dengue control: is it possible?
TRANSCRIPT
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Duane J Gubler, ScD, FAAAS, FIDSA
Professor and Founding Director
Signature Research Program in Emerging Infectious Diseases,
Duke-NUS Medical School, Singapore, and
Chairman, Partnership for Dengue Control
Dengue Control: Is It Possible?
Asia Dengue Summit,13-15 January 2016, Bangkok
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Disclosure
Provided consultation and advice on dengue to: Sanofi Pasteur Takeda Inviragen NIH Merck GSK Janssen Globavir Novartis Hawaii Biotech Patent holder of Takeda vaccine Investor in Takeda Pharmaceuticals
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Dengue Control: Is It Possible?
• Introduction
• Mosquito control
• Vaccines
• Conclusions
Talk Outline
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What can we do to prevent and control
dengue?
Efforts to prevent the spread of dengue viruses and control the disease in the past 40 years, have failed!
Mosquito Control
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Traditional Aedes aegypti Control Methods have Failed
• Space spraying
• Perifocal control around cases
• Targeted source reduction
• Integrated vector management
• Community participation
• Bio-control?
• Genetic control?
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• Mosquito control
• Vaccines
• Antiviral drugs
Promising New Tools in Dengue Control Pipeline
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New insecticides
Genetic Control
Biological Control
Spatial Repellents Lethal Traps, ITMs
Promising New Tools in Dengue Control Pipeline
Mosquito Control
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• Indoor spraying • Treating oviposition sites • Cryptic larval habitat • Good efficacy • Resistance an issue
NEW RESIDUAL INSECTICIDES
Courtesy Scott Ritchie
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Lethal Ovitraps
Attractive Lethal OviTrap (A LOT) courtesy D. Wesson
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Vapor active, spatial repellents Metofluthrin/transluthrin
Courtesy Scott Ritchie
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Potential for use in some situations
From Manrique-Saide et al. 2014 EID
Insecticide treated curtains and screens
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lethal effector tTA tetO promoter
Tet
Female specificity
Repressible dominant lethality RIDL
Courtesy Luke Alphey
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Sterile Male Release
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WOLBACHIA-FOUR INDEPENDENT EFFECTS
VIRAL INTERFERENCE Wolbachia infected mosquitoes do not support dengue
BENDY PROBOSCIS Wolbachia infected mosquitoes do not feed properly when old
LIFE SHORTENING Infected mosquitoes do not live as long and so transmit less
EGG VIABILITY Reduce population size during dry season
Courtesy Scott O’Neil
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Wolbachia Rationale
Courtesy Scott O’Neil
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Promising New Tools in Mosquito Control Pipeline
Lethal Ovitraps
Spatial Repellants
IT curtains/screens
New Residual Insecticides
Sterile Male Release
Wolbachia Viral Interference
• Uncertainties
• Must be used properly by trained personnel • Surveillance for resistance
• Important to realize that none of these will likely control dengue if used alone
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Prevention and Control of Dengue Fever in the 21st Century
• Benefits of Aedes aegypti Control
DEN/DHF
Yellow Fever
Chikungunya
Zika
Epidemic Polyarthritis
Others?
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What can we do to prevent and control
dengue?
Are they the answer to dengue control?
Vaccines
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Sanofi-Pasteur Takeda NIH/Merck
Doses 3 2 1
Potency 5, 5, 5, 5 4, 4, 4, 5 3, 4, 3, 3
% tetravalent response (naïve subjects & SQ dosing)
78%* 100%** 90%
T-cell epitopes YFV DENV-2 DENV-1, -3, -4
Clinical phase 3 2-3 2-3
Overall efficacy 56% – 61% ? ?
Live attenuated dengue vaccines
* Villar, et al. 2011. Ped. Inf. Dis. J. Oct 2013.
** Takeda, internal data
Courtesy Steve Whitehead; modified
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Dengue vaccines at a crossroad!
• 70 years on, a major milestone in 2015! First dengue fever vaccine licensed Sanofi Dengvaxia approved by Mexico, 9 Dec
• Sanofi Dengvaxia approved in the Philippines, 22 Dec
• Sanofi Dengvaxia approved in Brazil, 28 Dec
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Attributes of Sanofi Dengvaxia
• Variable efficacy against four serotypes
• Overall moderate efficacy of 56-61%
• Increased efficacy in people with prior dengue infection
• High efficacy in protecting against DHF
• Good efficacy in decreasing hospitalization
• Safe
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For 50 years experts have said we need a tetravalent vaccine that protects against all four dengue serotypes
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But Is a Tetravalent Dengue Vaccine Really Necessary?
Based on what we think we know about dengue infection and immunity, and depending on the endpoint we want, my opinion is: NO! .
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What do We Know?
• High seroprevalence in endemic countries
• Most (all?) severe dengue disease occurs during the 1st and 2nd dengue infections*
• 3rd and 4th dengue infections are mild or asymptomatic*
• Risk of ADE relatively low Good risk management
* Gibbons, et al Am J Trop Med Hyg November 2007 77:910-913
* Olkowski, et al, J. Infect. Dis. 2013. 208: 1026-1033.
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Uncertain whether any of the lead live attenuated candidate vaccines will provide balanced tetravalent protection
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Assumption
Assume we use a vaccine with attributes similar to the Sanofi Dengvaxia
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Public Health Rationale for use of Moderately Effective Dengue Vaccines in Endemic Countries
• Priming effect of previous dengue infection
• Majority of persons in hyper-endemic areas have already had at least one dengue infection
• Vaccinees should be protected against 2 or more serotypes
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Public Health Benefits of Moderately Effective Dengue Vaccines
Beyond Direct Efficacy
• Decreased dengue transmission Reduced risk of epidemics
Reduced risk of health care overload ‒ Better management of severe disease
‒ Decrease in case fatality rate
• Decrease in severe disease
• Decrease in hospitalization
• Economic benefits
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Uncertainties Related to Use of Moderately Effective Vaccines
• A paucity of research on 3rd & 4th infections • Surveillance inadequate to distinguish infection sequence • Uncertain vaccine viruses will perform as wild type viruses • Uncertainty about the role of the virus strain • Uncertainty about the role of patient age • Uncertainty about the temporal distribution of infections with
different serotypes • Uncertainties about the role of cellular immunity • Uncertainties can best be addressed by controlled introductions
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Can We Use Moderately Effective Vaccines to Help Control Dengue?
• The answer is yes, but under controlled conditions Vaccine safety and impact need careful evaluation
• Do not deploy the vaccines in widespread national programs at this time Step-wise rollout with strong evaluation and quality control
• Learn by doing Uncertainties and safety issues can only be resolved by
introducing the vaccine in endemic countries Safety issues can be mitigated by:
‒ Good risk management program ‒ Active surveillance for infection and severe disease ‒ Clinical management training
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What can we do to prevent and control
dengue?
Unfortunately, like mosquito control, it is unlikely that vaccines alone will be effective in controlling dengue as a public health problem
Vaccines
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Challenges for Dengue Prevention and Control
Uncontrolled Urbanization
• Effective sustainable strategies for mosquito control in Large urban areas
.
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Challenges for Dengue Prevention and Control
• Movement of viruses and vectors
via globalization
PNAS, 2004
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Challenges for Dengue Prevention and Control
• Cryptic or hidden larval habitats
Wells
Underground cisterns
Mine shafts
Septic tanks
Flooded basements
Storm drains and rain gutters
Others?
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Challenges for Dengue Prevention and Control
Build Capacity
• Laboratory • Epidemiologic • Entomologic • Highly trained personnel • Laboratory-based surveillance • Effective response plans
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Challenges for Dengue Prevention and Control
• Economic support
• Public health leadership
• Regional control
Political Will
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09 Dec15
WHO
Dengue Vaccine
Initiative
Sabin Vaccine Institute
IVAC at Johns
Hopkins University
Partnership for Dengue
Control (PDC)
WHO (observer partner)
GLOBAL DENGUE PREVENTION & CONTROL CONSORTIUM [GDC]*
*Formed by a merger between PDC and DVI
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Multiagency funded, globally networked alliance,
The GDC
VISION
MISSION
OBJECTIVES
ELIMINATE DENGUE AS A PUBLIC HEALTH PROBLEM
PROMOTE DEVELOPMENT AND IMPLEMENTATION OF INNOVATIVE AND SYNERGISTIC APPROACHES FOR DENGUE PREVENTION AND CONTROL
• SUPPORT the WHO global strategy for dengue control • STRENGTHEN advocacy, capacity building and networking • WORK CLOSELY with vaccine early adopter countries • PROMOTE integration and innovation
09 Dec15
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Targeted Control program
Community
engagement
Vector
Control
Vaccination
New GDC Paradigm to Rollback Dengue Using New Tools in
the Control Pipeline
Clinical
management/
therapeutics
Integration and Synergy
Improved
Surveillance
International mobilization of resources Build public health capacity Fund program implementation Fund research
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CONCLUSIONS
• Dawn of a new era in the fight against dengue First dengue vaccine licensed; others in pipeline
We can use moderately effective vaccines
New vector control measures and antivirals in pipeline
• None of new tools will likely be effective if used alone
• Effective prevention & control will require integration of vaccines and mosquito control
• Enhanced surveillance to monitor both disease and mosquitoes
• Strategy will help WHO reach 2020 dengue objectives
Dengue Control: Is It Possible?
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CONCLUSIONS
• An international mobilization of resources is needed to support this strategy
• Research is still needed to better understand the disease, its pathogenesis, transmission dynamics and immunology
• We now have or will have the tools to prevent and control dengue if used properly
• Help control other Aedes transmitted diseases chikungunya, Zika and yellow fever
Dengue Control: Is It Possible?