Pan Am J Public Health (5) ; 2J Clin Microbiol , ;3J Med Virol

7 1Linhares and Breese, Pan Am J Public Health (5) ; 2Parashar et al, Emerg Infect Dis (4) Group A Rotavirus Divided into 14 serotypes (G1-G14) 1,2 10 of these 14 serotypes infect humans (G1-G6, G8-G10 & G12) 1,2 8 P serotypes (P1-P8) characterized Theoretically 80 different strains of rotavirus could result from various combinations of 10G & 8P serotypes of human rotaviruses 1,2

8 Rotavirus serotypes in Thailand, G1 G2 G3 G No. of specimens Maneekarn et al, Paediatrics International 2000 Aug 42(4)

9 Pathogenesis 9 Rotaviruses adhere to the GI tract epithelia (jejunal mucosa) * * Atrophy of the villi of the gut Loss of absorptive area Flux of water and electrolytes NSP4 viral enterotoxin Enteric nervous system activation *Rotavirus infection in an animal model of infection. Photographs are from an experimentally infected calf. Reproduced with permission from Zuckerman et al, eds. Principles and Practice of Clinical Virology. 2nd ed. London: John Wiley & Sons; 1990:182. Micrographs courtesy of Dr. Graham Hall, Berkshire, UK. VOMITING AND diarrhoea

10 10 Cholera infantum Dehydration in an infant with acute diarrhea

11 Parashar et al, Emerg Infect Dis (5) Rotavirus- Burden of Disease Estimated global prevalence of rotavirus disease Risk of Particular Event Event 1 : ,000 deaths 1 : 65 2 million inpatient visits 1 : 5 25 million outpatient visits 1 : million domiciliary episodes

12 12 Nongkhai Maesod Sakaeo Ramathibodi Chanthaburi Nongkhai Measod Sakaeo Surveillance sites and surveillance period Ramathibodi Chanthaburi Hadyai Hadyai Feb44 Jun44 Dec44 Jun45 Dec45 Jun46 Chuleeporn Jirapongsa

13 Proportion of rotavirus identification by site Percentage Chanthaburi Hadyai Sakaeo Nongkhai Maesod Ramathibodi

14 14 Rotavirus Hospitalizations in the Asian Rotavirus Surveillance Network 44% 49% Thailand 44% 53% 59% 57% 53% Bresee et al, Emerg Infect Dis Jun (6)

15 15 Proportion of rotavirus positive sample by age group, Feb Mar Percentage 97% Age in Month

16 Rotavirus Seasonality in Thailand 16 Bresee et al. Emerg Infect Dis 2004;10:

17 Signs and Symptoms Clinical manifestations Tenesmus Abdominal pain Mucous-bloody stool Watery stool Nausea/Vomiting Fever N = 713 cases Percentage

18 Rotavirus Surveillance Project Thailand, Feb 2001-Mar Rotavirus 39% 5% Bacteria 7%

19 Parashar et al, Emerg Infect Dis May (5) Rotavirus Mortality By Income Group 19 Percentage of deaths in children <5 years that are attributable to diarrhea for countries in different World Bank income groups by gross national product (GNP) per capita of the country

20 20 Rotavirus Hospitalisation By Income Group Percentage of diarrhea hospitalizations attributable to rotavirus for countries in different World Bank income groups by GNP per capita of the country, IQR, interquartile range Parashar et al, Emerg Infect Dis May (5)

21 21 Prevention of rotavirus infection High standard hygienic practice can not prevent Prevention Non-immune - breast feeding, probiotics Immune - rotavirus vaccine rapid changing in serotype

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23 Need for Vaccination 23 State of the World s Vaccines & Immunization WHO, 2003

24 *Velazquez FR, Matson DO et al NEJM 335: Rationale for Vaccination 24 Natural infection leads to protection Large disease burden makes effective prevention a high global health priority Remains a problem despite improvement in sanitation & hygiene Bresee J, Glass R et al. Rotavirus in The Vaccine Book Bloom B, Lambert PH. 2003

25 25 Rationale for Vaccination Impact study in USA estimated a nationwide vaccination program would prevent : 95,000 / 160,000 emergency room visits : 33,600 / 50,000 hospitalizations : / deaths annually

26 Burden estimation of Thailand, 2002 p 1 : % of rotavirus positive of hospitalized cases = % (838 / 1,950) n 1 : Number of hospitalized diarrhea cases = 131,360 : 50,418 of 506 report 38.38% coverage N : 0 to 5 years population = 5,005,904 Burden of rotavirus diarrhea = (p1 X n1) / N Burden of rotavirus diarrhea Hospitalize cases = (42.97% X 131,360) / 5,005,904 = per 1,000 population under 5

27 27 Economic Burden Diarrhea episodes approximate 1 episodes/child/yr Children underfive 5 million Diarrhea episodes + 5 million 50% rotavirus = 2.5 million episodes 12% admitted =300,000 cases 3 days hospitalization hospital charge + 2,500 b Country cost = 300,000 x 2,500 = 75 millions Bangkok alone = 22.5 millions

28 28 Rotavirus Vaccine Human strain vaccines Reassortant vaccines

29 29 RotaShield (RRV-TV) Tetravalent Rhesus-Human Reassortants G1,2, 4 and G3

30 RotaShield : Clinical Efficacy % % 97% 75% 100% 100% 70% 73% US Multi Finland Venezuela 69% 71% Dehydration Hospital admittance MD visits or illness >4 days Rennels et al Pediatrics 1996;97: Santosham et al J Pediatr 1997;131: Joensuu et al Lancet 1997;350: Pérez-Schael et al N Engl J Med 1997;337:

31 31 RotaShield : Intussusception First rotavirus vaccine licensed in the US in 1998: Rhesus-based tetravalent human reassortant vaccine (RRV-TV) Govt funded national immunisation program Withdrawn in 1999 due to observed link with intussusception (IS) Striking temporal association Murphy et al, N Engl J Med Copyright 200x [2001] Massachusetts Medical Society. All rights reserved

32 32 RotaShield Increase intussusception risk : 37 times (95%CI ) 3-7 days (1-2 weeks)

33 33 Rotavirus Seasonal Incidence and IS cases in US Vaccines Seasonal distribution of rotavirus diarrhea and IS in children <3 years old Proportion of Cases (%) Rotavirus Intussusception July Aug Sep Oct Nov Dec Jan Feb Mar Apr May June Month Chang et al Pediatr Infect Dis J (Southern California Kaiser Permanente

34 Seasonality of Rotavirus & Intussusception in Hong Kong 34 Rotavirus (n=1607) Intussusception (n=190) Proportion of cases 25% 20% 15% 10% 5% 0% Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Month Nelson et al. Pediatr Infect Dis J. 2002;21:701 3

35 35 Rotavirus vaccine Human-derived monovalent live-attenuated : Rotarix Lamb-derived, monovalent live-attenuated Bovine -human reassortant penatavalent liveattenuated oral vaccine : RotaTeg Human-bone reassortant tetravalent Human neonatal strain-derive live-attenuated

36 36 Rotavirus vaccine 2, 4, 6 mo 2, 4 mo Rotarix : 86% G1 serotype : non G1 73%

37 37 RotaTeq (Merck) WC-3 based bovine-human reassortants G1,2,3 and P1a[8]

38 38 Pentavalent Bovine - Human Reassortant Rotavirus Vaccine Efficacy against any RV diarrhoea % Efficacy against severe RV diarrhoea % Reactogenicity : not different to that of the placebo group Vesikari et al, ESPID, Tampere, 2004

39 39 RotaTeq (Merck) Efficacy and safety trial Conducting large scale safety and efficacy trial in 11 countries (mostly USA and Europe) >65,000 infants vaccinated to date Several cases of IS reported but believed that none in the window period after vaccination (3-14 days) Recruitment is completed (2004)

40 40 Rotarix (GSK) Attenuated human monovalent GI P1a[8] strain

41 41 Rotarix Mild reactogenic profiles : same incidence of solicited symptoms as in placebo group (fever, diarrhea, vomiting) : no increase with 2 nd dose : no increase when co-administered

42 42 Efficacy - conclusions Vaccine is effective against any and severe rotavirus gastroenteritis in the 1st and 2nd year of life Vaccine is effective against hospitalisation Vaccine is effective against G1 and non-g1 RV strains

43 43 Phase II-III ongoing studies with RIX4414 Total > 70,000 subjects enrolled in large safety and efficacy studies 2-dose vaccination schedule in infants to fit existing recommendations : 2-4; 3-4 months; , weeks; Co-administered AG s: DTPw, DTPa, HBV,Hib,IPV,OPV

44 No of infants with Intussusception Interval Between Vaccination And IS* Post dose one RotaShield** RotaRix/Placebo*** Post dose two Days * Comparison of IS cluster occurrence after vaccination RotaShield; Rotarix/Placebo. Denominators and background IS differ for both studies ** TV Murphy N Engl J Med 2001 *** Additional cases at 75, 83 and 227 days post dose 1 (post dose 2 at day 71, 86, 107,127, 128,139, 201,222, 329) and 15 days post dose 3

45 45 Rotarix that emerges from these trials is of a : well-tolerated, immunogenic & efficacious : widely effective in protecting against commonly prevalent rotavirus serotypes Rotarix TM was licensed in Mexico in July 2004 De Vos B et al Pediatr Infect Dis J Oct;23(10 Suppl):S

46 46 Conclusion Rotavirus Vaccines Search by many groups for vaccine since first trials in 1983 Two new efficacious vaccines nearing licensure Other credible vaccine candidates in development Global commitment to rotavirus vaccine development Need to evaluate the vaccines in developing world populations is well understood New public / private partnerships (GAVI, ADIP, RVP)

47 47 New vaccine Should we give vaccines to children? : Incidence : Severity : Safety : Feasibility : Acceptibility : Cost : Budget

48 48 Should we give RV vaccine to our children? Incidence high Severity less severe Safety waiting Feasibility oral Acceptibility good Cost expensive Budget depend

49 49 Acknowledgement ศาสตราจารย แพทย หญ ง ว นด วราว ทย คณะกรรมการควบค มไวร สโรตา

50 Rotavirus Slide Kit 50

51 Thank you 51

52 Geneva The Task Force on Research and Development of GAVI has selected rotavirus vaccines as one of three specific priority to be targeted for accelerated development

53 Epidemiology- Developing Countries 53 Peak incidence of RV disease among children 6 24 months of age No. of RVassociated cases of diarrhoea (%) Developing countries: China, India, Mexico, Pakistan* 2-year studies initiated February 1982 October 1985 *combined data from four study centers Age (months) No. of RVassociated cases of diarrhoea in children less than 6 months old (%) <1 1 <2 2 <3 3 <4 4 <5 5 <6 Age (months) Huilan et al, WHO Bull

54 54 Thailand: Epidemiology of Rotavirus Infection Diarrhoea Disease Burden Estimated 5,100 deaths per year Rotavirus Disease Burden Maneekarn (2000) found: Prevalence of 30-36% of hospitalized diarrhoea CDC (2003) found: Estimated 1,275 deaths per year ARSN (2004) found: 44% of hospitalizations for diarrhoea Rotavirus Seasonality Detected year round Peak incidence: October - February et al,paediatrics International ;Bresee et al,emerging Infectious

55 55 Thailand: Epidemiology of Rotavirus Infection Rotavirus serotypes ( ) G1 (37.8%) G2 (21.8%) G4 (7.0%) G3(2.5%) G9 (0.4%) G9 is becoming increasingly common. Manikarn et al,paediatrics International

56 Thailand: Detection of Rotavirus in the Stool of Children Hospitalized with Diarrhoea, BK-Bangkok ;CM-Chiang Mai; PB-Phetchaburi; RB-Ratchaburi; EM-Electron microscopy; IEM-Immune electron microscopy; ELISA- Enzyme- linked immunosorbent assay; latex; latex agglutination;page-polyacrylamide gel electrophoresis Incidence of rotavirus: The prevalence of rotavirus was found to range from % Maneekarn et al, Paediatrics International 2000 Aug 42(4)

57 57 WHO Position on Rotavirus Vaccines The WHO steering committee on diarrheal disease vaccines maintains rotavirus vaccine development as its first priority

58 58