1. Rotavirus Vaccines An Update
Penelope H. Dennehy, MD
Director
Division of Pediatric Infectious Diseases
Hasbro Children’s Hospital
Professor of Pediatrics
Brown Medical School
Providence, RI.

2. Background
Rotavirus is the most common cause of severe diarrhea in infants and young children worldwide
Nearly all children infected by age 5 years
Universal morbidity from rotavirus supports vaccination as the primary public health intervention to prevent rotavirus gastroenteritis

3. Rotavirus Structure
Double-layered outer shell around a central core of segmented double stranded RNA
Outer layer made of VP7 and VP4 proteins
VP7 determines G-serotype
VP4 determines P-serotype
VP7 and VP4 are important for immunity
VP4
(P serotype)
VP6
VP7
(G serotype)
Figure adapted from Estes MK. J Infect Dis. 1996;174(Suppl 1):S37-S46.

4. Prevalent Strains of Rotavirus Among Children <5yrs in the US, 1996-1999

5. Natural Immunity and Rotavirus Gastroenteritis
Many children infected more than once
First infections more likely to result in severe gastroenteritis
Protective immunity
develops after natural infection
strongest against moderate-to-severe disease
Serologic correlates of immunity have not been established

6. Goals for a Rotavirus Vaccine
To duplicate the degree of protection that follows natural infection
To prevent moderate-to-severe disease but not mild disease from rotavirus
To reduce the disease burden
To provide vaccine in developing countries where rotavirus mortality is high

7. Vaccine Development Approaches
Monovalent animal rotavirus vaccines
Multivalent human−animal reassortant vaccines
Attenuated human strains

8. Multivalent Human-Animal Reassortant Vaccines
Vaccines contain genes from an animal parent virus and VP4 and/or VP7 gene from human strain
Simian-based vaccines - Rotashield®
Bovine-based vaccines - RotaTeq™

9. Rotashield Story
CDC reports preliminary data suggesting association with intussusception
FDA approves Rotashield
October 1998
August 1998
CDC presents data confirming association with intussusception
Universal recommendation rescinded
Vaccine withdrawn from market

10. Rotavirus Vaccine and Intussusception CDC Case Control Study
Interval Between Vaccination and Intussusception (N=74)
CDC, Centers for Disease Control.
Reprinted with permission from Murphy TV, et al. N Engl J Med. 2001;20:410.

11. Bovine Rotavirus Vaccine RotaTeq®
Contains 5 human−bovine reassortants
Given as 3 oral doses at 2, 4, and 6 months of age
RotaTeq was efficacious and generally well tolerated in Phase 2 studies
Rotavirus Efficacy and Safety Trial (REST)

12. 70,301 subjects were randomized in 11 countries
REST Study
70,301 subjects were randomized in 11 countries
Germany
Belgium
Finland
United States
Puerto Rico
Jamaica
Navajo &
White Mt.
Apache Nations
Sweden
Taiwan
Mexico
Guatemala
Costa Rica
Italy

13. REST Endpoints Safety Cohort All Subjects N=69,274 Safety Sub-study
Efficacy Sub-study
N=5686
All serious adverse experiences including intussusception and hospitalization emergency visits for rotavirus acute gastroenteritis
All adverse experiences (serious and nonserious)
Efficacy against and office visits for rotavirus acute gastroenteritis
Vesikari T, et al. N Engl J Med. 2006;354:23-33.

14. REST: Confirmed Intussusception Cases - 42-Day Period After Any Dose 6 Vaccine : 5 Placebo
RR=1.6
95% CI=0.4, 6.4
Vesikari T, et al. N Engl J Med. 2006;354:23-33.

15. Subjects with Any Gastrointestinal Illness Within 42 Days After Any Vaccination
Vesikari T, et al. N Engl J Med. 2006;354:23-33.

16. Efficacy of RotaTeq: Disease Severity
Number of Cases
Disease
Severity
% Efficacy
95% CI
Vaccine
Placebo
Any
Severe 82 1
315 51
74.0
98.0
66.8,79.9
88.3,100.0
Vesikari T, et al. N Engl J Med. 2006;354:23-33

17. Efficacy of RotaTeq: Serotype Specific Against Rotavirus Disease of Any Severity
Number of Cases
% Efficacy
95% CI
Serotype
Vaccine
Placebo G1 G2 G3 G4 G9 72 6 1 3
286 17 6 3
74.9
63.4
82.7
48.1
65.4
67.3,80.9
2.6,88.2
<0.0,99.6
<0.0,91.6
<0.0,99.3
Vesikari T, et al. N Engl J Med. 2006;354:23-33

18. Efficacy of RotaTeq: Reduced Health Care Contacts for Rotavirus Gastroenteritis
Type of Health Care
Contact
Number of Cases
% Rate
Reduction
Vaccine
Placebo
95% CI
Hospitalizations
Emerg. Dept. Visits
Office Visits 6 13
138
191 99
95.8
93.7
86.0
90.5, 98.2
88.8, 96.5
73.9,92.5
Vesikari T, et al. N Engl J Med. 2006;354:23-33

19. RotaTeq Availability Licensed in the US - February 3, 2006
ACIP recommendations - February 21, 2006
Applications for license
Australia
Canada
European Union
Mexico
Parts of Asia
Parts of Latin America

20. Attenuated Human Rotavirus Vaccine Rotarix®
G1, P1A[8] human virus attenuated by passage through cell culture
Shares neutralizing epitopes with G1, G3, G4, and G9 RV types
Two oral doses from 6 weeks of age a minimum of 4 weeks apart
Rotarix was efficacious and generally well-tolerated in several small efficacy studies

21. Rotarix: Phase 1−3 Studies Worldwide
Mexico
Panama
Costa Rica
Venezuela
Brazil
Honduras
Nicaragua
Dominican Rep.
Colombia
Peru
Chile
Argentina
South Africa
Singapore
Bangladesh
Hong Kong
Taiwan
Thailand
India
Korea
Belgium
Germany
Finland
USA
Canada
Check Republic
France
Spain
Italy

22. Rotarix Phase III Study in Latin America & Finland
Primary Immunization Phase:
Analysis of Intussusception & Safety
N: > infants
1-Year follow-up : Nested Analysis of Efficacy & Safety
N: > infants
Ruiz-Palacios et al. NEJM 2006;354:11-22

23. Intussusception: Rotarix Compared with Rotashield
Dose 1
V, Vaccine
P, Placebo
IS cases V P V P P P P P P V
Dose 2 V P
IS cases V P V V P P P P P P V P
Murphy TV, et al. N Engl J Med. 2001;187:
Ruiz-Palacios et al. NEJM 2006;354:11-22

24. Efficacy of Rotarix: Gastroenteritis in Latin America
Disease Severity
Cases, N
% Efficacy
95% CI
Vaccine (N=9009)
Placebo (N=8858)
Severe 12 77
84.7
71.7, 92.4
Hospitalizations 9 59
85.0
69.6, 93.5
Ruiz-Palacois GM, et al. N Engl J Med. 2006;354:11-22

25. Efficacy of Rotarix: Serotype Specific Against Rotavirus Disease of Any Severity
Cases, N
% Efficacy
95% CI
Vaccine (N=9009)
Placebo (N=8858) G1 3 36
91.8
74.1, 98.4 G2 1 6
41.0
<0.0, 82.4
G3, G4 or G9 4 31
87.3
64.1, 96.7
Ruiz-Palacois GM, et al. N Engl J Med. 2006;354:11-22.

26. Rotarix Summary
Licensing concentrated in areas of the world where rotavirus results in high morbidity and mortality
Licensed in Mexico (2004) and 17 other countries
Will be licensed in European Union in 2006
Licensure in the US expected in

27. Summary
Rotavirus prevention efforts were setback by the withdrawal of Rotashield
New safe and effective rotavirus vaccines offer the best hope of reducing the toll of acute rotavirus gastroenteritis in developed and developing countries
RotaTeq and Rotarix have demonstrated safety and efficacy in controlled clinical trials