The Pediatric Dengue Vaccine Initiative (PDVI) Thailand, 2007
The Vaccine Enterprise-the the disease Clinical data Surveillance data Laboratory data/diagnostics Input, analysis and reporting
The Vaccine Enterprise-the the disease Clinicians/care givers Epidemiologists Statisticians Data monitors Outreach workers Health educators Health communicators Public health workers
The Vaccine Enterprise-the the products Diagnostics Vaccines
Vaccine Enterprise-the the products Scientists Product developers/distributors Regulators Policy makers Public health officials Communities/media Individuals
Dengue Burden 2.5-3 billion people (40% of the world) at risk of infection An estimated 50 and 100 million cases of dengue fever occur annually 250,000 and 500,000 people develop DHF and DSS each year 20,000 deaths each year
Dengue en Puerto Rico, 1963-2003 Casos (x10 3 ) 30 25 20 15 10 DEN-3 DEN-2 DEN-2,?3 DEN-3 DEN-1 DEN-4 DEN-1,2,4 DEN-3, 2 60 50 40 30 20 5 10 0 0 1963 1967 1971 1975 1979 1983 1987 1991 1995 1999 2003 Casos Tasa/1000 Casos DH positivos por lab
Age group-specific dengue incidence by year, Puerto Rico 1999-2003 1.4 1.2 IncidenceX1000 Lab-positive cases 1 0.8 0.6 0.4 0.2 0 00-00 01-04 05-09 10-14 15-19 20-24 25-34 35-44 45-54 55-59 60-64 65-74 75-84 85-99 Agegroup 1999 2000 2001 2002 2003
Dengue cases by age, Ratchaburi Province, Thailand, 2003-2005 2005 120 100 patients 80 60 40 20 0 < 1 y 1-4 y 5-9 y 10-14 Y > 15 y 2003 1 23 87 96 88 2004 5 18 75 99 50 2005 1 22 88 103 58
Dengue Virus Infection Infection Incidence 1-5% / year Asymptomatic 75% Symptomatic 25% Major cause of febrile illness in endemic areas Dengue Fever 98-99% DHF/DSS 1-2% High morbidity, relatively low Vaccine 2002; 3043-3046 mortality disease Survive Death 0.5-5%
Dengue Cost of Illness: Preliminary Data Costs were expressed in 2005 international dollars (I$) to adjust for purchasing power parity Ambulatory patient Mean total cost per case I$514 (SD $601) Range: I$158 (Guatemala) I$699 (Brazil) Hospitalized patients Mean total cost per case I$1491 (SD $1052) Range: I$752 (Guatemala) I$2182 (Thailand)
Some Background Formed in late 2001 at a meeting in Ho Chi Minh City, Vietnam 2001-2006 2006 Rockefeller Foundation funding (~$1.7 million) July 2003 5-year grant from Bill and Melinda Gates Foundation for $55 million A product development partnership (PDP) Program of International Vaccine Institute (IVI) Vaccine 2002; 3043-3046
PDVI Mission To accelerate evaluation and introduction of dengue vaccine for use in developing countries Measure of Success Introduce dengue vaccine into national immunization program of at least one developing country in each dengue endemic region
Strategic Plan www.pdvi.org
PDVI Program Directions The Vaccine Pathway Discovery Evaluation (Development) Introduction (Distribution) PDVI Programs Strategic Partnerships Supportive R&D Vaccine Evaluation Vaccine Access
The Programs
Strategic Partnerships Partnerships with both public and private institutions Portfolio of vaccines
Public and Private Sector Partnerships Private Sector Vaccine manufacturers Biologicals E Butantan GlaxoSmithKline Hawaii Biotech InViragen Panacea sanofi pasteur Shantha Biotechnics Diagnostics Standard Diagnostics, Korea Pentax,, Japan Pan Bio, Australia Public Sector World Health Organization Initiative for Vaccine Research (IVR) Special Programme in Tropical Disease Research (TDR) Developing Country Vaccine Regulators Network (DCVRN) US Department of Defense US Centers for Disease Control and Prevention Novartis Institute of Tropical Diseases
The PDVI Vaccine Portfolio Developer WRAIR Acambis Commercial Partner Live Attenuated GSK Sanofi Pasteur Approach Cell culture passage 17D Yellow fever Dengue chimera NIH / LID CDC Hawaii Biotech Biological E Butantan Panacea InViragen / Shantha Subunit Hawaii Biotech Dengue 4-4 dengue chimeras or attenuation by gene deletion Dengue 2 - dengue chimeras and attenuated dengue 2 Envelope + NS1 recombinant proteins
Where are we Today with Dengue Vaccines?
Status of Dengue Vaccines- 2007 5 candidates different vaccine types Phase 2 trials 2 vaccines GlaxoSmithKline sanofi pasteur Phase 1 trials NIH vaccine v Pre-clinical 2 vaccines Hawaii Biotech InViragen / Shantha No large-scale proof of concept trials
Estimated Dengue Vaccine Timeline 2005 2006 2007 2008 2009 2010 2011 2012 Expanded Phase 2 trials children and adults Preparations for Phase 3 trials Asia, Americas Phase 3 / 2b Clinical Trials Phase 3b Phase 4 Effectiveness / Safety studies Registration / Introduction 2013 2014 2015
Why PDVI is Working with a Portfolio of Dengue Vaccines No assurance that any one vaccine will be successful in a Phase 3 trial getting multiple types of vaccines into clinical trials Availability of multiple vaccines is more likely to ensure: An affordable vaccine Sustained and sufficient availability of product
What are we Doing - 2007 Big Companies Collaboration / participation in PDVI program activities Supportive R&D, Vaccine Evaluation, Vaccine Access Small Companies Direct funding: Process development cgmp vaccine to enter Phase 1-21 2 trials
Supportive Research and Development
Supportive Research and Development The Gaps - 2003 No high throughput assays to measure virus- type specific protective antibody to dengue virus infection (correlate of protection) No assays to measure antibodies associated with antibody enhanced disease (AED) No tools to validate existing dengue diagnostics or plaque reduction neutralization assay
Filling the Gaps Network of research laboratories (virology, structural biology, cell biology, immunology, assay development) has developed a portfolio of specialized assays to measure: protective antibody to dengue virus infection immune enhancing antibody Tools to evaluate diagnostic tests and specialized assays Dengue Diagnostics Laboratory Network Evaluation Panel for IgM anti-dengue tests Commercially available IgM anti-dengue tests evaluated Guidance document for performance of PRNT
Vaccine Evaluation
Vaccine Evaluation The gaps - 2003 Multiple vaccines under development with no plan forward to evaluation Limited sites in dengue endemic countries with adequate data on disease (dengue fever) incidence and capacity to conduct clinical trials No agreement on key elements for clinical trials of dengue vaccines (e.g., primary endpoint)
PDVI Vaccine Evaluation Program Facilitate evaluation of vaccines, primarily in large-scale clinical trials Develop guidelines for large-scale clinical trials of dengue vaccines Develop provisional guidelines for dengue immunization strategies
The PDVI Field Site Consortium Multiple sites Asia and Americas Multiple partners academia, NGOs, governments Networked case definitions, proficiency testing, data sharing, pooled data analysis PDVI Support epidemiologic, data management, laboratory proficiency Governance access to specimens, access to sites for clinical trials
Field Site Consortium, 2007 Managua Nicaragua Medellin Colombia Puerto Rico Kampong Cham Cambodia Ratchaburi Thailand Khamphaeng Phet Thailand Guadalupe Kolkata, India Colombo Sri Lanka Long Xuyen Vietnam My Tho Vietnam Philippines Brazil Mexico Indonesia Bangladesh Singapore
Vaccine Access
Vaccine Access The Gaps - 2003 Lack of regulatory pathways in developing countries to approve dengue clinical trials and vaccines No organized advocacy for dengue vaccines among endemic countries or the vaccine community No provisional Dengue Vaccine Investment Case
Better information Vaccine Access Epidemiologic - surveillance, burden of disease Economic Costs of dengue and vector control Comparative economic studies Vaccine markets Models Effects of immunization Prepare for vaccine introduction Advocacy - regional networks of experts ( dengue( prevention boards ) Capacity building among developing country vaccine regulators Mechanisms to sustain vaccine access
Dengue Prevention Boards Asia Pacific Dengue Prevention Board Inaugural meeting December 9-11, 9 2006 2 nd meeting: Dengue Surveillance June 21-23, 23, 2007 Colombo, Sri Lanka Americas Dengue Prevention Board Inaugural meeting July 23-25, 25, 2007 Managua, Nicaragua
Dengue Prevention Boards Contribute to and encourage actions to improve prevention and control of dengue virus infection in the region, particularly as they relate to the anticipated availability of dengue vaccines.
The Future
Near-term (2008 2015) Create an enabling environment Facilitate and collaborate in Phase 3 trials Improve diagnostics / validate assays for vaccine correlates of protection Develop new assays to identify breakthrough infections/disease in vaccinated persons Guide vaccine registration in developing countries Expand field sites and lead post-phase 3 vaccine trials / studies
Longer-term (2012 2020) Achieve the Public Health Outcome Enable availability of dengue vaccine for developing countries - the dengue vaccine investment case Guide introduction of dengue vaccine, including safety monitoring, into national immunization programs of dengue endemic countries Monitor effectiveness of vaccine introduction through national dengue surveillance programs
Discussion Vaccine Evaluation Vaccine Access PDVI Strategic Partnerships Supportive Research & Development