Transcript ภาพนิ่ง 1

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Global Impact of Enteric Disease Deaths
in young children
Average of 2.2 million deaths per year worldwide
Typhoid
600 000
Cholera
120 000
ETEC
380 000
Rotavirus
450 000
Shigella
670 000
WHO, 2000
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Viral Agents Causing Gastroenteritis
Rotavirus
Norwalk like
particles
Enteric
Adenovirus
Astrovirus
Human
Calicivirus
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
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
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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%
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The Virus- Classification

Rotavirus has 7 major groups (A-G).


Group A


Only groups A-C infect humans1
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 2000 8(5)
305-331; 2J Clin Microbiol 2003 41, 2187-2190 ;3J Med Virol
2004 72 149-155.
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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 2000 8(5) 305-331; 2Parashar
et al, Emerg Infect Dis 1998 4(4) 561–570
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Rotavirus serotypes in Thailand,1982-1997
200
160
140
G1
120
100
G2
80
G4
G3
60
40
1996-1997
1995-1996
1992
1990-1991
1989-1990
1989
1988-1989
1988-1989
1987-1988
1987-1988
1987-1988
1986-1987
1985-1986
1983-1984
20
0
1982-1983
No. of specimens
180
Maneekarn et al, Paediatrics International 2000 Aug 42(4) 415-421
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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
*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
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Cholera infantum
Dehydration in an infant with acute diarrhea
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Rotavirus- Burden of Disease
Estimated global prevalence of rotavirus disease
Risk of Particular Event
1 : 293
1 : 65
1:5
1:1
Event
440,000 deaths
2 million inpatient visits
25 million
outpatient visits
111 million
domiciliary
episodes
Parashar et al, Emerg Infect Dis 2003 9(5) 565–572
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Surveillance sites and
surveillance period
Nongkhai
Maesod
Nongkhai
Ramathibodi
Sakaeo
Chanthaburi
Measod
Sakaeo
Ramathibodi
Chanthaburi
Hadyai
Hadyai
Feb44 Jun44 Dec44 Jun45 Dec45 Jun46
Chuleeporn Jirapongsa
Proportion of rotavirus identification by site
Percentage
80
60
50
48.6
40.9
40
41.7
Chanthaburi
Hadyai
Sakaeo
43.1
40
20
0
Nongkhai
Maesod
Ramathibodiี
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Rotavirus Hospitalizations in the Asian
Rotavirus Surveillance Network
44%
49%
Thailand 44%
59%
53%
57%
53%
Bresee et al, Emerg Infect Dis Jun 2004 10(6) 988-995
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Proportion of rotavirus positive sample by age
group, Feb 2001 - Mar 2002
Percentage
97%
70
60
50
40
30
20
10
0
0-2
3-5
6-11 12-17 18-23 24-29 30-35 36-41 42-47 48-53 54-60
Age in Month
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Rotavirus Seasonality in Thailand
Bresee et al. Emerg Infect Dis 2004;10:988-95.
Clinical manifestations
Signs and Symptoms
0.9
Tenesmus
10.7
Abdominal pain
14.8
Mucous-bloody stool
68.7
Watery stool
76.8
Nausea/Vomiting
79.2
Fever
0
N = 713 cases
10
20
30
40
Percentage
50
60
70
80
90
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Rotavirus Surveillance Project
Thailand, Feb 2001-Mar 2002
Rotavirus 39%
5%
Bacteria
7%
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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 2003 9(5) 565–572
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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 2003 9(5) 565–572
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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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Need for Vaccination
State of the World’s Vaccines & Immunization – WHO, 2003
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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. 1996. NEJM 335:1022-1028
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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
: 13-26 / 20-40 deaths annually
Burden estimation of Thailand, 2002



p1 : % of rotavirus positive of hospitalized cases
= 42.97 % (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
= 11.28 per 1,000 population under 5
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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
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Rotavirus Vaccine
• Human strain vaccines
• Reassortant vaccines
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RotaShield® (RRV-TV)
Tetravalent Rhesus-Human Reassortants G1,2, 4 and G3
RotaShield® : Clinical Efficacy
%
100
80
100% 97%
US Multi
Finland
Venezuela
100% 100%
75%
70%
73%
†
69% 71%
60
40
20
0
Dehydration
Hospital admittance
MD visits or
†
illness >4
days
Rennels et al Pediatrics 1996;97:7-13. Santosham et al J Pediatr 1997;131:632638. Joensuu et al Lancet 1997;350:1205-1209. Pérez-Schael et al N Engl J Med
1997;337:1181-87
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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 2001 344 564–72. Copyright © 200x [2001] Massachusetts
Medical Society. All rights reserved
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RotaShield

Increase intussusception risk
: 37 times (95%CI 12.6 -110.1)

3-7 days (1-2 weeks)
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Vaccines
Rotavirus Seasonal Incidence and IS
cases in US
60
50
Rotavirus
Intussusception
40
30
20
10
e
Ju
n
ay
M
A
pr
ar
M
Fe
b
Ja
n
D
ec
N
ov
ct
O
Se
p
Ju
l
A
ug
0
y
Proportion of Cases (%)
Seasonal distribution of rotavirus diarrhea and IS in children
<3 years old
Month
Chang et al Pediatr Infect Dis J 2002 21 97–102 (Southern California Kaiser Permanente
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Seasonality of Rotavirus & Intussusception in
Hong Kong
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
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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
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Rotavirus vaccine

2, 4, 6 mo

2, 4 mo Rotarix
: 86% G1 serotype
: non G1 73%
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RotaTeq™ (Merck)
WC-3 based bovine-human
reassortants
G1,2,3 and P1a[8]
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Pentavalent Bovine - Human Reassortant
Rotavirus Vaccine
Efficacy against any RV diarrhoea
43-74 %
Efficacy against severe RV diarrhoea
88-100 %
Reactogenicity
: not different to that of the placebo group
Vesikari et al, ESPID, Tampere, 2004
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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 (314 days)

Recruitment is completed (2004)
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Rotarix™ (GSK)
Attenuated human monovalent GI P1a[8]
strain
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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
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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
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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; 6-1014, 10-14 weeks;

Co-administered AG’s: DTPw, DTPa,
HBV,Hib,IPV,OPV
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Interval Between Vaccination And IS*
Post dose one
No of infants with Intussusception
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RotaShield**
15
RotaRix/Placebo***
10
5
0
0
20
10
20
30
40
50
60
70
20
30
40
50
60
70
Post dose two
15
10
5
0
0
10
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
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
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. 2004 Oct;23(10 Suppl):S179-82.
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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)
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New vaccine
Should we give vaccines to children?
: Incidence
: Severity
: Safety
: Feasibility
: Acceptibility
: Cost
: Budget
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Should we give RV vaccine to our children?
Incidence
high

Severity
less severe

Safety
waiting

Feasibility
oral

Acceptibility
good

Cost
expensive

Budget
depend

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Acknowledgement
ศาสตราจารย์ แพทย์ หญิง วันดี วราวิทย์
คณะกรรมการควบคุมไวรัสโรตา
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Rotavirus Slide Kit
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Thank you
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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 ”
www.who.int/vaccine_research/documents/new_vaccines/en/index1.html
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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
45
40
No. of RV- 35
associated30
cases of 25
diarrhoea 20
(%)
15
10
5
0
No. of RV- 25
associated
20
cases of
diarrhoea 15
in children
less than 10
6 months old
5
(%)
0
0–5
6–11
12–23
Age (months)
24–35
0–<1 1–<2 2–<3 3–<4 4–<5 5–<6
Age (months)
Huilan et al, WHO Bull 1991 18 549–-555
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Thailand: Epidemiology of Rotavirus Infection

Diarrhoea Disease Burden


Estimated 5,100 deaths per year
Rotavirus Disease Burden

Maneekarn (2000) found:
•

CDC (2003) found:
•

Estimated 1,275 deaths per year
ARSN (2004) found:
•

Prevalence of 30-36% of hospitalized diarrhoea
44% of hospitalizations for diarrhoea
Rotavirus Seasonality

Detected year round

Peak incidence: October - February
http://www.cdc.gov/ncidod/EID/vol9no5/02-0562_appB.htm,Maneekarn et
al,Paediatrics International 2000 42 415-421;Bresee et al,Emerging Infectious
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Thailand: Epidemiology of Rotavirus Infection


Rotavirus serotypes (1982-1997)

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 2000 42 415-421
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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; ELISAEnzyme- linked immunosorbent assay; latex; latex agglutination;PAGE-Polyacrylamide gel electrophoresis
Incidence of rotavirus: The prevalence of rotavirus was found to range from 16.8-58.2%
Maneekarn et al, Paediatrics International 2000 Aug 42(4) 415-421
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WHO Position on Rotavirus Vaccines
“The WHO steering committee
on diarrheal disease vaccines
maintains rotavirus vaccine
development as its first priority”
www.who.int/vaccines-diseases/diseases/RotaPP.shtml
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