Dengue Control: Is It Possible?

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

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


• Introduction

• Mosquito control

• Vaccines

• Conclusions

Talk Outline

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

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?

• Mosquito control

• Vaccines

• Antiviral drugs

Promising New Tools in Dengue Control Pipeline

New insecticides

Genetic Control

Biological Control

Spatial Repellents Lethal Traps, ITMs

Promising New Tools in Dengue Control Pipeline

Mosquito Control

• Indoor spraying • Treating oviposition sites • Cryptic larval habitat • Good efficacy • Resistance an issue

NEW RESIDUAL INSECTICIDES

Courtesy Scott Ritchie

Lethal Ovitraps

Attractive Lethal OviTrap (A LOT) courtesy D. Wesson

Vapor active, spatial repellents Metofluthrin/transluthrin

Courtesy Scott Ritchie

Potential for use in some situations

From Manrique-Saide et al. 2014 EID

Insecticide treated curtains and screens

lethal effector tTA tetO promoter

Tet

Female specificity

Repressible dominant lethality RIDL

Courtesy Luke Alphey

Sterile Male Release

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

Wolbachia Rationale

Courtesy Scott O’Neil

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

Prevention and Control of Dengue Fever in the 21st Century

• Benefits of Aedes aegypti Control

DEN/DHF

Yellow Fever

Chikungunya

Zika

Epidemic Polyarthritis

Others?


dengue?

Are they the answer to dengue control?

Vaccines

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

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

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

For 50 years experts have said we need a tetravalent vaccine that protects against all four dengue serotypes

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! .

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.

Uncertain whether any of the lead live attenuated candidate vaccines will provide balanced tetravalent protection

Assumption

Assume we use a vaccine with attributes similar to the Sanofi Dengvaxia

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

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

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

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


dengue?

Unfortunately, like mosquito control, it is unlikely that vaccines alone will be effective in controlling dengue as a public health problem

Vaccines

Challenges for Dengue Prevention and Control

Uncontrolled Urbanization

• Effective sustainable strategies for mosquito control in Large urban areas

.


• Movement of viruses and vectors

via globalization

PNAS, 2004


• Cryptic or hidden larval habitats

Wells

Underground cisterns

Mine shafts

Septic tanks

Flooded basements

Storm drains and rain gutters

Others?


Build Capacity

• Laboratory • Epidemiologic • Entomologic • Highly trained personnel • Laboratory-based surveillance • Effective response plans


• Economic support

• Public health leadership

• Regional control

Political Will

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

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

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

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


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?

Documents