Rotavirus Ge And Rv Vaccine Ppt

ROTAVIRUS GE AND ROTAVIRUS VACCINES : UPDATE

Dr Abdulla Al Tuhami Ped Consultant / Cardiologist Riyadh Care Hospital [email protected]

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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

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 1

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Annual Burden

Risk by 5th Birthday

610,000

2.4 million

24 million

114 million

Deaths

1 : 205

Hospitalizations Outpatient Visits

RV Episodes

1 : 50 1:5 1:1

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

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Annual Burden

Risk by 5th Birthday

20-60

Deaths

55,000-70,000

Hospitalizations

600,000

Outpatient Visits

2.7 million

RV Episodes

1 : 100,000

1 : 80 1:7 4:5

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

Maddina, Maddina 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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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%

North America (n=2,892) 2%

18%

3% 11% 73%

Europe (n=17,475) 11% 1%

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

7% 4%

77%

11%

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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moderate to severe diarrhea mild diarrhea asymptomatic infection

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

One Previous RV infection

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

Two Previous RV infections

1 2

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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

Placebo Recipients 5 cases

13 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®) Bernstein et al, Lancet, 1999; 354:287-290

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G1P[8]

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Summary of Clinical Studies in BLA Total Exposure ==75029 subjects Total Exposure 75029 subjects

Rotarix Rotarix<10Rotarix Rotarix 6.0 6.0 CCID50 >106.0 CCID50 6.0 <10 CCIDn50= 3076 >10 CCID50 n = 37214 n = 3076 n = 37214 Phase II Phase II

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

n=135

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

n = 1139 n=570 n=567

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

n = 1158 n=653 n=653

Placebo Placebo n =34739 n =34739

PhasePhase III III

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

Safety, Safety, Immuno

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

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

Lot consistency,

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

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

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

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

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

n=2646n=50 n=1348 n=100

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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 4061 (6.4%)

Honduras 4195 (6.6%)

Venezuela 4250 (6.7%)

Nicaragua 4057 (6.4%)

Brazil

Colombia

3218 (5.1%)

3910 (6.2%)

Peru Argentina

12044 (19.0%)

4671 (7.4%)

Chile 3458 (5.5%)

• LA: efficacy & safety • Finland: safety only

Finland 2060 (3.3%)

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Study 023: Phase III Safety & Efficacy Study in Latin America and Finland

1st Dose

2nd Dose

Rotarix N=31,673

month 0

Month 1-2

N=63,225 infants age 6-13 weeks randomized (1:1) Placebo N=31,552

Month 2-4 Safety surveillance (N=63,225)

Month 9-10

Month 21-22

1 yr Efficacy analysis (ATP N=17,867)

2 yr Efficacy analysis (ATP N=14,237)

Routine immunizations were co-administered according to local regulations

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

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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

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“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]

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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

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Severe RV GE during 1st year efficacy period – Clinical Case Definition

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Efficacy against RV hospitalizations, all-cause severe GE Type-specific efficacy Second year efficacy

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Efficacy Latin America (Study 023)

Vaccine efficacy (%)

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%

85%

85%

[72;92]

[71;93]

[70;94]

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

Vaccine efficacy (%)

From 2 weeks post-dose 2 until 24 months of age (ATP cohort) 100 90 80 70 60 50 40 30 20 10 0

+

87%

82%

[73;94]

79%

[65;92]

[25;96]

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

1st dose

2nd dose

Rotarix N=2,646

Month 0

Months 1–2

N=3,994 infants age 6-14 wks randomized (2:1) Placebo N=1,348

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)

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

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Efficacy Europe (Study 036) Primary Efficacy Objective

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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

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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

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GE: diarrhea (≥3 loose stools in 24 hrs) with or without vomiting

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Severity assigned using Vesikari scale; score ≥11 = “severe”

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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

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Any and Severe RV GE during 1st RV season

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Type-specific efficacy

Efficacy against RV hospitalizations, medically-attended RV, all-cause GE hospitalizations 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)

Vaccine efficacy (%)

96% 100

87%

90

[80;92]

[90;99]

100% [82;100]

92% [84;96]

75%

80

[46;89]

70 60 50 40 30 20 10

24V:94P

5V:60P

0V:12P

10V:62P

11V:22P

Medicallyattended RV GE

All-cause GE Hosp

0 Any RV GE

Severe RV GE RV 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

Vaccine efficiacy (%)

90

90%

100% [-23;100]

[9;100]

80 70 60 50 40 30 20 10

1V:5P

0V:3P

Any RV GE

Severe RV GE

0

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

96% [90;99]

Vaccine efficacy (%)

90

94% 86%

[53;100]

95% [68;100]

85%

[24;99]

[72;93]

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

Sep-Ad group

Pediarix Prevnar ActHIB

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Month of Age 4 5 Rotarix Pediarix Prevnar ActHIB

Rotarix

Pediarix Prevnar ActHIB

Rotarix

6

7

Pediarix Prevnar ActHIB

Blood Sample Serology Testing

Pediarix Prevnar ActHIB

Blood Sample Serology Testing

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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

1st Dose

2nd Dose

Rotarix N=31,673

month 0

Month 1-2

N=63,225 infants age 6-13 weeks randomized (1:1) Placebo N=31,552

Month 2-4 Safety surveillance (N=63,225)

Month 9-10

Month 21-22

1 yr Efficacy analysis (ATP N=17,867)

2 yr Efficacy analysis (ATP N=14,237)

Routine immunizations were co-administered according to local regulations

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

Cases of IS within 31 days

Rotarix group

Placebo group

Safety cohort N=31,673

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) 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

Hematochezia

Reports with RotaShield RotaTeq US Package Insert

Kawasaki disease

RotaTeq US Package Insert

Convulsion

RotaTeq US Package Insert Imbalance in single study (Rota-023)

Pneumonia deaths

Imbalance in single study (Rota-023)

Pneumonia

Imbalance in single study (Rota-036)

Bronchitis

Imbalance in single study (Rota-006)

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Events of Clinical Interest: Core ISS Within 31 Days of Any Dose Rotarix

Placebo

N=36,755

N=34,454

n (%)

n (%)

Hematochezia SAE

0

0

-

Kawasaki disease

0

0

-

Convulsion SAE

9 (0.02%)

7 (0.02%)

1.18 (0.39 – 3.76)

Pneumonia deaths

7 (0.02%)

5 (0.01%)

1.39 (0.38 – 5.57)

Pneumonia SAE

122 (0.33%)

122 (0.35%)

0.99 (0.76 – 1.28)

Bronchitis SAE

21 (0.06%)

24 (0.07%)

0.85 (0.45 – 1. 59)

Adverse Event (MedDRA PT)

Relative Risk adjusted for study effect

Relative Risk (95% CI)

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Rotarix (RV1)

RotaTeq (RV5)

2

3

Min age

6 wks

6 wks

Max age- 1st dose

20 wks

12 wks

Max age- any dose

24 wks

32 wks

Doses

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

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Rotarix (RV1)

RotaTeq (RV5)

2

3

ACIP Reco 2009 --

Min age

6 wks

6 wks

6 wks

Max age1st dose

20 wks

12 wks

14 wks 6 days*

Max ageany dose

24 wks

32 wks

8 mon 0 days*

Doses

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Latest Rotavirus Vaccines Recommendations Rotarix (RV1)

RotaTeq (RV5)

2

3

ACIP Reco 2009 --

Min age

6 wks

6 wks

6 wks

Max age1st dose

20 wks

12 wks

14 wks 6 days*

Max ageany dose

24 wks

32 wks

8 mon 0 days*

Doses

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IVIG

FFP

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

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Rotavirus Vaccine Precautions*

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

• 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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