A A 11

Dr Abdulla Al Tuhami

Ped Consultant / Cardiologist

Riyadh Care Hospital

abdulla_tuhami@hotmail.com

ROTAVIRUS GE AND ROTAVIRUS ROTAVIRUS GE AND ROTAVIRUS VACCINES : UPDATEVACCINES : UPDATE

A A 22

A A 33

RIYADH CARE HOSPITAL

Nov 2008

A A 44

VIRAL AGENTS CAUSINGVIRAL AGENTS CAUSINGGASTROENTERITISGASTROENTERITIS

1. Rotavirus

2. Enteric adenoviruses

3. Calicivirus

4. Astrovirus

A A 55

A A 66

A A 77

A A 88

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

A A 99

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

A A 1010

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

A A 1111

A A 1212

A A 1313

A A 1414

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.

A A 1515

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

A A 1616

A A 1717

A A 1818Figure adapted from Cunliffe et al, Lancet 2002;359:640–642

A A 1919

Share cross reactive epitopes

A A 2020

A A 2121

A A 2222

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

A A 2323

A A 2424

GIP8GIP8GIP8GIP8

A A 2525

A A 2626

A A 2828

A A 2929

A A 303030

A A 3131

A A 3232

A A 3333

A A 3434

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

A A 3535

A A 3636

VS

A A 3737

A A 3838

A A 4040

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]

A A 4141

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

A A 4242

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

A A 4343

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

A A 4747

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

A A 4848

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

A A 4949

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%

A A 5050

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

A A 5454

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

A A 5555

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

A A 5656

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

A A 5757

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

A A 5858

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

A A 5959

A A 6060

A A 6161

A A 6262

• 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

A A 6464

A A 6565

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

A A 6666

A A 6767

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

A A 6868

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

A A 7979

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

A A 8383

A A 878787

A A 888888

A A 9090

A A 9191

A A 9292

A A 9494

A A 959595