Alternative Rotavirus Vaccine Candidates: Why should we bother? Duncan Steele Initiative for Vaccine Research, WHO 7 th International Rotavirus Symposium 12-13 June 2006, Lisboa, Portugal
Rotavirus Vaccines in 2006
UN Millennium Development Goals Goal #4: Reduce child mortality Target: Reduce by two thirds, between 1990 and 2015, the under-five mortality rate (U5MR) Indicators: 13 Under-five mortality rate 14 Infant mortality rate http://www.who.int/mdg
10.5m early childhood (<5y) deaths World Health Report (Annex table 2, unpublished data for 2002) 2004 and The Lancet, 2003; 361:226-34. 10 countries account for 6,7 million (>60%) of childhood deaths 42 countries account for 90%
Global Mortality of Rotavirus Infection Each dot = 1,000 deaths Parashar et al, EID. 2005
Millennium Development Goals
Rotavirus Vaccine Introduction Rotarix vaccine introduction in Latin America Brazil, Panama, Venezuela: Price of approx $7 per dose for public health use Prices in private market though: approx 90 per dose in France > 120 per dose in Austria Roger Glass, personal communication RotaTeq vaccine introduction in USA: Price of $62.50 per dose
Traditional Vaccine Market Development Private Market Low vol High price Low vol High price Mid vol Mid price High Vol Low price capacity $ time R&D clinical manufacture Adapted from W. Vandersmissen, Vaccine 19, 2001
Public Sector needs: Rapid high capacity and "mature" price Private Market High Vol Low price Efficiency gained Fund research & clinical studies capacity Help create market $ time R&D clinical manufacture
Million doses 200 The Challenge: The Lessons from hepatitis B and Hib vaccines HepB -- all developing countries 150 100 50 0 HepB available in the US The Vaccine Fund established Asian producers enter market 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 GAVI forecasts* HepB -- all developing countries, excluding India, China, Indonesia Hib all developing countries
Capacity and Price Industrialised country manufacturers Emerging manufacturers Capacity Market Emerging manufacturers can contribute to: needed capacity (not necessarily always at lower prices) early "maturity" of price (which in turn could increase demand)
Rotavirus Vaccine Strains Upstream Rotavirus Vaccines Meeting Meeting in Geneva, 28-30 March 2006 Vaccine Manufacturers GSK Bio and Merck Emerging Vaccine Manufacturers Rotavirus Vaccine Developers Regulatory authorities Rotavirus experts
Other Candidate Live Oral RV Vaccines Vaccine Name Company Strain(s) Lanzhou Lamb LLR Lanzhou Biologicals, China G10,P[12] LLR reassortants LLR + Kantai, China G10,P[12] reassort Indian Neonatal 116E Bharat Biotech Ltd, India G9, P[11] Australian RV3 QIMR/ Biofarma, Indonesia G2, P[6] neonatal Rhesus TV RRV-TV BIOVIRx / IDT, Germany Rhesus + G1,G2, G4 NIH Bovine Reassortant UK Butantan, Brazil Wuhan, Chengdu, China Serum Institute, Shanta Biologicals E, Bharat, India Bovine + G1,G2,G3, G4, ++ reassortant
The Return of RotaShield? Vaccine master seeds, dossiers, licenses acquired by BIOVIRx from Wyeth/NIH New safety figures suggested by re-analysis of IS - significantly lower than reported (~1 in 32,000) Most widely studied RV vaccine with full FDA regulatory profile/strains etc IDT- Tornau Germany, partner to produce pilot lots of vaccine Targeting clinical trials in the developing world Seeking FDA licensure Len Ruiz, Geneva, March 2006
Lanzhou Lamb Rotavirus (LLR) Lamb rotavirus - G10P[12] strain Licensed in China, 2000 >1,00,000 doses have been administered Single oral dose regimen Given to children up to 10 years of age ~$16 per dose in private market International concerns about safety This vaccine is not pre-qualified (GMP) Randomised, double-blinded efficacy trial is required (GCP) Lanzhou Institute plans to develop a reassortant lamb vaccine candidate (Bai et al, Beijing. October, 2003)
Bovine-human Rotavirus Reassortant Vaccine Developed by Al Kapikian, NIAID Tetravalent vaccine tested in Finland Less reactogenic than RRV-TV Efficacy comparable to RRV-TV Courtesy R Glass Possible designer vaccine for different strains Suggested neonatal immunizations Licensed by NIH to 7 companies/3 countries J Infect Dis. 2005 Sep 1;192 Suppl 1:S22-9.
Reassortant bovine-human rotavirus UK Bovine-human rotavirus reassortant strain (UK G6P[7]) Quadrivalent reassortant vaccine (with human rotavirus VP7 genes for G1-G4) Safe and non-reactogenic in phase I trials Satisfactory immunogenicity in phase II trials (Clements-Mann et al, Vaccine 1999; 17: 2715-25) Immunogenicity trial in infants administered concomitantly with childhood vaccines Safe and well tolerated after 3 doses at 10 5 ffu Non-inhibitory to other routine childhood vaccine immune responses 95% of infants developed serum neutralizing antibody responses (Clements-Mann et al, Vaccine 2001; 19: 4676-84)
Human Neonatal Strain (RV3) Courtesy G Barnes RV3 neonatal strain Naturally attenuated strain in maternity units Infants followed for 3 years Protected against rotavirus disease G3P[6] - both human rotavirus immunogens Clinical trials with neonatal rotavirus Safe, but low immunogenicity Infants who sero-converted were protected in following year (Barnes et al, Vaccine, 2002) Further development of pilot lots at higher viral concentration with QIMR and transfer to Vero approved cell line Further development as a vaccine candidate with a local manufacturer in Indonesia (BioFarma)
Bovine-human rotavirus reassortant neonatal strains Bovine-human rotavirus reassortant strains (116E, I321) Naturally occurring strains in India Bovine / human rotavirus reassortants Collaboration between CDC & Stanford, USA and AIIMS & Bharat BioTech in India to develop this candidate for Indian sub-continent Development funded by PATH
Bovine-human rotavirus reassortant neonatal strains Phase I trial in Cincinnati 30 adults, 10 5 ffu of I321, 116E or placebo no virus shedding 2 x seroconversion (both 116E) 2 x mild diarrhoea 30 children 2-12 years 1 x virus shed 4 x seroconversion (all 116E) Glass et al JID 2005:192 (Suppl 1)
Parenteral Rotavirus Vaccines VP6 vaccine candidate (Dick Ward) VP7 VP4 VP6 Virus like particles (Margaret Conner) VP2 Inactivated approach (Baoming Jiang)
WHO Meeting Recommendations General recommendation that each candidate should be taken forward for clinical evaluation Minimum standard of global expectations for rotavirus vaccine clinical development to ensure that there is not a potential spill over effect of "unforeseen" problems or R&D processes Solid phase I and II development programmes encouraged to ensure international compliance Encourage development of inactivated approaches Recognise that there are National and Institutional prerogatives for rotavirus vaccine R&D Role of WHO DCVMN and DCVRN to alert, influence and assist the R&D process and ultimately prequalification
Rotavirus Vaccines Future Introduction and the MDG