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1. 2 Global Impact of Enteric Disease Deaths in young children Cholera 120 000 ETEC 380 000 Typhoid 600 000 Average of 2.2 million deaths per year worldwide.

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Presentation on theme: "1. 2 Global Impact of Enteric Disease Deaths in young children Cholera 120 000 ETEC 380 000 Typhoid 600 000 Average of 2.2 million deaths per year worldwide."— Presentation transcript:

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

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

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 7 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 1Linhares and Breese, Pan Am J Public Health (5) ; 2Parashar et al, Emerg Infect Dis (4) 561 – 570

8 8 Rotavirus serotypes in Thailand, Maneekarn et al, Paediatrics International 2000 Aug 42(4)

9 9 Pathogenesis 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 VOMITING AND diarrhoea *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.

10 10 Dehydration in an infant with acute diarrhea Cholera infantum

11 11 Rotavirus- Burden of Disease Estimated global prevalence of rotavirus disease Parashar et al, Emerg Infect Dis (5) 565 – million outpatient visits 111 million domiciliary episodes 1 : : 65 EventRisk of Particular Event 440,000 deaths 2 million inpatient visits 1 : 5 1 : 1

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

13 Proportion of rotavirus identification by site Percentage ChanthaburiHadyaiSakaeoNongkhaiMaesod Ramathibodi ี

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

15 15 Proportion of rotavirus positive sample by age group, Feb Mar 2002 Percentage Age in Month 97%

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

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

18 18 Bacteria 7% 5%Rotavirus 39% Rotavirus Surveillance Project Thailand, Feb 2001-Mar 2002

19 19 Rotavirus Mortality By Income Group Parashar et al, Emerg Infect Dis May (5) 565 – 572 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 Parashar et al, Emerg Infect Dis May (5) 565 – 572 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

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

22 22

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

24 24 Rationale for Vaccination 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 *Velazquez FR, Matson DO et al NEJM 335:

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 Hospitalize cases = (42.97% X 131,360) / 5,005,904 = per 1,000 population under 5 Burden of rotavirus diarrhea = (p1 X n1) / N

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 US Multi FinlandVenezuela % 97% 75% 100% 70% 73% 71% † % 100% 69% Dehydration Hospital admittance MD visits or † illness >4 days Rennels et al Pediatrics 1996;97:7-13. Santosham et al J Pediatr 1997;131: Joensuu et al Lancet 1997;350: P é rez-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 – 72. 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 Vaccines Chang et al Pediatr Infect Dis J – 102 (Southern California Kaiser Permanente Health Care Plan) Rotavirus Seasonal Incidence and IS cases in US Seasonal distribution of rotavirus diarrhea and IS in children <3 years old

34 34 Nelson et al. Pediatr Infect Dis J. 2002;21:701 – 3 Seasonality of Rotavirus & Intussusception in Hong Kong

35 35 Rotavirus vaccine Human-derived monovalent live-attenuated : Rotarix Lamb-derived, monovalent live-attenuated Bovine -human reassortant penatavalent live- attenuated 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 Efficacy against any RV diarrhoea % Efficacy against severe RV diarrhoea % Reactogenicity : not different to that of the placebo group Pentavalent Bovine - Human Reassortant Rotavirus Vaccine 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 44 Interval Between Vaccination And IS* RotaShield**RotaRix/Placebo*** ** TV Murphy N Engl J Med 2001 No of infants with Intussusception Days Post dose two *** 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 * Comparison of IS cluster occurrence after vaccination RotaShield; Rotarix/Placebo. Denominators and background IS differ for both studies Post dose one

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 ศาสตราจารย์ แพทย์หญิง วันดี วราวิทย์ คณะกรรมการควบคุมไวรัส โรตา

50 50 Rotavirus Slide Kit

51 51 Thank you

52 52 “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 ” Geneva

53 53 Epidemiology- Developing Countries Peak incidence of RV disease among children 6 – 24 months of age Developing countries: China, India, Mexico, Pakistan* 2-year studies initiated February 1982 – October 1985 * combined data from four study centers Huilan et al, WHO Bull – No. of RV- associated cases of diarrhoea (%) 0–50–56 – 1112 – 2324 – 35 Age (months) – <11 – <22 – <33 – <44 – <55 – <6 Age (months) No. of RV- associated cases of diarrhoea in children less than 6 months old (%)

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 diseases June (6)

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 56 Thailand: Detection of Rotavirus in the Stool of Children Hospitalized with Diarrhoea, Maneekarn et al, Paediatrics International 2000 Aug 42(4) Incidence of rotavirus: The prevalence of rotavirus was found to range from % 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

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

58 58


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