rotavirus ge and rv vaccine ppt
TRANSCRIPT
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Dr Abdulla Al Tuhami
Ped Consultant / Cardiologist
Riyadh Care Hospital
ROTAVIRUS GE AND ROTAVIRUS ROTAVIRUS GE AND ROTAVIRUS VACCINES : UPDATEVACCINES : UPDATE
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RIYADH CARE HOSPITAL
Nov 2008
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VIRAL AGENTS CAUSINGVIRAL AGENTS CAUSINGGASTROENTERITISGASTROENTERITIS
1. Rotavirus
2. Enteric adenoviruses
3. Calicivirus
4. Astrovirus
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1Parashar et al, Emerg Infect Dis 1998 4(4) 561–5702Linhares and Bresee, Pan Am J Public Health 2000 8(5) 305–331
3Parashar et al, Emerg Infect Dis 2003 9(5) 565–572
Estimated global distribution of 440,000 annual deaths in children <5 years old caused by
rotavirus diarrhea3 1 dot = 1000 deaths
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Risk by 5th BirthdayAnnual Burden
1 : 5
1 : 1
1 : 205
1 : 50
610,000
2.4 million
24 million
114 million
Deaths
Hospitalizations
Outpatient Visits
RV Episodes
Glass RI, et al. Lancet 2006;368:323-332
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1 : 7
4 : 5
20-60
55,000-70,000
1 : 100,000
1 : 80
600,000
2.7 million
Deaths
Hospitalizations
Outpatient Visits
RV Episodes
Risk by 5th BirthdayAnnual Burden
Glass RI, et al. Lancet 2006;368:323-332
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Temporal distribution of rotavirus diarrheal cases in children less
than 5 years of age in Al Al MaddinaMaddina, Saudi Arabia.Journal of Clinical Microbiology, April 2008, p. 1185-1191, Vol. 46, No.
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Distribution of rotavirus diarrhea cases among children less than 5 years of age.
Journal of Clinical Microbiology, April 2008, p. 1185-1191, Vol. 46, No. 4
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A A 1818Figure adapted from Cunliffe et al, Lancet 2002;359:640–642
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Share cross reactive epitopes
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Latin America (n=2,950)
2%
3%
73%
11%
11%
G1 TypeG2 TypeG3 TypeG4 Type
G9 TypesOther Types
North America (n=2,892)
1%
7%
4%
11%
77%
Europe (n=17,475)
2%
4%
9%58%
9%
18%
n= number of RV infections analyzedSantos et al. Rev Med Virol 2005;15:29-56
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GIP8GIP8GIP8GIP8
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010
20304050
607080
90100
Percent Efficacy
moderate to severe diarrhea
mild diarrhea
asymptomatic infection
1 Velazquez et al, N Eng J Med 1996 335 1022–10282 Bernstein DI, et al. JID. 1991; 164(2); 277-833 Velazquez et al, J Infect Dis 2000 182 1602–1609
Two Previous RV infectionsOne Previous RV infection
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VS
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33 passages in cell culture
Limiting dilution cloning in Vero cells and further passage in tissue culture
Initial Safety and Efficacy studies1
Live-Attenuated Human Rotavirus Vaccine
(RIX4414 - Rotarix®)
Human rotavirus strain circulating in Cincinnati in 1989
1Bernstein et al, Lancet, 1999; 354:287-290
G1P[8]
G1P[8]
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Phase III
Immuno, Safety
Study 039 Thailand
n=174 n=52
Immuno US coadvaccines, Safety
Study 060 US
n=459
Efficacy, Safety (IS), Immuno
Study 023 Latin America, Finland
n=31673 n=31552
Lot consistency,Safety, Immuno
Study 033 Latin American=730 n=124
Efficacy, Safety,Immuno
Study 036 Europe
n=2646 n=1348
Phase II
Study 004 Finland
n=270 n=135
Study 006 Latin America
n = 1139 n=570 n=567
Study 007 Singapore
n = 1158 n=653 n=653
Safety, Immuno
Study 005 US, Canada
n=212 n=209 n=108
Immuno OPV Coad, Safety
Study 014S. Africa
n=297 n=150
Immuno,Safety
Study 048Finland
n=100 n=50
Efficacy, Safety,Immuno
Efficacy, Safety,Immuno
Efficacy, Safety,Immuno
Summary of Clinical Studies in BLASummary of Clinical Studies in BLA
Rotarix <106.0 CCID50
n = 3076
Rotarix>106.0 CCID50
n = 37214Placebon =34739
Total Exposure = 75029 subjects
Phase II
Study 004 Finland
n=270 n=135
Study 006 Latin America
n = 1139 n=570 n=567
Study 007 Singapore
n = 1158 n=653 n=653
Safety, Immuno
Study 005 US, Canada
n=212 n=209 n=108
Immuno OPV Coad, Safety
Study 014S. Africa
n=297 n=150
Immuno,Safety
Study 048Finland
n=100 n=50
Efficacy, Safety,Immuno
Efficacy, Safety,Immuno
Efficacy, Safety,Immuno
Phase III
Immuno, Safety
Study 039 Thailand
n=174 n=52
Immuno US coadvaccines, Safety
Study 060 US
n=459
Efficacy, Safety (IS), ImmunoStudy 023
Latin America, Finlandn=31673 n=31552
Lot consistency,Safety, Immuno
Study 033 Latin American=730 n=124
Efficacy, Safety,ImmunoStudy 036 Europe
n=2646 n=1348
Rotarix <106.0 CCID50
n = 3076
Rotarix>106.0 CCID50
n = 37214
Placebon =34739
Total Exposure = 75029 subjects
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Dominican Republic4056 (6.4%)
Mexico13245 (20.9%)
Brazil3218 (5.1%)
Nicaragua4057 (6.4%)
Honduras4195 (6.6%)
Panama4061 (6.4%)
Chile3458 (5.5%)
Argentina4671 (7.4%)
Venezuela4250 (6.7%)
Colombia3910 (6.2%)
Peru12044 (19.0%)
Finland2060 (3.3%)
Study 023: Phase III Study in Latina & FinlandStudy 023: Phase III Study in Latina & Finland18 sites in 12 countries ~63,000 infants
• LA: efficacy & safety• Finland: safety only
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N=63,225infants age 6-13 weeks
randomized (1:1)
month 0
Placebo N=31,552
Rotarix N=31,673
1st D
ose
2nd D
ose
Month 1-2 Month 2-4Safety
surveillance(N=63,225)
Month 9-10
1 yr Efficacy analysis
(ATPN=17,867)
Routine immunizations were co-administered according to local regulations
Study 023: Phase III Safety & Efficacy Study 023: Phase III Safety & Efficacy Study in Latin America and FinlandStudy in Latin America and Finland
Month 21-22
2 yr Efficacy analysis
(ATPN=14,237)
Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354:11-22
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0102030405060708090
100
Severe RV GEClinical
Severe RV GEVesikari
RV GEHospitalization
All-causeSevere GE
Vac
cin
e ef
fica
cy (
%)
From 2 weeks post-dose 2 until 12 months of age (ATP cohort)
85%[72;92]
85%[71;93]
85%[70;94]
40%[28;50]
12V:77P 11V:71P 9V:59P 183V:300P
Efficacy Latin America (Study 023) Efficacy Latin America (Study 023)
randomization 1:1
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01020
3040506070
8090
100
G1P[8] G2P[4] G3P[8] G4P[8] G9P[8]
Va
cc
ine
eff
ica
cy
(%
)
From 2 weeks post-dose 2 until 24 months of age (ATP cohort)
*Not statistically significant
82% [65;92]
79% [25;96]
87% [73;94]
39%* [-112;84]
62% [4;87]
10V:55P 3V:14P+ 7V:18P 9V:66P5V:8P
+ one episode was P[6]
Type-specific Type-specific Efficacy Latin America Efficacy Latin America (Study 023) - severe RV GE(Study 023) - severe RV GE
randomization 1:1
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StudyStudy 036: Phase III 036: Phase III StudyStudy in Europe in Europe124 Sites in 6 EU Countries ~4000 Infants124 Sites in 6 EU Countries ~4000 Infants
Spain7.5%Spain7.5%
Germany7%
Germany7%
France3.7%France3.7%
Italy0.6%Italy0.6%
Finland74%
Finland74%
CzechRepublic7.5%
CzechRepublic7.5%
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Study 036: Phase III Safety & Study 036: Phase III Safety & Efficacy Study in EuropeEfficacy Study in Europe
Month 0
Placebo N=1,348
Co-administered with DTaP-HepB-IPV/Hib (all), PCV7 (subset), MenC (subset)
Rotarix N=2,646
1st d
ose
2nd d
ose
Months 1–2Months 7-9
Season 1 Efficacy analysis
(ATP N=3,874)
Months 19-21
Season 2 Efficacy analysis
(ATP N=3,848)
N=3,994infants age 6-14 wks
randomized (2:1)
Vesikari T et al. Lancet 2007;370:1757-63
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0
10
20
30
40
50
60
70
80
90
100
Any RV GE Severe RV GE RV GE Hosp Medically-attended RV
GE
All-cause GEHosp
Vac
cin
e ef
fica
cy (
%)
From 2 weeks post-dose 2 until end of the 1st RV season (ATP cohort)
87% [80;92]
75% [46;89]
92% [84;96]
100% [82;100]96%
[90;99]
Efficacy Europe (Study 036)Efficacy Europe (Study 036)
24V:94P 5V:60P 0V:12P 10V:62P 11V:22P
randomization 2:1
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0
10
20
30
40
50
60
70
80
90
100
Any RV GE Severe RV GE
Vac
cin
e ef
fici
acy
(%)
100%[-23;100]
90%[9;100]
From Dose 1 up to before Dose 2 (Total Vaccinated Cohort)
Efficacy Europe (Study 036)Efficacy Europe (Study 036)
1V:5P 0V:3P
TVC = all subjects who received at least one dose regardless of protocol adherence
randomization 2:1
Rotarix prevents RV GE as early as dose 1
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0
10
20
30
40
50
60
70
80
90
100
G1P[8] G2P[4] G3P[8] G4P[8] G9P[8]
Vac
cin
e ef
fica
cy (
%)
From 2 weeks post-dose 2 until end of the 2nd RV season (ATP cohort)
96% [90;99]
86% [24;99]
85% [72;93]
95% [68;100]
94% [53;100]
4V:57P 1V:8P 1V:11P 13V:44P+
* P genotype not typable for one episode, + P[8] genotype not detected for one episode
2V:7P*
Type-specific Type-specific Efficacy Europe Efficacy Europe (Study 036) - Severe RV GE(Study 036) - Severe RV GE
randomization 2:1
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Summary of EfficacySummary of Efficacy
• Rotarix prevents:– Severe RV GE disease (96% EUR; 85% LA)
– Any RV GE disease (87% EUR)
– RV GE hospitalizations (100% EUR: 85% LA)
– Medically attended RV GE (92% EUR)
– RV GE as early as dose 1 (90% EUR)
• Rotarix prevents RV GE caused by G1, G2, G3, G4 and G9 strains
• Rotarix efficacy persists through 2 years/seasons after vaccination
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Clinical Trial Data to be PresentedClinical Trial Data to be PresentedEfficacy• Phase III Latin America • Phase III Europe
Immunogenicity• Seroconversion and Vaccine Take• Coadministration with US licensed Vaccines• Fecal Antigen and Live Virus Shedding
Safety• Intussusception• Integrated Summary of Safety: SAEs• Events of Clinical Interest• Integrated Summary of Safety: Reactogenicity
• Reactogenicity: Europe, US & Canada
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• Randomized 1:1, controlled, open label
• 1º Objective: Non-inferiority immunogenicityRotarix + coads vs. coads alone
• N=484 (1:1)
Month of Age
2 3 4 5 6 7
Co-Ad group
RotarixPediarix PrevnarActHIB
RotarixPediarix PrevnarActHIB
Pediarix PrevnarActHIB
Blood Sample
Serology Testing
Sep-Ad group
Pediarix PrevnarActHIB
Rotarix Pediarix PrevnarActHIB
Rotarix Pediarix PrevnarActHIB
Blood Sample
Serology Testing
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Clinical Trial Data to be PresentedClinical Trial Data to be PresentedEfficacy• Phase III Latin America • Phase III Europe
Immunogenicity• Seroconversion and Vaccine Take• Coadministration with US licensed Vaccines
Safety• Intussusception• Integrated Summary of Safety: SAEs• Events of Clinical Interest• Integrated Summary of Safety: Reactogenicity
• Reactogenicity: Europe, US & Canada
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N=63,225infants age 6-13 weeks
randomized (1:1)
month 0
Placebo N=31,552
Rotarix N=31,673
1st D
ose
2nd D
ose
Month 1-2 Month 2-4Safety
surveillance(N=63,225)
Month 9-10
1 yr Efficacy analysis
(ATPN=17,867)
Routine immunizations were co-administered according to local regulations
Study 023: Phase III Safety & Efficacy Study 023: Phase III Safety & Efficacy Study in Latin America and FinlandStudy in Latin America and Finland
Month 21-22
2 yr Efficacy analysis
(ATPN=14,237)
Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354:11-22
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Placebo groupRotarix group
within 31 days 66 77
Relative Risk = 0.85 (0.30 ; 2.42)
Risk Difference = -0.32 (-2.91 ; 2.18)
99 1616within median 100 days
Cases of IS
Safety cohort N=31,673 Safety cohort N=31,552
Relative Risk = 0.56 (0.25 ; 1.24)
Risk Difference = -2.23 (-5.7 ; 0.94)
Study 023: No Increased Risk of Study 023: No Increased Risk of Intussusception Compared to PlaceboIntussusception Compared to Placebo
A A 7171
A A 7272
A A 7373
A A 7474
A A 7575
Rotarix (RV1) RotaTeq (RV5)
Doses 2 3
Min age 6 wks 6 wks
Max age- 1st dose
20 wks 12 wks
Max age- any dose
24 wks 32 wks
www.cdc.gov/vaccines/recs/provisional/
A A 7676
Rotarix (RV1)
RotaTeq (RV5)
2 3
6 wks 6 wks
20 wks 12 wks
24 wks 32 wks
ACIP Reco
2009--
6 wks
14 wks 6 days*
8 mon 0 days*
Doses
Min age
Max age- 1st dose
Max age- any dose
A A 7777
Rotarix (RV1)
RotaTeq (RV5)
2 3
6 wks 6 wks
20 wks 12 wks
24 wks 32 wks
Latest Latest Rotavirus Vaccines RecommendationsRotavirus Vaccines Recommendations
ACIP Reco
2009--
6 wks
14 wks 6 days*
8 mon 0 days*
Doses
Min age
Max age- 1st dose
Max age- any dose
A A 7878IVIG FFP
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ACIP. MMWRACIP. MMWR 2009;58:(RR-2):1-24. 2009;58:(RR-2):1-24.
A A 8181MMWRMMWR 2009;58:(RR-2):1-24. 2009;58:(RR-2):1-24.
A A 8282
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A A 878787
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A A 9090
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