Emergence of epidemic dengue and DHF in Mexico: Lessons learned towards better vector and disease control Barry J Beaty IOM Forum on Microbial Threats Fort Collins, Colorado June 19 and 20, 2007
American countries with Aedes aegypti in 1970 at the end of the mosquito eradication program and in 2002
VECTOR GENETIC DETERMINANTS OF EPIDEMIC DENGUE
Collecting points
Ae. aegypti altitudinal range is from sea level to ~2000 feet (Ibañes-Bernal, 1995)
Geographical groups of Aedes aegypti in Mexico and the U.S.
Oral Infection Route
5’ 3’(An) Open Feeding Frame
• Sindbis Virus Pathology and Midgut Infections
Extrinsic incubation period is the time from ingestion of an infectious blood meal until transmission capability. Alphaviruses: 4-12 days
Time course of DENV-2 Jam 1409 midgut infection after oral challenge of Aedes aegypti.
Salazar-Sanchez, et al., BMC, 2007
Quantification of DENV-2 in midguts of orally infected Chetumal mosquitoes.
8
7
*
*
6 5 4 7
14
dpiBM
21
6 5
6
***
5
*** 4
PFU/ m idgut
8
TCID 50 / m idgut
Log 10 copy # per midgut
9
7
C) Plaque assays
B) End point titrations
A) qRT-PCR
4 3
**
2
**
1
3 7
14
dpiBM
21
7
14
dpiBM
21
Aedes aegypti salivary glands infection by DENV-2 Jam 1409 after an oral challenge.
Temporal and spatial infection of DENV-2 Jam 1409 in Chetumal mosquitoes.
Days post-infectious blood meal 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Trachea
Midgut
Abdomen
Salivary glands Head tissues
Malpighian tubules
10-25%
26-50%
51-75%
76-95%
19
20
21
Is the barrier to gene flow between northeastern Mexico and the Yucatan epidemiologically significant?
Correlation between Dengue Seroprevalance, Vector Competence and Vector Serotype 80%
68%
70%
20%
34%
30%
31%
40%
43%
49%
50%
56%
60%
10% 0% TABASCO
CAMPECHE Seroprevalence Vector Competence
YUCAT AN
Viral determinants of epidemic dengue and dengue hemorrhagic fever in Mexico
Phylogeny of DENV-2 Sylvatic
MALAYSIA/70/P8 1407 100 IVORY COAST/80/DAKAr578 GUINEA/81/PM33974 100 NIGERIA/66/IBH11208* 87 SENEGAL/90/DAKHD10674
Asian 1 100
Asian 2
57
American- Asian
Diaz, et al. Dengue virus circulation and evolution in Mexico: A phylogenetic perspective. Arch. Med Res. 37:760-773, 2006
Cosmopolitan
American
0.1
THAILAND/64/16681 THAILAND/89/PUO218 THAILAND/93/ThNH7 98 MALAYSIA/87/M1 PHILIPPINES/83 100 PHILIPPINES/DOH 078 100 96 TAIWAN/87 CUBA/81/A15 VIETNAM/97/CTD113 100 CHINA/87/43 NEW GUINEA/44/NGC MX/GUERRERO/97/C932* 100 MX/GUERRERO/97/C1077* 98 THAILAND/80/D80 141 CHINA/85/04 VIETNAM/98/CTD29 JAMAICA/83/1409 VENEZUELA/90/MARA4 81 VENEZUELA/98/3146 100 BRAZIL/90/40247 COLOMBIA/96/PTCOL96 100 VENEZUELA/97/1657 VENEZUELA/00/5207 100 MARTINIQUE/88/703 100 NICARAGUA/99/541* MX/YUCATAN/02/13381* MX/YUCATAN/02/13382* 100 MX/YUCATAN/02/13404* MX/OAXACA/00/468 MX/YUCATAN/01/11936* 100 MX/YUCATAN/01/12914* 100 MX/YUCATAN/01/12021* 100 SEYCHELLES/77/SEY42 100 SRI LANKA/85/1592 UGANDA/93/CAMR11 SAUDI ARABIA/92/CAMR16 100 AUSTRALIA/92/CAMR5 100 INDIA/94/CAMR10 AUSTRALIA/93/TSV01 THAILAND/98/CAMR14 100 BORNEO/88/620* SOMALIA/94/S9* INDONESIA/76 100 100 MX/YUCATAN/96/ BC17* TRINIDAD/53/TRI1751 INDIA/57 100 PUERTO RICO/69/159 100 MEXICOX/83/200787 PUERTO RICO 77 1328* 100 PERU 96 IQT2913 MEXICOX/84/1482* VENEZUELA 87 VEN2 100 MEXICOX/83/1421* 80 MX/94/QUINTANA ROO BC139* MX/SONORA/92 131 66 100 MX/TAMAULIPAS/95/328298
96
Correlation Between Dengue Occurrence and DENV Introductions DHF cases
DF cases
50,000
2,000
40,000
1,500
30,000 1,000 20,000 500
10,000
0
0
Years Æ 78
tr n I
uc d o
s: n tio DE
-1 V N
80
DE
82
4 ,2 NV
84
86
88
90
92
94
96
98
00
02
n” a i -3 -2 s V As V V N N N pe E anE D y DE D t ric 2 no e m ge “A -2
Southeast Asian Dengue 2 genotype viruses disseminate in Aedes aegypti much more efficiently than anAmerican genotype dengue 2 virus
B) Salivary glands
100 90 80 70 60 50 40 30 20 10 0
%dissemination
%infection
A) Midguts
94QRoo
Yuc11936
Yuc12914
Yuc14497
Virus strain
Salazar-Sanchez, et al.
Yuc14757
100 90 80 70 60 50 40 30 20 10 0
*** ***
** **
94QRoo
Yuc11936
Yuc12914
Yuc14497
Virus strain
Yuc14757
Increased Probability of DHF / SS
Increased Probability of Virulent Strain Selection
Increased Transmission Trafficking of Viruses
Increased Probability of Immune Enhancement
Increased Vector Abundance & Hyperabundance
Increased Probability of Secondary Infection
HYPERENDEMICITY
Not-so-Novel Vector-borne Disease Control: For the foreseeable future, traditional approaches to reducing vector populations or repelling vectors will remain the first lines of defense against emerging and resurging diseases. Clearly, the development of new, environmentally acceptable pesticides and formulations will be critical to mitigate the potential for dramatic increases in such diseases.
IOM / NAS Study: Microbial Threats to Health Emergence, Detection and Response , 2003
Innovative Vector Control Consortium: Improved Control Of Mosquito-Borne Diseases In And Around The Home Janet Hemingway, Barry J. Beaty, Mark Rowland, Thomas W. Scott and Brian L. Sharp Trends in Parasitology, 2006
¾Control of vectors in and around the house ¾Major POC for transmission of: Malaria Dengue Filariasis Leishmaniasis Chagas ¾Successful in the past
Background • • •
Five year public private partnership programme started Nov 2005 Funded by a US$50million award from the Bill and Melinda Gates Foundation Consortium Members 1. 2. 3. 4. 5.
Colorado State University Liverpool School of Tropical Medicine London School of Hygiene and Tropical Medicine Medical Research Council, South Africa University of California Davis
Need for IVCC • No new public health chemical pesticides for vector control in DECs for 30 years • Development of new public health insecticides demands investment. The cost of developing a single new insecticide is in the range of $70 million. The overall annual public health insecticide market – for all diseases and all developing countries - is around $151.2 million. Clearly, market size limits commercial sector investment and the pipeline of new insecticide candidates • The IVCC can facilitate development of products with industrial partners
IVCC Major Thematic Areas • Objective 1. Development of new public health products (e.g. insecticides and their formulations) • Objective 2. Development of better tools and approaches to facilitate malaria and dengue vector control
AIM: To produce new insecticide based products that will improve our ability to control insect vectors of disease in the home. • The Vision. 1. To develop a pipeline of innovative vector control products that achieve a significant advance on current vector control options. 2. To develop a pipeline of vector control products to protect and promote the sustainability of both ITN and IRS approaches to vector control.
A Portfolio Approach • Balanced portfolio: The IVCC aims to support a range of vector control products that will have a major impact on malaria and dengue transmission. • Portfolio selection: Similar principles to those used in industry but with the added criteria of global access (which will be discussed later). • Scope: The exact scope of the portfolio is not fixed but will be revisited as the portfolio grows. • Industry: Expected to cover some of the development costs in cash or in kind, with relative contribution agreed through consultation • Global Access Plan: All projects receiving support and funding from the IVCC will develop a GAP to maximize product uptake and impact on vector borne disease.
OBJECTIVE 1: NEW INSECTICIDES AND FORMULATIONS • • • •
The portfolio approach Pipeline of products Industrial partners – IP worked out New insecticides for ITM and IRS applications will include alternative active ingredients, longer lasting formulations, and new combinations of existing insecticides • External Scientific Advisory Boards
IVCC Critical Path for Public Health Pesticide Product Development
IVCC Decision Support Systems
Repurposing
Discovery
Large Scale Tender Market Analysis Individual Consumer
Phase I Evaluations Efficacy/Safety Resist./Toxicology
WHOPES Phase II Phase III Small Scale Field Trails
Large Scale Field Trials
Phase IV Specifications, final formulations, data analysis
Proof of concept Field trials in disease endemic sites
IVCC Contributions
Large Scale Tender
Markets Individual Consumer
Aim: To establish the partnership in a format that stimulates improved delivery of these products and systems. The Vision • To involve major employers, international organisations, Ministries of Health, DEC communities, operational control programs in the partnership from the outset to stimulate improved delivery of the products as they are developed and marketed.
OBJECTIVE 2. IMPROVED TOOLS FOR VECTOR CONTROL. PYRETHROID QUANTIFICATION KIT Rapid determination of pyrethroid activity in ITM/ITN/IRS in the field – enzyme based systems for field relevant testing POPULATION MONITORING TOOLS Molecular based rapid detection of insecticide resistance (eg, pyrethroid, temephos) in dead insects* Other phenotypes of interest – eg, infection status *David JP, Strode C, Vontas J, Nkou D, Vaughn a, Pignatelli, PM, Louis C, Hemingway, J, Ranson H. The Anopheles gambiae detoxification chip: a
highly specific microarray to study metabolic-based insecticide resistance in malaria vectors. Proc Natl Acad Sci 102(11):4080-4, 2005.
OBJECTIVE 2. IMPROVED DECISION SUPPORT TOOLS FOR VECTOR CONTROL. • DECISION SUPPORT SYSTEMS FOR MALARIA AND DENGUE VECTOR CONTROL • SIMULATION MODELS FOR MALARIA AND DENGUE
The Dengue Decision Support System • A rationally designed, computer-based dengue information system (DIS) with multiple subcomponents (DMS, DWS, ESS, EIS, SDMS) that is functional at different capacity levels: • DIS 1 – Local and regional vector control to achieve more efficient usage of resources in very resource limited environments. Basis dengue and Aedes aegypti information for control DIS 2 – In addition to DIS 1, information on insecticide resistance for operation management for vector control. DIS 3 – Proactive surveillance, modeling, GIS-based data analysis.
Outline of DDSS structure
DDSS project demonstrations - 3
Spatial dengue case clustering; Merida and Chetumal, 2006
Chetumal Merida
DENGUE VECTOR CONTROL •Larviciding and source reduction (Temephos resistance) •Spraying and vector control around premises to intervene in impending epidemics (need for early intervention)
DDSS project demonstrations - 13
Syndromic surveillance algorithm for dengue (DENSYND) - 1
Syndromic surveillance
45
refers to methods relying
40
on detection of clinical
35
discernable before laboratory confirmed diagnoses are made.
Merida
Number of dengue cases
case features that are
Laboratory diagnosis (wk 33)
Chetumal
30 25
Syndromic surveillance (wk 29)
20 15 10
CRF may be key for success
5 0
New national policy on sample collection
1
5
9
13
17
21
25
29
33
37
Epidemiological week
41
45
49
DDSS project demonstrations - 10
Dengue Warning System components
80
Likelihood of introduction of serotypes with potential for causing epidemics
Number of dengue cases
70 60
Clinical diagnosis
50 40
Syndromic surveillance
30 20
Mosquito abundance
10
Weather 0 1
5
9 13 17 21 25 29 33 37 41 45 49
Epidemiological week
Vector control
DDSS project demonstrations - 2
Seasonality of dengue cases; Merida and Chetumal 2006 45 Chetumal
40 Merida
Yucatan
Quintana Roo
Number of dengue cases
35 30 25 20 15 10 5 0 1
5
9
13
17
21
25
29
33
37
Epidemiological week
41
45
49
DENGUE VECTOR CONTROL TIME TO REVISIT THE ISSUE OUTDOOR ULV SPRAYING INEFFECTIVE FOCUS UPON THE BIOLOGY OF THE VECTOR IN TRANSMISSION EXPLOIT NEW TECHNOLOGIES TO EXPAND THE ARMAMENTARIUM FOR Aedes aegypti CONTROL
DENGUE VECTOR CONTROL: ULV Indoor Spraying and Targeted Larviciding Evaluation of emergency vector control measures during dengue epidemic in Iquitos, Peru 2002-2003. Morrison AC, Astete H, Rocha C, Rodriguez H, Sifuentes GA, Alava F, Diaz G, Sihuincha M, Zamara E, Scott TW. ASTMH Annual Meeting Abstract 756
Intradomicile Intervention managed disease: 2002 Dengue Epidemic in Iquitos • Clinical disease was reduced for ~ 1 year following vector intervention (Dec 2002 to Dec 2003). During 2004 clinical cases began to increase. • DEN-3 epidemic was aborted (~30% prevalence would have increased to ~60% without vector intervention).
140
Number of cases (febrile illness)
120 100
80 60
Intradomicile spray
ELISA DEN3 DEN2
40
DEN1
20
0 4
5
6
7
8 2000
9 10 11 12 1
2
3
4
5
6
7
2002
8
9 10 11 12 1
Year
2
3
4
5
6
7
2003
8
9 10 11 12
DENGUE VECTOR CONTROL: ITMs The effect of Olyset net screen to control the vector of dengue fever in Vietnam. Nguyen HT, Tien TV, Tien HC, Ninh TU, and Hoa NT. Dengue Bulletin 20: 87-92, 1996. Impact of dengue virus infection and its control. Igarashi, A. FEMS Immunol and Med Mcrobiol 18:291-300, 1997. Permethrin-treated bamboo curtains for dengue vector controlfield trial, Viet Nam. Dengue Newslett. 18:23-28, 1993. Nam VS, Nguyen HT, Tien TV, Niem TS, Hoa NT, Thao NT, Tron TQ, Yen NT, Ninh TU, and Self LS.
Anti-dengue IgM-ELISA on healthy school children Hai Hung Province, Vietnam, 1994
Number of positive specimens (%)
Area
Number of specimens tested
April, before epidemic season
November after epidemic season
Study Area
78
1 (1.3)
5 (6.4)
Control Area
78
4 (5.1)
26 (33.3)
Kroeger, et al. BMJ, 2006 Curtains: Veracruz, Mexico Trujillo, Venezuela
lambdacyhalothrin treated deltamethrin (LLITM – PermaNet)
Water containers: Veracruz, Mexico Trujillo, Venezuela
Outcomes at both sites: Entomological Dengue infection
pyriproxyfen chips PermaNet covers
The reason for efficacy: Endophily and Endophagy Aedes aegypti, Anopheles gambiae, and Anopheles funestus (and Culex quinquefasciatus) seldom feed on plant sugar Anopheles and Aedes preferential and frequent feeding on human blood
Multiple other vectors (eg, sandflies, triatomids) feed preferentially in domicile
Regional Chagas Disease Control: Southern Cone Initiative - 1991
Triatoma infestans – the prototype of an endophilic vector
Controlling Chagas disease by attacking the epidemiologically significant point of contract between humans and the vector – the domicile
Enhancing Dengue Vector Control In Latin America: “CASA SEGURA” Developed country housing (screens, airconditioning, etc.) provides a Casa segura Incorporate ITMs/IRS/Repellents into existing control programs to effect a Casa segura in DECs
DDSS project demonstrations - 15
Casa Segura - 1 Benefits of “Casa Segura” approach with use of long-lasting ITMs to protect homes, schools etc from Ae. aegypti - Low cost allows for near universal coverage - Can be implemented by vector control programs as well as individual homeowners - Potential for protection against other arthropod vectors as well as “nuisance biters” - Integrated into MoH, SSY (state), and municipal (Merida) control programs
LLIN Estimate: 2 doors 3 windows eaves
Size estimate: If 1 door is 7 x 3.5ft = 24.5 sq ft, so 2 doors = 49 sq ft. If 1 window is 3 x 3 ft = 9 sq ft, so 3 windows = 27 sq ft 49 + 27 = 76 sq ft or 7 sq m + 2 sq m for eaves. Total of netting material needed = 9 sq m. Cost: LLIN Max cost (from WHO report) = 6.00 USD, 150cm x 180cm x 160cm = 13.08 sq m of netting material Approximate cost per house = 4.00-5.00 USD.
Cost effectiveness of dengue vector control by Casa segura (ITM/IRS) ¾vaccine targets only one pathogen. Ae. aegypti control targets DEN and YF as well as other pathogens transmitted in the domicile ¾protects against many diseases that are vectored principally in the endophilic environment ¾protects many people in one approach (eg, separate bednet for each person not essential, etc.) ¾protects against multiple vectors (mosquitoes, eg Anopheles & Culex, sand flies, kissing bugs, etc.) and pest species (eg, bed bugs, cockroaches) and pathogens (YF, DEN, malaria, Chagas, leishmaniasis). ¾provides economic incentives for people to purchase the product
Major arguments against “stovepiping” of diseases and infrastructure, resources, and talents to reduce or eliminate these diseases.
NIH NIAID/FOGARTY CENTER and GATES GRANTS
CSU-PIs Barry Beaty
Dengue research
RNAi
Alexander Franz
Kimberley Keene
Norma Gorrochetegui-Escalante
Brian Foy
Carol Blair
Irma Sanchez-Vargas
IVCC
William Black
Kristine Bennett
Lars Eisen
Jonathan Carlson Francisco Diaz
Saul Lozano-Fuentes
Ken Olson
Saul Lozano-Fuentes
Chet Moore
Isabel Salazar-Sanchez
Darwin Elizondo
Scott Bernhardt
SSY, Merida Health, UADY
Mexico PIs UANL:
Dr. Ildefonso Fernandez-Salas
UAY:
Dr. Jose Arturo Farfan-Ale Maria Alba Lorono-Pino
FIN
Project progress summary - 1 • Establishment through subcontract PIs Farfan-Ale and Fernandez-Salas of collaborations with vector control and health agencies in Merida (Merida Municipal Health Program, Yucatan State Health Services, Instituto Mexicano de Seguro Social) and Chetumal (Quintana Roo State Health Services). • Involvement of Drs. Farfan-Ale and Fernandez-Salas in ongoing revisions by the National Center for Epidemiological Surveillance and Disease Control (Drs. Pablo Kuri Morales, Carlos Alvarez Lucas, and Jorge Ricardo Esquinca) and the National Center for Diagnosis and Epidemiologic Reference (Dr. Celia Alpuche) for guidelines for vector and dengue control in Mexico: “Grupo de Expertos para la Prevencion del Dengue”. • Development of methodology for using free mapping tools (e.g., Google Earth or MS Virtual Earth) as a minimal cost alternative to GIS-software and use of Google Earth to generate city structure data layers for Chetumal and Merida. • Development of a Google Earth-based mock-up model for spatiotemporal spread of a dengue epidemic in Chetumal. • Georeferencing of cases in Chetumal and Merida. • Ongoing development of insecticide resistance database for Ae. aegypti.
Gene flow in Aedes aegypti in Southeastern Mexico Lozano-Fuentes, et al, 2007
Revisiting vector competence of Southeastern Aedes aegypti mosquitoes after 10 years Chetumal, Ciudad del Carmen, Saylula, Lerdo de Tejada, Martinez de la Torre, Moloacan, Minatitlan, Poza Rica, Alvarado. Bernhardt, Scott, et al.
2005 DENV-2 JAM 1409 Vector competence Cancun (72%) Merida (72%) Poza Rica (60%) Martinez de la Torre (60%) Paso del Cedro (53%)
Campeche (44%) Palma Sola (55%) Coatzacoalcos (70%) Ciudad Cardel (48%) Ciudad del Carmen (66%) Boca del Rio (47%) Alvarado (45%) Moloacan (69%)
Lerdo de Tejada (38%) Saylula (40%)
Minatitlan (61%) Cosoleacaque (64%) Acayucan (58%)
Chetumal (83%)
2005 SUSC 2003 SUSC 2001 SUSC
Collection Site
1998-99 SUSC
Chetumal
Cancun
Merida
Campeche
Ciudad del Carmen
Coatzacoalcos
Moloacan
Minatitlan
Cosoleacaque
Acayucan
Alvarado
Martinez de la Torre
Poza Rica
Percentage
Vector Compentence Comparison
0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00
