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.

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

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.

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

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

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

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

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™

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October 1998 August 1998 CDC presents data confirming association with intussusception Universal recommendation rescinded Vaccine withdrawn from market

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.

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)

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

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.

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.

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

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

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

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

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

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

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

Rotarix Phase III Study in Latin America & Finland Primary Immunization Phase: Analysis of Intussusception & Safety N: >63.000 infants 1-Year follow-up : Nested Analysis of Efficacy & Safety N: >20.000 infants Ruiz-Palacios et al. NEJM 2006;354:11-22

Intussusception: Rotarix Compared with Rotashield Dose 1 V, Vaccine P, Placebo IS cases V P V P P P P P P V 75 83 Dose 2 V P IS cases V P V V P P P P P P V P 107 145 Murphy TV, et al. N Engl J Med. 2001;187:1309-1313. Ruiz-Palacios et al. NEJM 2006;354:11-22

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

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.

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 2007-2008

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