ROTAVIRUS GE AND ROTAVIRUS VACCINES : UPDATE

Dr Abdulla Al Tuhami Ped Consultant / Cardiologist Riyadh Care Hospital abdulla_tuhami@hotmail.com

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RIYADH CARE HOSPITAL

Nov 2008

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VIRAL AGENTS CAUSING GASTROENTERITIS
1. Rotavirus 2. Enteric adenoviruses 3. Calicivirus 4. Astrovirus

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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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Parashar et al, Emerg Infect Dis 1998 4(4) 561–570 Linhares and Bresee, Pan Am J Public Health 2000 8(5) 305–331 3 Parashar et al, Emerg Infect Dis 2003 9(5) 565–572
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Annual Burden
610,000

Risk by 5th Birthday
1 : 205

Deaths

2.4 million

Hospitalizations Outpatient Visits

1 : 50 1:5 1:1

24 million

114 million

RV Episodes

Glass RI, et al. Lancet 2006;368:323-332

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Annual Burden
20-60

Risk by 5th Birthday
1 : 100,000

Deaths

55,000-70,000

Hospitalizations Outpatient Visits

1 : 80 1:7 4:5

600,000

2.7 million

RV Episodes

Glass RI, et al. Lancet 2006;368:323-332

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Temporal distribution of rotavirus diarrheal cases in children less than 5
Journal of Clinical Microbiology, April 2008, p. 1185-1191, Vol. 46, No.

years of age in Al

Maddina, Saudi Arabia. Maddina

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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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Figure 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% 9% 9% 58% 4% 18%

North America (n=2,892)
2% 3% 11%

Europe (n=17,475)
11% 1% 7% 4% 11% 77%

73%

G1 Type G2 Type G3 Type G4 Type G9 Types Other Types

n= number of RV infections analyzed Santos et al. Rev Med Virol 2005;15:29-56

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GIP8 GIP8 GIP8

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Percent Efficacy
100 90 80 70 60 50 40 30 20 10 0
1 2

moderate to severe diarrhea mild diarrhea asymptomatic infection

One Previous RV infection

Two Previous RV infections

Velazquez et al, N Eng J Med 1996 335 1022–1028 Bernstein DI, et al. JID. 1991; 164(2); 277-83 3 Velazquez et al, J Infect Dis 2000 182 1602–1609

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VS

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Rotavirus Vaccine and Intussusception*
Within 42 days of vaccination Within 1 year of vaccination Vaccine Recipients 6 cases 13 cases Placebo Recipients 5 cases 15 cases

*data shown are for RotaTeq; no increased risk of IS was observed in Rotarix clinical trials. New Eng J Med 2006;354:23-33

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Human rotavirus strain circulating in Cincinnati in 1989 G1P[8] 33 passages in cell culture

Initial Safety and Efficacy studies1 Limiting dilution cloning in Vero cells and further passage in tissue culture

Live-Attenuated Human Rotavirus Vaccine (RIX4414 - Rotarix®)
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Bernstein et al, Lancet, 1999; 354:287-290

G1P[8]

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Summary of Clinical Studies in BLA
Rotarix Rotarix Rotarix 50 >106.0 CCID50 Rotarix 6.0 <10 CCID <106.0 CCID50 3076 >106.037214 50 n= n = CCID n = 3076 n = 37214 Phase II Phase II

Total Exposure = 75029 subjects Total Exposure = 75029 subjects
Placebo Placebo n =34739=34739 n

Phase III III Phase
Immuno, Safety Immuno, Safety
Study 039 Study 039 Thailand Thailand n=174 n=52 n=174 n=52

Efficacy, Safety, Efficacy, Safety, Immuno Immuno
Study Study 004 004 Finland Finland n=270 n=135 n=270 n=135

Safety, Safety, Immuno

Efficacy, Safety (IS), Immuno Efficacy, Safety (IS), Immuno Immuno

Study 005 Study 005 023 Study 023 Study US, Canada Latin America, Finland Finland US, Canada Latin America, n=212 n=209 n=108 n=31673 n=31552

n=31552 n=212n=31673 n=108 n=209

Efficacy, Safety, Efficacy, Safety, Immuno Immuno
Study 006 006 Study Latin America Latin America n = 1139 n=570 n=567

Immuno OPV Immuno OPV Coad, Safety Lot consistency, Coad, Safety Safety, Immuno Immuno Safety,
Study 014 Study 014 033 Study Study 033 S. Africa S. AfricaAmerica America Latin Latin n=297 n=150 n=730 n=124 n=297 n=150 n=730 n=124

Lot consistency,

Immuno US coad Immuno US coad vaccines, Safety vaccines, Safety
Study 060 Study 060 US US n=459 n=459

n = 1139 n=570 n=567

Efficacy, Safety, Efficacy, Safety, Immuno Immuno
Study 007 007 Study Singapore Singapore n = 1158 n=653 n=653

Immuno, Safety

Immuno, Safety, Safety, Efficacy, Efficacy, Safety Immuno Immuno

n = 1158 n=653 n=653

Study Study 048 Study 048 036 Study 036 Europe Finland Europe Finland n=2646 n=1348 n=100 n=50 n=2646 n=1348 n=100 n=50

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Study 023: Phase III Study in Latina & Finland
18 sites in 12 countries ~63,000 infants
Mexico
13245 (20.9%)

Dominican Republic
4056 (6.4%)

Panama Honduras
4195 (6.6%) 4061 (6.4%)

Venezuela
4250 (6.7%)

Nicaragua
4057 (6.4%)

Colombia
3910 (6.2%)

Brazil
3218 (5.1%)

Peru
12044 (19.0%)

Argentina
4671 (7.4%)

Chile
3458 (5.5%)

Finland
2060 (3.3%)

• LA: efficacy & safety • Finland: safety only

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Study 023: Phase III Safety & Efficacy Study in Latin America and Finland
Rotarix N=31,673 N=63,225 infants age 6-13 weeks randomized (1:1) Placebo N=31,552 month 0 Month 1-2 Month 2-4 Safety surveillance (N=63,225) Month 9-10 1 yr Efficacy analysis (ATP N=17,867) Month 21-22 2 yr Efficacy analysis (ATP N=14,237)

Routine immunizations were co-administered according to local regulations

2nd Dose

1st Dose

Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354:11-22

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Efficacy Latin America (Study 023)
Primary Efficacy Objective

To determine if 2 doses of Rotarix can prevent severe RV GE caused by circulating RV strains starting from 2 weeks after dose 2 until 1 year of age

Secondary Efficacy Objectives

• • •

Efficacy against G1 and non-G1 serotypes Efficacy using Vesikari severity scale Efficacy through 2 years of age

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Efficacy Latin America (Study 023)
RV GE Case Definition

“Severe GE”: diarrhea (≥3 loose stools in 24 hrs) with or without vomiting that required hospitalization and/or re-hydration therapy in a medical facility [Clinical Case Definition] RV detection by ELISA Type determination by RT-PCR followed by reverse hybridization assay (or optional sequencing as needed)
– Discrimination between G1 vaccine virus and wild-type G1 RV

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Efficacy Latin America (Study 023)
Efficacy Endpoints

• • • •

Severe RV GE during 1st year efficacy period – Clinical Case Definition Efficacy against RV hospitalizations, all-cause severe GE Type-specific efficacy Second year efficacy

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Efficacy Latin America (Study 023)
From 2 weeks post-dose 2 until 12 months of age (ATP cohort)
100 90 80 70 60 50 40 30 20 10 0

85%
[72;92]

85%
[71;93]

85%
[70;94]

Vaccine efficacy (%)

40%
[28;50]

12V:77P

11V:71P

9V:59P

183V:300P

Severe RV GE Clinical

Severe RV GE Vesikari

RV GE Hospitalization

All-cause Severe GE

randomization 1:1

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Type-specific Efficacy Latin America (Study 023) - severe RV GE
From 2 weeks post-dose 2 until 24 months of age (ATP cohort)
100 90 80 70 60 50 40 30 20 10 0
82%
[65;92]

87% 79%
[25;96] [73;94]

Vaccine efficacy (%)

62%
[4;87]

39%*
[-112;84]

10V:55P

5V:8P

3V:14P+

7V:18P

9V:66P

G1P[8]
+

G2P[4]

G3P[8]

G4P[8]

G9P[8]

one episode was P[6]

*Not statistically significant

randomization 1:1

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Study 036: Phase III Study in Europe 124 Sites in 6 EU Countries ~4000 Infants

Finland 74%

France 3.7% Spain 7.5%

Germany Czech 7% Republic 7.5% Italy 0.6%

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Study 036: Phase III Safety & Efficacy Study in Europe
Rotarix N=2,646 N=3,994 infants age 6-14 wks randomized (2:1) Placebo N=1,348 Month 0 Months 1–2 Months 7-9 Season 1 Efficacy analysis (ATP N=3,874) Months 19-21 Season 2 Efficacy analysis (ATP N=3,848)

Co-administered with DTaP-HepB-IPV/Hib (all), PCV7 (subset), MenC (subset)

2nd dose

1st dose

Vesikari T et al. Lancet 2007;370:1757-63

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Efficacy Europe (Study 036)
Primary Efficacy Objective

To determine if 2 doses of Rotarix can prevent any RV GE caused by circulating RV strains starting from 2 weeks after dose 2 until end of the first RV season post-vaccination

Secondary Efficacy Objectives

• • • • •

Efficacy against severe RV GE Efficacy against G1 and non-G1 serotypes Efficacy against RV hospitalizations Efficacy against medically-attended RV GE Efficacy through 2 RV seasons post-vaccination

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Efficacy Europe (Study 036)
RV GE Case Definition

• • • •

GE: diarrhea (≥3 loose stools in 24 hrs) with or without vomiting Severity assigned using Vesikari scale; score ≥11 = “severe” RV detection by ELISA Type determination by RT-PCR followed by reverse hybridization assay (or optional sequencing as needed)
– Discrimination between G1 vaccine virus and wild-type G1 RV

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Efficacy Europe (Study 036)
Efficacy Endpoints

• • • • •

Any and Severe RV GE during 1st RV season Efficacy against RV hospitalizations, medically-attended RV, all-cause GE hospitalizations Type-specific efficacy Second RV season efficacy Efficacy from dose 1 to dose 2

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Efficacy Europe (Study 036)
From 2 weeks post-dose 2 until end of the 1st RV season (ATP cohort)
96%
100 90

100%
[82;100]

87%
[80;92]

[90;99]

92%
[84;96]

Vaccine efficacy (%)

80 70 60 50 40 30 20 10 0 Any RV GE Severe RV GE RV GE Hosp Medicallyattended RV GE
24V:94P 5V:60P 0V:12P 10V:62P

75%
[46;89]

11V:22P

All-cause GE Hosp

randomization 2:1

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Efficacy Europe (Study 036)
From Dose 1 up to before Dose 2 (Total Vaccinated Cohort) Rotarix prevents RV GE as early as dose 1
100 90

100%
[-23;100]

90%
[9;100]

Vaccine efficiacy (%)

80 70 60 50 40 30 20 10 0 Any RV GE Severe RV GE
1V:5P 0V:3P

TVC = all subjects who received at least one dose regardless of protocol adherence randomization 2:1

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Type-specific Efficacy Europe (Study 036) - Severe RV GE
From 2 weeks post-dose 2 until end of the 2nd RV season (ATP cohort)
100 90

96%
[90;99]

94% 86%
[24;99] [53;100]

95%
[68;100]

85%
[72;93]

Vaccine efficacy (%)

80 70 60 50 40 30 20 10 0
4V:57P 2V:7P* 1V:8P 1V:11P 13V:44P+

G1P[8]

G2P[4]

G3P[8]

G4P[8]

G9P[8]

* P genotype not typable for one episode, + P[8] genotype not detected for one episode

randomization 2:1

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Summary 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 Presented
Efficacy • 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 immunogenicity •
Rotarix + coads vs. coads alone N=484 (1:1)
2 Co-Ad group Rotarix Pediarix Prevnar ActHIB Pediarix Prevnar ActHIB Rotarix 3

Month of Age 4 5 Rotarix Pediarix Prevnar ActHIB Pediarix Prevnar ActHIB Rotarix

6 Pediarix Prevnar ActHIB

7 Blood Sample Serology Testing Blood Sample Serology Testing

Sep-Ad group

Pediarix Prevnar ActHIB

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Clinical Trial Data to be Presented
Efficacy • 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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Study 023: Phase III Safety & Efficacy Study in Latin America and Finland
Rotarix N=31,673 N=63,225 infants age 6-13 weeks randomized (1:1) Placebo N=31,552 month 0 Month 1-2 Month 2-4 Safety surveillance (N=63,225) Month 9-10 1 yr Efficacy analysis (ATP N=17,867) Month 21-22 2 yr Efficacy analysis (ATP N=14,237)

Routine immunizations were co-administered according to local regulations

2nd Dose

1st Dose

Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354:11-22

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Study 023: No Increased Risk of Intussusception Compared to Placebo
Rotarix group
Safety cohort N=31,673
Cases of IS within 31 days

Placebo group
Safety cohort N=31,552

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Relative Risk = 0.85 (0.30 ; 2.42) Risk Difference = -0.32 (-2.91 ; 2.18)

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within median 100 days

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Relative Risk = 0.56 (0.25 ; 1.24) Risk Difference = -2.23 (-5.7 ; 0.94)

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Events of Clinical Interest
Clinical Event Reason for Interest Reports with RotaShield RotaTeq US Package Insert RotaTeq US Package Insert RotaTeq US Package Insert Imbalance in single study (Rota-023) Imbalance in single study (Rota-023) Imbalance in single study (Rota-036) Imbalance in single study (Rota-006)

Hematochezia Kawasaki disease Convulsion Pneumonia deaths Pneumonia Bronchitis

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Events of Clinical Interest: Core ISS Within 31 Days of Any Dose
Adverse Event (MedDRA PT) Hematochezia SAE Kawasaki disease Convulsion SAE Pneumonia deaths Pneumonia SAE Bronchitis SAE Rotarix N=36,755 n (%) 0 0 9 (0.02%) 7 (0.02%) 122 (0.33%) 21 (0.06%) Placebo N=34,454 n (%) 0 0 7 (0.02%) 5 (0.01%) 122 (0.35%) 24 (0.07%) 1.18 (0.39 – 3.76) 1.39 (0.38 – 5.57) 0.99 (0.76 – 1.28) 0.85 (0.45 – 1. 59) Relative Risk (95% CI)

Relative Risk adjusted for study effect

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Rotarix (RV1) Doses Min age Max age- 1st dose Max age- any dose 2 6 wks 20 wks 24 wks

RotaTeq (RV5) 3 6 wks 12 wks 32 wks

www.cdc.gov/vaccines/recs/provisional/

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Rotarix (RV1) Doses Min age Max age1st dose Max ageany dose 2 6 wks 20 wks 24 wks

RotaTeq (RV5) 3 6 wks 12 wks 32 wks

ACIP Reco 2009 -6 wks 14 wks 6 days* 8 mon 0 days*

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Latest Rotavirus Vaccines Recommendations
Rotarix (RV1) Doses Min age Max age1st dose Max ageany dose 2 6 wks 20 wks 24 wks RotaTeq (RV5) 3 6 wks 12 wks 32 wks ACIP Reco 2009 -6 wks 14 wks 6 days* 8 mon 0 days*

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IVIG

FFP

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ACIP. MMWR 2009;58:(RR-2):1-24.

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• Altered immunocompetence • Recent receipt of blood product
• Acute, moderate to severe gastroenteritis
or other acute illness

Rotavirus Vaccine Precautions*

• Pre-existing chronic GI disease • Infants with history of intussusception

*the decision to vaccinate if a precaution is present should be made on a case-by-case risk and benefit basis

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MMWR 2009;58:(RR-2):1-24.

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