Viral Agents of Gastroenteritis : How Important are they?

Transcription

1 Viral Agents of Gastroenteritis : How Important are they? Roger I. Glass, M.D., Ph.D. Director, Fogarty International Center Associate Director for International Research, NIH Dijon June 14, 2007

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3 E stimated global distribution of the 2.2 million annual childhood deaths caused by diarrhea 1 dot = 5,000 deaths 20% of deaths < 5 yrs

4 The Estimated Burden of Gastroenteritis in the United States Total Deaths Hospitalizations 6, ,000 OPD Visits? Children ,000 (8-12%) 2,000,000 19,400,000 Episodes 267,000,000

5 The "Diagnostic Void" Survey of >30,000 specimens from 10 hospitals Bacterial (5.9%) Salmonella Shigella Campylobacter E. coli Unknown (94%) ref: L. Slutsker, 1997

6 r Bacterial (25%) ot he Sa NL V He pa Viral (1.8%) lm on e ll a Sh ige E. Co lla li Etiology of 7,458 Outbreaks of Gastroenteritis Reported to CDC, Parasitic (1.8%) Chemical (9%) Unknown (62%) ref: Bean & Griffin, 1990

7 Viral Agents of Gastroenteritis Rotavirus Adenovirus Astrovirus Calicivirus - SLV Torovirus Picobirnavirus Calicivirus - NLV Enterovirus 22

8 Noroviruses (a.k.a. Norwalk-like Viruses, human caliciviruses) Identified by electron microscopy (Kapikian)-1972 Do not grow in cell culture; no animal model Commercial detection assays under development Molecular detection by RT-PCR Many different genotypes Most common cause of outbreaks of nonbacterial acute gastroenteritis

9 Norovirus Detection by RT-PCR/EIA Hel 1 Pro Pol Capsid ' 3' ORF 3 ORF ORF 2 A CDC Primers Others 123 bp EU 327 bp 7588 B 213 bp PCR Target C 322 bp D 177/253 bp Expressed Antigen

10 Stool cup-to-sequence Detection & Characterization of NLVs RNA extraction Electron Microscopy RT-PCR 213bp A T G A T C G CC A TG G C A A T C A C G Purify Gel Band 213bp Automated sequencing EtBr stained Gel Sequence Analysis Phylogenetic Analysis

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15 Over a 3 day period, one sick fisherman contaminated 23,000 bushels of oysters sold in about 14 states with a single strain of norovirus

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17 Outbreaks aboard Cruise Ships, outbreaks on 10 ships Some repeated after cleanup By sequence, some linked to common sources Overcrowding major risk Multiple modes of spread Food, person- to-person

18 International Outbreaks of Norwalk like Virus

19 Enhanced Foodborne Outbreak Surveillance: CA, MD, TN; Unknown 22% S. enteriditis 4% C. perfringens 7% N =27 Norovirus 52% S. aureus 15% Active Outbreak Detection Aggressive sample collection (In-home kits) Comprehensive pathogen testing

20 Sporadic Norovirus Gastroenteritis in Adults: Emergency Department Patients 3 FoodNet sites (CT, NY, OR) 364 subjects enrolled 152 subjects with stool sample tested for all pathogens Norovirus most common pathogen detected Pathogen Viruses Norovirus Rotavirus Any bacteria Any parasite No. positive (%) 49 (32%) 30 (20%) 18 (12%) 21 (14%) 3 (2%) Any pathogen No pathogen 73/152 (48%) 79/152 (52%)

21 The Global Challenge Are noroviruses a problem in the developing world?

22 Etiology of Severe Diarrhea in Peruvian Children Parasite 5% Bacteria 20% Rotavirus 40% Unknown 10% Norovirus 25% U. Parasher, 2003 Will this translate into mortality?

23 Etiology of Diarrhea in Finnish Children Rotavirus 24% Parasite 2% Bacteria 2% Mixed/Other 14% Norovirus 19% Unknown 39% X. Pang, 2000 (PCR alone)

24 Research Challenges Diagnostics Receptors Vaccines Cell Culture Animal models A Kapikian B,C,D Prasad

25 Histoire Naturelle des Infections a Rotavirus La cause la plus frequente de diarrhee severe chez l enfant Touchera tous les enfants avant l age de 5 ans Un virus Democratique La premiere infection est symptomatique Immunite naturelle est bonne Peu de souches circulantes L amelioration de conditions d hygiene n influence pas l infection

26 Distribution des 600,000 deces annuel dus au rotavirus 1 dot = 1000 deaths Parashar, 2005

27 Importance de Rotavirus aux US Risk 1 : :80 1:7 1 : 0.9 Events Deaths 60-70,000 Hospitalizations 500,000 Outpatient visits 3.2 Million episodes Cost: $400 M medical; >$1 B total

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29 Genotypes de Rotavirus ( ) P[8]G1 52.2% P[8]G4 7.5% P[4]G2 11.5% P[8]G3 2.8% other 18.2% 5.5% N=21,256 P[6]G9 P[8]G9 2.3% Rare or regionally common strains (23 strains total): P[4]G1 (1.3%), P[6]G2 (0.8%), P[6]G1 (0.6%), P[6]G8 (0.6%), P[4], G3 (0.5%)

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31 Rhesus Rotavirus Vaccine Vaccins vivant oral 3 doses --2,4,6 mois Bien tolere Efficacite >90% contre hospitalisations Efficacite evaluee au Venezuela Acceptabilite rapide aux USA malgre le prix ( $38/dose)

32 Calendrier Vaccinal aux USA Age Vaccine Birth Hepatitis B Hep B 1 mo 2 mos 4 mos Hib Hib Polio IPV IPV Measles, Mumps, Rubella Varicella 15 mos Rv 18 mos 4-6 yrs Rv Hib yrs Hep B DTaP DTaP DTaP H. influenzae type b Rotavirus 12 mos Hep B Hep B Diphtheria, Tetanus, Pertussis 6 mos DTaP DTaP Td Hib Polio Polio Rv MMR Var MMR MMR Var yrs

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34 Interval between Vaccine and Intus s us ception M urphy TV, et al, 2001

35 Evaluation du risque d invagination intestinale apres RotaShield Study Author Risk Excess Cases for US Preliminary Data Livengood-NIP 1 in Reassessment Livengood-NIP Case Series Murphy-NIP 1 in Case Control Murphy-NIP 1 in Cohort Study Kramarz-NIP 1 in 11, Ecologic Studies Chang-NYS <1 in Simonsen-NIH all infants days -11% 1 in 28,

36 Immunization Schedules 50 US RATE UK 40 CASES No Cases Cases/1,000 child-years Taux d incidence et nombre d hospitalisations pour invagination intestinal par age (mois) VSD, EPI 20 BCG Months 80% des les inv. int. chez les enfants age de plus de 3 mois lors de la premiere dose

37 The next generation of rotavirus vaccines Bovine rotavirus with single human rotavirus gene substitution Human rotavirus G1 G1P[8] GSK Bio Rotarix G3 P[8] G2 G4 Merck RotaTeq

38 Human-Bovine Reassortant Rotavirus Vaccine - RotaTeq (Merck) Pentavalent Liquid vaccine with buffer, stabilizer 3 doses, 2ml/dose, easy to administer Grows poorly -high dose (107-8), low shedding

39 Clinical Trials of Rotateq Vac / Outcome Vac Placebo Placebo U.S., 2834/2839 Finland U.S. 650 /650 Efficacy (95%CI) Any Severe 83 / / (67-80) 98 (88-100) Any Mod/sev Severe 15 / / 42 0/6 73 (51-86) 76 (52-89) 100 (13-100)

40 GSK Attenuated Human Rotavirus Vaccine, Rotarix Monovalent Lyophilized vaccine, needs reconstitution 2 doses, 1 ml/dose Grows well -low dose (105.8); high shedding (>50%)

41 Clinical Trials of Rotarix Vac/Placebo Outcome Finland, 245 / 123 Brazil, 464 / 454 Mexico, Venezuela Latin 10,159 / 10,010 America Any Severe Vaccine Efficacy Placebo (95%CI) 13 / (42-87) 2 / (42-97) Any Severe. 15 / 49 5 / (46-84) 86 (63-96) Severe Hosp. NA 85 (72-92) 85 (77-94)

42 Efficacy of Rotarix 63,225 infants in 11 Latin American countries ~20,169 followed for severe GE until 12 mo. Efficacy - severe RVGE 85% G1 disease 92% non-g1 75% (G2 ~50% All GE hospitalizations 41%

43 Safety from Intussusception Rotarix Followup Vac/ Placebo 31 days 31,500/ 31,500 RotaTeq 42 days 35,150 35,150 IS cases Vac/Pl Dose 1 Dose 2 1/2 5/5 Total 6/7 Dose 1 Dose 2 Dose 3 0/1 4/ 1 2/ 3 Total 6/ 5 Was Intussusception due to Rotashield alone?

44 CDC Advisory Committee on Immunization Practices (ACIP) Feb Draft-- Recommendations for Pentavalent Bovine-Human Rotavirus Vaccine (PRV) Routine immunization of infants 3 doses at 2, 4, and 6 months of age Dose 1 between 6-12 weeks of age All doses by 32 weeks of age 4-10 week interval between doses In press: MMWR, 2006

45 Status of Rotavirus vaccine licensure, as of 15 March 2007 GSK Rotarix licensure (88 countries): WHO Region Countries that have licensed Rotarix Americas 22 Argentina, Aruba, Bolivia, Brazil, Chile, Colombia, Costa Rica, Curaçao, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Nicaragua, Panama, Paraguay, Peru, Suriname, Trinidad/Tobago, Venezuela Africa 17 Burkina Faso, Cameroun, Central African Republic, Congo, DRCongo, Guinea, Ivory Coast, Kenya, Madagascar, Malawi, Mali, Mauritania, Mauritius, Nigeria, Senegal, South Africa, Togo Europe 31 Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, UK Middle East 8 Bahrain, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, UAE, Yemen Southeast Asia 3 Bangladesh, Sri Lanka, Thailand Western Pacific 7 Australia, Hong Kong, Malaysia, New Zealand, Philippines, Singapore, Taiwan From: Robin Bielik, PATH

46 Status of Rotavirus vaccine licensure, as of 1 March 2007 Merck RotaTeq licensure (47 countries): WHO Region Countries that have licensed RotaTeq Americas 12 Africa 6 Europe 26 Middle East 0 Southeast Asia 0 Western Pacific 3 Argentina, Canada, Curação, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Perú, Puerto Rico, USA DRCongo, Guinea, Kenya, Niger, Rwanda, Togo Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden, Turkey, UK Australia, Hong Kong, Taiwan From: Robin Bielik, PATH

47 Les vaccins vivant oraux-- seront ils efficaces dans les pays en developpement? Less immunogenic/more doses needed for children in India (T. Jacob Johns) OPV Cholera Less immunogenic/higher titer needed in (Oralchol) Thai/Indonesian studies ( Mike Levine) Oral RV RIT WC3 RRV GSK Failed in Africa/Peru Failed in Africa Lower efficacy in Peru/Brazil Being tested in S.Africa/Bangladesh

48 Timelines

49 Reseau de rotavirus en Asie China: 41% Korea Taiwan: 41% Hong Kong: 29% Myanmar: 56% Vietnam: 60% Malaysia: 56% Indonesia: 39%

50 Reseaux regionaux de surveillance de rotavirus Euro Asia South Asia South America Africa EMRO

51 Vaccins rotavirus - le fruit le plus mur des vaccins en developpement Tb HIV RSV Malaria Jap B Dengue MenC disease burden is large & global principles to develop vaccines are well established extensive past experience with clinical trials achievable in 5-7 years Rotavirus impact of vaccine should be measurable within one year

52 Celles qui font peur et celles qui tuent! Media Attention Public Health Importance CJD Anthrax Smallpox SARS/Ebola monkeypox West Nile Virus ARI NLV diarrhea Malaria/ flu rotavirus Papilloma/ Tbc Hepatitis/ HIV <1,000 Deaths/Year >500,000

53 Utilisera-t-on le vaccin Rotavirus en Europe? Quelles seront les facteurs cles de decision?