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Rotavirus Infection.

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Presentation on theme: "Rotavirus Infection."— Presentation transcript:

1 Rotavirus Infection

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

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

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 ในปัจจุบันอัตราการเจ็บป่วยและเสียชีวิตจากโรคอุจจาระร่วงได้ลดลงทั่วโลก แต่การป่วยจนต้องเข้ารับการรักษาที่โรงพยาบาลยังคงสูงอยู่ ในปี 2545 รายงานการเฝ้าระวังโรคของสำนักระบาดวิทยา พบว่ามีผู้ป่วยโรคอุจจาระร่วง 1,055,393 ราย โดย 1 ใน 3 เป็นเด็กที่มีอายุต่ำกว่า 5 ปี และร้อยละ 12 เข้ารับการรักษาในโรงพยาบาล ความก้าวหน้าในการพัฒนาวัคซีนเพื่อป้องกันเชื้อโรต้าไวรัสที่ผ่านมากระตุ้นให้มีการศึกษาข้อมูลอัตราการเกิดโรคจากเชื้อดังกล่าวในเด็กไทยและความต้องการในการใช้วัคซีนโรต้าไวรัส MOPH 2002

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 The Virus- Classification
Rotavirus has 7 major groups (A-G). Only groups A-C infect humans1 Group A responsible for majority of childhood infections1 Group B has been associated with extensive epidemics of diarrhoea illnesses in adults in China and Bangladesh2,3 1Linhares and Breese, Pan Am J Public Health (5) ; 2J Clin Microbiol , ;3J Med Virol

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 rotaviruses1,2 1Linhares and Breese, Pan Am J Public Health (5) ; 2Parashar et al, Emerg Infect Dis (4) 561–570

8 Rotavirus serotypes in Thailand,1982-1997
Maneekarn et al, Paediatrics International 2000 Aug 42(4)

9 VOMITING AND diarrhoea
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 VOMITING AND diarrhoea Rotaviruses adhere to gastrointestinal (GI) tract epithelia, infecting the surface of cells of the villi in the upper parts of the small intestine. Following viral replication, the infection spreads further along the intestine, producing mucosal lesions by selectively destroying the tips of the villi of the gut and extensive viral shedding in the feces. Although infection is superficial, it is sufficient to trigger local and systemic immune responses. The damage is reversible but diarrhoea continues until the villi have regenerated. Hence, the seriousness of the lesions determine the time course of symptoms. diarrhoea results from the loss of absorptive area and the flux of water and electrolytes across the damaged surface. Rotavirus infection is also more likely to produce vomiting, dehydration and fever than other diarrhoea-producing viral pathogens. There are three broad types of virulence traits found in diarrhoeal pathogens, which allow the organism to: (ii) adhere to the cells lining the gut (ii) penetrate the cells lining the gut (viruses) (iii) produce toxins. There is evidence that one of the rotavirus proteins acts as an exotoxin which causes fluid loss from infected cells, in a similar way to shigella and cholera. However, this is the first time that an exotoxin has been associated with a virus1. Another recent study suggested that the virus activates the enteric nervous system, triggering nerves that control the peristaltic movement of the intestines and the extent to which they can absorb fluid2. Kapikian A and Chanock R. Rotaviruses. In: Fields B et al, editors. Fields Virology, 3rd ed; 1996: p. 1657–1708 1Carnell, BMJ 2WHO Int J Pub Health, 2000 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.

10 Cholera infantum Dehydration in an infant with acute diarrhea

11 Rotavirus- Burden of Disease
Estimated global prevalence of rotavirus disease Risk of Particular Event Event 1 : 293 440,000 deaths 1 : 65 2 million inpatient visits 1 : 5 25 million outpatient visits Consider the estimated global prevalence of rotavirus disease to understand its impact1: Annually, rotavirus is responsible for approximately: 111 million episodes of gastroenteritis requiring home care alone 25 million cases requiring a clinic visit 2 million cases requiring hospitalization A median death rate of 440,000 in children less than 5 years old This means that by the age of 5 years: Almost all children will have an episode of rotavirus gastroenteritis, 1 in 5 will require a clinic visit, 1 in 65 will require hospitalization, and An estimated 1 in 293 will die 1Parashar et al, Emerg Infect Dis (5) 565–572 111 million domiciliary episodes 1 : 1 Parashar et al, Emerg Infect Dis (5) 565–572

12 Surveillance sites and surveillance period
Nongkhai Maesod Nongkhai Sakaeo Measod Ramathibodi Chanthaburi Sakaeo Ramathibodi ทำการศึกษาในโรงพยาบาล 6 แห่ง กระจายตามภาคต่างๆ ได้แก่ Chanthaburi Hadyai Hadyai Feb44 Jun44 Dec44 Jun45 Dec45 Jun46 Chuleeporn Jirapongsa

13 Proportion of rotavirus identification by site
Percentage เชื้อโรต้าไวรัสที่พบในแต่ละโรงพยาบาลมีสัดส่วนตั้งแต่ร้อยละ 40 ถึง 50 Chanthaburi Hadyai Sakaeo Nongkhai Maesod Ramathibodiี

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

15 Proportion of rotavirus positive sample by age group, Feb 2001 - Mar 2002
Percentage 97% Age in Month

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

17 Clinical manifestations
Signs and Symptoms Tenesmus Abdominal pain Mucous-bloody stool Watery stool Nausea/Vomiting สำหรับอาการที่พบ ส่วนใหญ่ ได้แก่ ไข้ คลื่นไส้ อาเจียน ถ่ายเป็นน้ำ พบว่ามาด้วยอาการถ่ายเป็นมูกเลือดได้ร้อยละ15 Fever Percentage N = 713 cases

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

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

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) 565–572

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


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

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. 2003 *Velazquez FR, Matson DO et al NEJM 335:

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
p1 : % of rotavirus positive of hospitalized cases = % (838 / 1,950) n1 : 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 สไลด์นี้แสดงการคำนวณอุบัติการณ์ โดยการคูณสัดส่วนการพบเชื้อโรต้าไวรัสในผู้ป่วยที่พบจากการเฝ้าระวัง กับจำนวนผู้ป่วยในโรคอุจจาระร่วยอายุต่ำกว่า 5 ปีที่ได้รับรายงานทั่วประเทศ ชดเชยเรื่องความครอบคลุมแล้ว ทั้งหมดหารด้วยจำนวนเด็กอายุต่ำกว่า 5 ปีของประเทศไทย

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 Rotavirus Vaccine Human strain vaccines Reassortant vaccines

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

30 RotaShield® : Clinical Efficacy
% US Multi Finland Venezuela 100% 100% 100% 100 97% 80 75% 73% 70% 71%† 69% 60 40 20 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 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 Clinical research and development of rotavirus vaccines began in the 1970s. Work mainly focused on the development of live-attenuated vaccines because it was thought that protection against rotaviruses would be best achieved by inducing a local intestinal immune response, in addition to systemic and cell-mediated immunity. Furthermore, heterotypic protection was also required and oral administration would facilitate vaccine integration into the EPI schedule. The first candidate vaccine to be fully investigated was the monovalent bovine-human reassortant RIT 4237 vaccine, which induced 88% heterotypic protection against severe RV diarrhea in Finnish trials. However, despite encouraging results in developed countries, vaccine development was halted during the early 80s, when its protective efficacy could not be confirmed in developing countries. Many experts feel that clinical evaluation was halted prematurely, preventing a true assessment of its real protective efficacy profile. Some 15 years later, in 1998, Wyeth-Lederle launched the tetravalent human-rhesus reassortant vaccine (RRV-TV), Rotashield®, in the US. However, in July 1999, less than a year after its launch, Rotashield was withdrawn after it was linked with rare cases of intussusception (IS)—a serious bowel obstruction—following administration of the first dose.1 1Centers for Disease Control and Prevention, MMWR –20 Murphy et al, N Engl J Med –72. Copyright © 200x [2001] Massachusetts Medical Society. All rights reserved

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

33 Rotavirus Seasonal Incidence and IS cases in US
Vaccines Rotavirus Seasonal Incidence and IS cases in US Seasonal distribution of rotavirus diarrhea and IS in children <3 years old Epidemiology data from the US refute that natural rotavirus causes IS as there is no observed seasonal incidence of IS relative to the winter peak of rotavirus disease. Chang et al Pediatr Infect Dis J –102 (Southern California Kaiser Permanente Health Care Plan)

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

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

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

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

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

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 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 Interval Between Vaccination And IS*
Post dose one 5 10 15 20 30 40 50 60 70 RotaShield** RotaRix/Placebo*** No of infants with Intussusception 5 10 15 20 30 40 50 60 70 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 Rotarix that emerges from these trials is of a
: well-tolerated, immunogenic & efficacious : widely effective in protecting against commonly prevalent rotavirus serotypes RotarixTM was licensed in Mexico in July 2004 De Vos B et al Pediatr Infect Dis J Oct;23(10 Suppl):S

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

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 Acknowledgement ศาสตราจารย์ แพทย์หญิง วันดี วราวิทย์

50 Rotavirus Slide Kit

51 Thank you

52 2001- 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
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 30 5 10 15 20 25 30 35 40 45 No. of RV- associated cases of diarrhoea (%) 0–5 6–11 12–23 24–35 Age (months) 25 No. of RV- associated cases of diarrhoea in children less than 6 months old (%) 20 15 10 The results of several studies highlight that the peak incidence of rotavirus disease occurs among children 6–24 months of age: Huilan et al, WHO Bull –555 A two-year etiological survey of acute diarrhoea in children aged 0–35 months was conducted at five hospitals in China, India, Mexico, Myanmar and Pakistan. Data from four of the study centers (China, India, Mexico and Pakistan) were used to examine the age distribution of children with RV diarrhoea. The highest incidence of RV-associated cases of diarrhoea were found in children aged 6–11 months. Further analysis of the data for 0–6 month olds from these study sites, by monthly age groups, revealed the highest incidence of RV-associated diarrhoea was found in children between 5 months and less than 6 months of age. 5 0–<1 1–<2 2–<3 3–<4 4–<5 5–<6 Age (months) Huilan et al, WHO Bull –-555

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 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, 1977-1996
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 WHO Position on Rotavirus Vaccines
“The WHO steering committee on diarrheal disease vaccines maintains rotavirus vaccine development as its first priority”


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