Claim catégorie: Events

The Partnership for Dengue Control (PDC) organized a workshop on pre-vaccination screening for the use of dengue vaccines with differential performance dependent on serostatus: vaccine clinical updates, rapid diagnostic tests and implementation strategies, at Les Pensières Center for Global Health, January 20-22, 2020. This workshop was developed with the Global Dengue & Aedes-Transmitted Diseases Consortium (GDAC) Advisory Committee as a continuation of the workshop held in January 2019.

Dengue is a major public health problem with more than 3.6 billion people at risk for dengue virus (DENV) infection and an estimated 390 million infections annually in over 120 tropical and sub-tropical countries. In the absence of truly effective and sustainable vector control measures, a dengue vaccine is urgently needed. The first dengue vaccine was licensed in 2015; the live attenuated recombinant tetravalent vaccine CYD-TDV (Dengvaxia). However, new evidence highlighted the serostatus-dependent vaccine performance of Dengvaxia; a retrospective analysis of clinical trial data, stratifying participants according to their dengue serostatus before the first vaccine dose, revealed an excess risk of severe dengue in seronegative vaccine recipients, while in seropositive vaccine recipients, the vaccine was efficacious and safe.

The WHO recommended a pre-vaccination screening as the preferred strategy as with such a strategy predominantly persons with evidence of a prior dengue infection would be selected to be offered vaccination (based on serological test, or documentation of laboratory confirmed dengue infection in the past. To support the strategy, WHO and many expert panels highlighted the urgent need for rapid diagnostic tests (RDTs) to determine serostatus. To date, no RDT has been licensed for the indication of prior dengue infection status. Pre-vaccination screening strategies will benefit from RDTs that can be performed at point of care (POC), provide rapid test results, are sensitive and specific, as well as inexpensive for use in a population wide program.

Objectives of the meeting

Updates on new clinical data for CYD-TDV

• Discuss updates on recent clinical study results
• Address the impact of such data in terms of WHO recommendation / guidelines and on field implementation

Screening for prior dengue infection: Rapid diagnostic tests (RDTs) development updates

• Discuss RDT Target Product Profile (TPP) development status: where are we and next steps
• Updates on RDT development for pre-vaccination screening
• Address qualified- RDTs access for countries

Discuss implementation strategies for pre-vaccination screening programs for dengue vaccines

• Discuss practical issues for programmatic roll-out and get regional experiences feed-back on CYD-TDV
• Address programmatic challenges encountered by countries and the needs required for a successful implementation
• Discuss communication strategies with regards to vaccine confidence, both for policy makers, the medical community and the lay public
• Discuss cost-effectiveness data and modeling implementation approaches

Discuss Public health strategy for outbreak response

World Dengue Day target and expectations

Scientific Committee

• Duane Gubler, Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
• Annelies Wilder-Smith, Partnership for Dengue Control; Lee Kong Chian School of Medicine, Singapore; Institute of Public Health, University of Heidelberg; Department of Global Health and Epidemiology, University of Umea
• Eng-Eong Ooi, Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
• Anna Durbin, The Anna Durbin Lab; Johns Hopkins University School of Medicine

Download the program

Download the report

On September 7, 2018, WHO published its new position on the dengue vaccine, Dengvaxia®. The WHO guidance was updated to account for new long-term clinical data on the vaccine that led Sanofi Pasteur to recommend a label update for their vaccine at the end of last year.

Dengue continues to pose a public health threat to people living in countries where the disease is present–as evidenced by recent news reports of dengue outbreaks on the island of La Reunion and in India. Still, the question remains: Can the only approved vaccine against dengue be used effectively in the global fight against this disease?

In order to shed some light on this topic and give an expert overview of the WHO position on Dengvaxia® along with the data and processes on which it is based, the Global Dengue & Aedes-Transmitted Diseases Consortium (GDAC) hosted a media briefing webinar on the September 28, 2018 at 8am EDT.

Watch the full recording of the webinar

The aim of the Partnership for Dengue Control (PDC) is to cast a wider net to facilitate and expedite urgently needed technology development, both for research and to be rolled out in countries affected by arboviral diseases.

This workshop was organized, therefore, by the PDC and the Mérieux Foundations, with the support of the Bill & Melinda Gates Foundation, bioMérieux, Takeda and Sanofi Pasteur. Its purpose was to identify the gaps in the diagnosis of these viral infections, to review the new technological innovations that may be available to fill those gaps and to promote and develop mechanisms for accelerating the pathway from tool development to impact.

Critical need

The driving force behind the event was the critical need for more sensitive, specific and accurate diagnostic tests to support more effective surveillance and prevention and to halt the increased frequency and magnitude of epidemics and the higher incidence of severe disease outcomes caused by Zika, dengue and other arboviral infections.

Workshop outcomes

Key insights emerged to the 3 questions posed during the workshop:

Where are where are we now?

• Diagnostic methods to detect DENV and ZIKV infections are still mainly laboratory-based and require further clinical evaluations,
• Few validated assays are available on the market to differentiate ZIKV from other flavivirus infections,
• Diagnostics that can be used at or near the point-of-patient care (POC) to detect and discriminate between the different flaviviral infections are needed.

Where do we go?

• Towards specific molecular, serological, antigen-based and combination assays to identify and differentiate co-circulating flaviviral infections at or near POC, as well as for surveillance, in the intermediate and long-term future.

How do we make it happen?

• Identify and address challenges: uncoordinated efforts, lack of funding mechanisms, limited access to well-characterized clinical samples, lack of definition of evaluation methods and sites, lack of regulatory harmonization, market opacity, low guarantee of return on investment (ROI), as well as slow and fragmented pathway to implementation,
• Offer solutions: establish early partnerships and promote information sharing, facilitate access to samples and standardized protocols, promote regulatory harmonization, define priorities and build diagnostic preparedness strategies.

Workshop Report

Approximately 80 people attended the event including participants from academia, industry, NGOs, UN agencies (including WHO), investor organizations, policy makers and regulatory bodies. A full report has been published and includes a full list of participants and a summary of all the presentations, comments and strategies that resulted from the 3-day event.

Download full summary

Tuesday, May 2 – Day 1

Where are we now?

Session 1 Chairs: Annelies Wilder-Smith, Duane Gubler Landscape analysis of the current status of Flavivirus diagnostics (dengue and Zika) – Maurine Murtagh, The Murtagh Group Download Presentation

Session 2 Chairs: Francis Moussy, Amy Lambert Learning from successful novel technologies that made it to the market – Mark Miller, BioMerieux Download Presentation Demand forecasting and market considerations – Nagwa Hasanin, UNICEF Download Presentation Learning from past emergency authorizations – Elliot Cowan, Partners in Diagnostics Download Presentation

Wednesday, May 3 – Day 2

Where do we go? Technological innovations in Flavivirus diagnostics

Session 3: Detecting acute infection Chairs: Maurine Murtagh, Arlene Chua Imminent technological innovations Cutting edge innovations for the intermediate and long-term future Discussion

Near-care molecular testing for Dengue, Zika and related pathogens – Jesse Waggoner, Emory University Download Presentation Tetracore T-COR8 diagnostic system for the detection of Dengue and other arboviruses using real-time-rtPCR at the point-of-care – Bill Nelson, Tetracore Download Presentation Triplex PCR ZIKV/DENV/CHIKV assay and simple to operate real-time portable device – Craig Mosman, Kirkland Biosciences Download Presentation

Molecular test to detect dengue, Zika & Chikungunya and run on the QuRapID LV platform – Emily Adams, LSTM & David Edge, BioGene Download Presentation NS1 antigen capture assays for the specific detection of different dengue virus serotypes and other arboviruses – Katharina Roeltgen, Swiss TPH Download Presentation Multiplex Diagnosis kit for Zika, Dengue, Chikungunya and Japanese Encephalitis Viruses using Printed Array Strip based on Single-stranded Tag Hybridization method – Takahiro Haruyama, AVSS Download Presentation

Session 4: Detecting past infections Chairs: Eva Harris, Aravinda de Silva

Dx antigen discovery and imminent technological innovations New discoveries about the molecular specificity of the human antibody response to dengue and Zika viruses – Aravinda de Silva, UNC Download Presentation NS1 blockade-of-binding ELISA distinguishes between dengue and Zika virus antibodies – David Corti – Humabs BioMed SA Download Presentation In-country development and evaluation of new molecular and serological methods for Zika diagnosis and surveillance and their applications – Eva Harris, Berkeley University Download Presentation

Cutting Edge Innovations For The Intermediate And Long-Term Future VIDAS Zika and Dengue: Preliminary results on an automated immunoAssay platform – Nathalie Renard, Biomerieux Download Presentation A nanoscale plasmonic-gold platform for specific diagnosis of Zika and differentiation from other Flavivirus infections – Benjamin A. Pinsky, Stanford, CA Download Presentation

Thursday, May 4 – Day 3

How do we make it happen? From idea to market

Session 5: Preparing for the inevitable: open technology platforms for rapid outbreak response Chairs: Bill Rodriguez, Bernadette Murgue Preparing for the inevitable: open platform technologies for rapid outbreak response WHO call for open technology platforms to accelerate test development – Bernadette Murgue, WHO Blueprint Download Presentation Diagnostics preparedness platform – Thomas Ullrich, Alere Download Presentation Genetic analysis tool kit for rapid outbreak response – Michael Baffi, Thermo Fisher Download Presentation

Session 6: Critical steps to ensure quality products Chairs: Rosanna Peeling, Piero Olliaro Critical steps to ensure quality products – Bill Rodriguez Download Presentation Lessons learnt on bringing diagnostics to the market in low and middle income countries – Cassandra Kelly, FIND Download Presentation Regional regulatory harmonization working parties – Rosanna Peeling, LSHTM Download Presentation Streamlining from bench-to-bedside – Piero Olliaro, WHO TDR Download Presentation

Session 7: Identifying PDC’s roles to support innovative diagnostics Chairs: May Chu, Julie Schäfer Panel 1: Networks and alliances Dhamari Naidoo, WHO Download Presentation Francois-Xavier Babin, Merieux (Networks of Laboratories) Download Presentation

Overall, the aim of this meeting was to generate consensus on the current understanding of the immune response to and protection from dengue virus infection, identify key unanswered questions, and address how to improve measurement of efficacy in vaccine trials.

Deliverables

Suggested Research Agenda for investigation of dengue immune correlates; manuscript/conference report; draft of potential “reporting standards” for immune correlates data and plans for comparison of results across assays/consortia.

Speakers & Participants

• Ralph Baric, UNC School of Medicine
• Beth-Ann Coller, Merck and Co.
• Josefina Coloma, University of California, Berkeley
• Derek Cummings, University of Florida
• James Crowe, Vanderbilt Vaccine Center
• Hansi Dean, University of Wisconsin – Madison
• Aravinda De Silva, UNC School of Medicine
• Anna Durbin, Johns Hopkins University
• Michael Diamond, Washington University in Saint Louis
• Neil Ferguson, Imperial College London
• Peter Gilbert
• Aubree Gordon, University of Michigan / School of Public Health
• Duane Gubler, PDC / Duke University
• Bruno Guy, Sanofi Pasteur
• Scott Halstead, Dengue Vaccine Initiative
• Eva Harris, University of Berkeley
• Elizabeth Halloran, School of Public Health / University of Washington
• Joachim Hombach, WHO
• Richard Jarman
• Leah Katzelnick, University of Cambridge
• Shee-Mei Lok, DUKE Nus Medical School
• Nelson Michael, Walter Reed Army Institute of Research / U.S. Military HIV Research Program
• Eng Eong Ooi, DUKE Nus Medical School
• Ted Pierson, Viral Pathogenesis Section / Laboratory Viral Disease
• Stanley Plotkin, University of Pennsylvania
• Alex Precioso, Instituto Butantan
• Robert Reiner, Indiana University
• Felix Rey, Institut Pasteur
• Isabel Rodriguez-Barraquerv, John Hopkins Bloomerg School of Public Health
• Alan Rothman, University of Rhode Island
• Alex Schmidt, GSK
• Gavin Screaton, Imperial College London
• Cameron Simmons, Doherty Institute
• Tom W. Scott, University of California
• Alessandro Sette, La Jolla Institute for Allergy and Immunology
• Ashley St. John, DUKE Nus Medical School
• Wellington Sun, Center for Biologics Research and Review
• Remy Teyssou, PDC
• Stephen Thomas, WRAIR
• Joe Torresi, University of Melbourne
• John Tsang, NIH
• Kirsten Vannice, WHO
• Stephen Whitehead, Laboratory of Infectious Diseases, NIAID
• In-Kyu Yoon, AFRIMS

March 8 – Day 1

8:30 am	Opening and Welcome Duane Gubler and Remy Teyssou (PDC) (10 min) Introduction of participants (5 min) Eva Harris: Meeting Overview (10 min)
8:55 am	Stanley Plotkin: Overview talk I – What do we mean by immune correlates of protection? (15 min)
9:10 am	Joachim Hombach: Overview talk II – Immune correlates of protection in the dengue field (15 min)
9:25 am	Q&A (5 min)
9:30 am	Session 1: What have we learned from natural infections?: Humoral immunity and immune correlates (Neutralizing antibodies (titer/quantity) as immune correlates; epidemiology; virus serotypes and strains (serotype sequence and pathogenic genotypes); maternal antibody and infants; role of cellular immunity)
9:30 am	In-Kyu Yoon: Thai cohort studies (15 min)
9:45 am	Eva Harris: Nicaraguan cohort study (15 min)
10:00 am	Tom Scott: Iquitos cohort studies (15 min)
10:15 am	Cam Simmons: Infant studies (15 min)
10:30 am	Discussion (15 min)
10:45 am	Coffee Break (15 min)
11:00 am	Working Session 1 (1 hour)
	Breakout group 1: Epidemiology Discussion Leaders: Aravinda de Silva and Aubree Gordon; Rapporteur: Robert Reiner Primary infections: Is there truly protection against homotypic infection? What is the duration of cross protection from infection and disease? Is there a difference in the quality and quantity of antibodies after inapparent versus apparent primary infections? Is there a difference in the quality and quantity of antibodies in those exposed to primary infection at different ages (i.e. as infants, children or adults)? Secondary infections: Is there a critical window (time interval) after a first infection when second infections are more likely to be clinically severe? After recovery from a second infection, is there protection against serotypes not yet seen? Does the quality and quantity of cross neutralizing and cross protective antibodies depend on the sequence of 1st and 2nd infections? Third and fourth infections: How often have such infections been documented, what do we know about clinical outcome, what are their associated levels of viremia and transmissibility? Natural infections: Serum antibodies and B cells Discussion Leaders: Mike Diamond and Josefina Coloma; Rapporteur: Isabel Rodriguez-Barraquer Antibodies: Are there differences in protection/enhancement among serotypes? What can we conclude about protective and enhancing antibody responses from infant studies? Can we extrapolate from passive antibodies in infants to quantity and quality of protective antibodies required to protect children and adults? Aside from virus neutralization, what other measures of antibody function should be prioritized? B cells: MBC versus LLPCs: what is more important for protection? MBCs vs LLPCs: are the specificities the same or different? Does the quality and quantity of cross neutralizing and cross protective antibodies depend on the sequence of 1st and 2nd infections? How are functionally important antibody clones from 1st, 2nd and 3rd infections related to one another?
12:00 am	Report back to Plenary (30 min)
12:30 – 1:45 pm	Lunch
1:45 pm	The HIV experience with immune correlates Moderator: Betz Halloran Peter Gilbert: The HIV experience (20 min)
2:05 pm	Discussion (10 min)
2:15 pm	Session 2: Immune correlates in the context of dengue vaccines Moderator: Eng Eong Ooi
2:15 pm	Aravinda de Silva: Compare and contrast B cell responses to natural infections and vaccines (15 min)
2:30 pm	Derek Cummings: Modeling correlates from natural infections and vaccine trial data (15 min)
2:45 pm	Neil Ferguson: Modeling dengue vaccines: immunogenicity, correlates of protection and impact (15 min)
3:00 pm	Nick Jackson: The SP experience in the context of Phase 3 efficacy trials (15 min)
3:15 pm	Round Table of vaccine developers: Bruno Guy (SP), Hansi Dean (Takeda), Stephen Whitehead (NIH), Alex Schmidt (GSK), Beth-Ann Coller (Merck) (30 min)
3:45 pm	Discussion (15 min)
4:00 pm	Coffee Break (15 min)
4:15 pm	Working Session 2 (1 hour)
	Breakout Group 1: Efficacy Discussion Leaders: Betz Halloran and Cam Simmons; Rapporteur: Robert Reiner How should we define and measure protection for dengue vaccines? How do responses differ in DENV-naïve vs. DENV-exposed vaccinees and do we need different correlates for naïve vs. exposed vaccine recipients? Does age affect this response? What metrics should be used to characterize unbalanced/balanced responses to vaccines? Is an unbalanced immune response to vaccine predictive of increased risk of infection or disease? Is an unbalanced or partially effective immune response protective for severe disease? Is it possible to simultaneously immunize a DENV-seronegative subject against multiple DENV serotypes without immunodominance/interference giving rise to an asymmetric or ‘primary-like’ immune response? Do we need a vaccine to provide a balanced tetravalent response? Should we consider sequential immunization with different DENV serotypes? Should other factors beyond efficacy be considered in determining vaccine effectiveness? Breakout Group 2: Safety and other issues Discussion Leaders: Stanley Plotkin and Scott Hastead; Rapporteur: Leah Katzelnick How important is the potential of vaccine-induced ADE and immune enhancement from a public health perspective? If vaccination in seronegative recipients gives a ‘primary-like’ response, does it carry the same increased risks of symptomatic/severe disease upon next infection that are associated with the immune responses following a natural primary infection? Can safety issues be mitigated by improved risk management? Breakout Group 3: Lessons learned from ongoing vaccine clinical trials Discussion Leaders: Nick Jackson and Anna Durbin; Rapporteur: Kirsten Vannice What endpoints could improve measurement of vaccine effectiveness for dengue? What is the right balance of overall participants and intensively monitored individuals (serological cohorts)? What samples and measurements should be obtained from vaccine participants? What kind of risk management plans need to be implemented to ensure safety?
5:15 pm	Report back to Plenary (30 min)
5:45 pm	Plenary wrap-up Day 1 (15 min)
6:00 pm	Adjourn Day 1
	Dinner

March 9: Day 2

8:30 am	Learning from immune correlates research in HIV and influenza Moderator: Stephen Thomas
8:30 am	John Tsang: The influenza experience (15 min)
8:45 am	Nelson Michael: HIV vaccine immune correlates (15 min)
9:00 am	Discussion (15 min)
9:15 am	Session 3: Considerations for defining immune correlates Moderator: Shee-Mei Lok
9:15 am	Ted Pierson: How can we control for variables such as maturation and breathing in our search for immune correlates? (15 min)
9:30 am	Gavin Screaton: The role of highly neutralizing, cross-reactive antibodies/epitopes (15 min)
9:45 am	Leah Katzelnick: Antigenic cartography (15 min)
10:00 am	Wellington Sun: Assays, immune correlates, and dengue vaccines from the regulatory perspective (15 min)
10:15 am	Discussion (15 min)
10:30 am	Coffee Break (15 min)
10:45 am	Working Session 3 (1 hour)
	Breakout group 1: The virus Discussion Leaders: Felix Rey and Duane Gubler; Rapporteur: Leah Katzelnick Does intra-serotype variation lead to breakthrough infections/disease from homotypic or heterotypic immunity? Why are some DENV strains more virulent or have greater epidemic potential than others and does this have implications for identifying correlates and mechanisms of protective immunity? Which parameters are most critical in terms of modulating neut assays: viral dynamics, cell substrate, virus source, complement…? Does virus strain influence the type of serologic response elicited? Breakout group 2: Quality/repertoire of neutralizing antibodies Discussion Leaders: Ralph Baric and Joseph Torresi; Rapporteur: Josefina Coloma Can current understanding be improved through more sophisticated modelling and/or more epitope-specific assays? How to measure functional avidity? What other anti-viral functions of antibodies should we measure? Does age of infection/vaccination influence breadth/quality of repertoire? Breakout Group 3: Qualified assays Discussion Leaders: Wellington Sun and Stephen Whitehead; Rapporteur: Kirsten Vannice What are the features of a qualified assay? Role of reference panels and/or international standards in qualified assays What are the alternative or adjunctive assays that might provide better correlates of immunity in natural history or vaccine studies? Can they be qualified?
11:45 am	Report back to Plenary (30 min)
12:15 – 1:45 pm	Lunch
1:45 pm	Session 4: Research agenda for dengue immune correlates Moderator: Stephen Thomas All participants: Participants identify key research agenda items and/or elements of a target product profile for a dengue immune correlate (1 minute each); Discussion (1 hour)
2:45 pm	Coffee Break (15 min)
3:00 pm	Working Session 4 (1 hour)
	Breakout Group 1: Outstanding questions and cross-site analyses in natural DENV infections Discussion Leaders: Eva Harris and Derek Cummings; Rapporteur: Aubree Gordon Immune correlates: What immune correlates should be tested? What should be reported? What are critical elements of a ‘better’ immune correlate? What is the Target Product Profile of an immune correlate? Cross-site analysis: What questions should be addressed? How should data be “harmonized” and compared? Breakout Group 2: Antibody repertoire and next-gen vaccines Discussion Leaders: Aravinda de Silva and Jim Crowe; Rapporteur: Ashley St. John How do we optimally measure epitope-specific responses in polyclonal antibody responses after infection or vaccination? How can we direct the antibody repertoire towards the “best” epitopes? What will 2nd generation dengue vaccines look like? Breakout Group 3: The role of CMI studies Discussion Leader: Alan Rothman and Alex Sette; Rapporteur: Kirsten Vannice What is the evidence for any or various T cell subsets contributing to immunity to DENV re-infection? How could we gather such evidence? Are there precedents in other diseases for T cells being correlates of vaccine-elicited immunity? What would a correlative T cell assay look like? Could T cell vaccines work? Are T cell follicular responses useful correlates of B cell responses/memory?
4:00 pm	Report back to Plenary (30 min)
4:30 pm	Meeting wrap-up (30 min)
5:00 pm	Meeting adjournment

This meeting was designed to follow up on a first workshop concerning the status of new dengue control strategies, held in November 2013. Participants reviewed currently available dengue control tools and strategies, providing expert opinion on the most effective ones targeting the primary urban dengue vector, Aedes aegypti, which can be utilized in combination with vaccination.

Continuing to focus on the vector control approach with the largest impact

The workshop’s overriding goal was to reach consensus on what vector control tools and strategies have the biggest impact on the reduction of DENV transmission. Another objective of the meeting was to address the design of trials, either alone or in combination with vaccination.

A triple focus to advance scientific understanding

The workshop was organized around three pillars:

• A questionnaire was used to obtain expert opinion on the relative effectiveness of vector control interventions
• Reviews of major dengue and malaria control interventions, dengue epidemiology, dengue vaccines, and trial design were presented
• A recommendation on currently available vector control strategies that should be coupled with dengue vaccination was presented

Workshop outcomes

Of currently available methods, indoor residual spraying (termed “targeted IRS” or TIRS, to distinguish it from malaria IRS interventions) was thought to be most effective, although insecticide resistance would reduce efficacy in certain situations and must be prospectively evaluated. Experts concluded that TIRS is the best available strategy to control urban populations of Ae. aegypti and prevent dengue. While there is evidence TIRS significantly reduces populations of adult Ae. aegypti, randomized controlled trials (RCTs) with epidemiological-endpoint data have not been conducted. Moreover, TIRS associated with larvae control could provide the highest effectiveness.

It was agreed that the “gold standard” trial design is an RCT. The working group also made several other recommendations.

Progress towards reducing transmission of the virus

PDC’s expectation is that when an effective DENV vaccine is commercially available, the public health community will continue to rely on vector control because the two strategies complement and enhance one another. The work accomplished by workshop participants supports efforts to determine which vector control approaches, when utilized in combination with vaccination, will have the greatest impact on reduction of DENV transmission.

Download full summary

Speakers & Participants

• Nicole Achee, Uniformed Services University of the Health Sciences / University of Notre Dame
• Kate Antrobus, Lion’s Head
• Roberto Barrera, CDC
• Thomas Burkot, James Cook University
• David Chadee, University of the West Indies
• Greg Devine, Queensland Institute of Medical Research
• Benjamin D’Hont, PDC
• Catherine Dutel, PDC
• Timothy Endy, Upstate Medical University
• Duane Gubler, PDC / Duke University
• Joachim Hombach, WHO
• Immo Kleinschmidt, London School of Hygiene & Tropical Medicine
• Andrew Lane, LANE medical writing services
• Audrey Lenhart, CDC
• Steve Lindsay, Durham University
• Mathias Mondy, IVCC
• Amy Morrison, University of California
• Alan Perkins, University of California
• Robert Reiner, Indiana University
• Paul Reiter, Pasteur Institute
• Scott Ritchie, James Cook University
• Peter Ryan, Monash University
• Mitra Saadatian-Elahi, PDC
• Thomas W. Scott, University of California
• François Simondon, IRD
• Daniel Strickman, Bill & Melinda Gates Foundation
• Rémy Teyssou, PDC
• Kirsten Vannice, WHO
• Gonzalo Vazquez-Prokopec, Emory University
• Raman Velayudhan, WHO
• Simon Warner, OXITEC Ltd

Program – Day 1

09h00 – 12h00	General opening session and introduction (T. Scott) Conclusions from 2013 ASTMH meeting (Washington) (N. Achee) Prioritized list of vector control for dengue control: Feasibility matrices (S. Ritchie, G. Devine, D. Chadee) New insecticide formulations/methods in development (A. Lenhart) Lessons learned from vector control assessments for malaria (T. Burkot)
13h00 – 17h00	Measuring epidemiological impact for assessing efficacy (S. Lindsay) Lessons learned from dengue prevention programs: Traditional dengue control (A. Morrison) Wolbachia (P. Ryan) Spatial repellants (N. Achee) Lethal ovitraps (R. Barrera) RIDL (S. Warner) How to define and implement appropriate metrics (D. Smith)

Program – Day 2

09h00 – 10h30	Develop a study design (T. Scott) The vaccine perspective (T. Endy) The vector control perspective (S. Ritchie)
11h00 – 12h00	Study design options and considerations (Part 1) (R. Reiner)
13h00 – 16h30	Study design options and considerations (Part 2) (R. Reiner)
16h30 – 17h00	Conclusions

Case definitions for dengue were first developed using clinical experiences from dengue outbreaks involving children in Southeast Asia. The case definitions were published in the World Health Organization (WHO) technical guide in 1975 and updated in 1997. The WHO 1997 classification offers the possibility of grading of the severity of dengue cases. In November 2009, a new dengue case classification using a set of clinical and/or laboratory parameters was released by WHO to improve clinical management and surveillance across the globe in all settings, regardless of resources.

The value of a standardized dengue clinical case classification system

The workshop’s main objective was to reach consensus on a dengue clinical case classification (DCCC) system for moderate and severe dengue to be used in pathogenesis studies and/or intervention trials. Standardized definitions are very important to help ensure complete, accurate and harmonized classification of cases to monitor the long-term safety and effectiveness of dengue vaccines and to compare interventions. Currently, manufacturers use their own endpoints for severity.

Contributing to more targeted clinical research on dengue

The WHO case definitions established in 2009 are widely applied in endemic countries for case detection, patient triage and clinical management. However, they are of limited use in clinical research, especially as regards criteria for severe disease.

The workshop addressed this challenge by developing a refined clinical case classification for moderate and severe dengue that can be applied in interventional trials and pathogenesis studies as secondary endpoints. Case definitions are to be used to classify study subjects who are being monitored as part of an interventional trial or pathogenesis study and who meet the primary efficacy endpoint (i.e., two days of fever plus laboratory-confirmed DENV infection).

Workshop outcomes

Although the final definition of a proposed clinical case classification for clinical trials was not reached, workshop participants made progress in the identification of clinical and laboratory parameters to clearly approach a consensus about the definition of severe dengue. After the April workshop, a follow-up meeting was planned to coincide with the 64th Annual Meeting of the American Society of Tropical Medicine and Hygiene, October 25-29 2015.

At this follow-up workshop, held in Philadelphia on October 29, participants continued to move forward to reach consensus about clinical trial endpoints for the purpose of measuring the efficacy of dengue interventions on disease severity.

Assessing the impact of PDC’s holistic approach

Improving the comparability of data obtained from interventional trials and pathogenesis studies is particularly useful for the purpose of measuring the impact of PDC’s integrated vaccine intervention and vector control approach and to accurately assess the clinical benefit of a vaccine or drug. Standardization was requested during the Mexico meeting on surveillance. Comparability between interventions is a key step for assessing public health strategies.

Download full summary

Speakers & Participants

• Ana Carvalho, Sabin Vaccine Institute
• Danilo Casimiro, Merck
• Cristina Cassetti, NIAID
• Beth-Ann Coller, Merck and Co.
• Norma De Bosch, Universidad Central de Venezuela
• Walla Dempsey, NIAID
• Benjamin D’Hont, PDC
• Anna Durbin, Johns Hopkins University
• Catherine Dutel, PDC
• Robert Edelman, University of Maryland
• Michael Fay, NIAID
• Duane Gubler, PDC / Duke University
• Adrienne Guignard, GSK
• Scott Halstead, Dengue Vaccine Initiative
• Eva Harris, University of Berkeley
• Katharina Hartmann, Takeda Vaccines Inc.
• Joachim Hombach, WHO
• Elizabeth Hunsperger, CDC
• Thomas Jänisch, University Heidelberg
• Denny Kim, Takeda Vaccines
• Andrew Lane, LANE medical writing services
• Catherine Laughlin, NIAID
• Maïna L’Azou, Sanofi Pasteur
• Lucy Lum, Univ Malaya Medical Center
• Harold Margolis, CDC
• Morgan Marks, Merck and Co. Inc
• Federico Narvaez, Hospital Infantil Manuel de Jesus Rivera
• Van Vinh Chau Nguyen, Hospital for Tropical Diseases
• Fernando Noriega, Sanofi Pasteur
• Alexander Precioso, Instituto Butantan
• Elsa Rojas, Universidad Industrial de Santander
• Alan Rothman, University of Rhode Island
• Mitra Saadatian, PDC
• Alexander Schmidt, GSK
• Thomas W. Scott, University of California
• João Bosco Siqueira, Federal University of Goias
• Daniel Stoughton, DMID/NIAID/NIH
• Piyarat Suntarattiwong, Queen sirikit Nat’l Inst of Child Health
• Rémy Teyssou, PDC
• Stephen Thomas, WRAIR
• Laurent Thomas, Emergency Department / University Hospital
• Hasitha Tissera, Ministry of Health Sri Lanka
• Kay Tomashek, NIAID
• Harshini Turner, Takeda Vaccines Inc.
• Kirsten Vannice, WHO
• Frank Von Sonnenburg, Department Infectious Diseases and Tropical Medicine, University of Munich, LMU
• Derek Wallace, Takeda
• Stephen Whitehead, Laboratory of Infectious Diseases, NIAID
• Annelies Wilder-Smith, IVI
• Bridget Wills, Oxford University Clinical Research Unit
• Dana Yancey, Emmes Corporation
• Yee Sin Leo, National University of Singapore
• In-Kyu Yoon, AFRIMS

Program – Day 1

08h00 – 10h00	Concomitant Scientific Working Group Meetings
10h00 – 10h30	Welcome and Introduction
10h30 – 12h00	Session I: Framing the issue: the challenges of measuring dengue disease severity in pathogenesis studies and interventional research Observational/pathogenesis studies in international clinical settings (Thomas Jänisch) Sanofi’s experience on disease classification from Phase II/Phase III vaccine trials (Fernando Noriega) Takeda’s experience on disease classification from Phase II vaccine trials (Derek Wallace) Oxford University’s experience from Phase II therapeutic trials (Bridget Wills) Status of rapid dengue diagnostics for use in interventional trials (Elizabeth Hunsperger)
13h00 – 13h50	Session II: Defining dengue severity markers: acute febrile illness (Bob Edelman and Stephen Thomas)
13h50 – 15h00	Session III: Defining dengue severity markers: severe bleeding Lucy Lum and Norma de Bosch)
15h30 – 17h30	Session IV: Defining dengue severity markers: plasma leakage (Bridget Wills and Elsa Rojas)

Program – Day 2

08h00 – 12h00	Session V: Defining dengue severity markers: organ involvement Liver and gastrointestinal tract (Kay Tomashek) Central nervous system and lung (Lucy Lum and Laurent Thomas) Muscle, heart, and kidney (Laurent Thomas and Anna Durbin)
13h00 – 14h00	Session VI: Plans to evaluate a refined dengue clinical case definition (Thomas Jänisch and João Bosco Siqueira)
14h30 – 16h30	Session VII: Summary and next steps (Walla Dempsey and Stephen Thomas)

Accurate and effective surveillance of dengue is fundamental to measuring the burden of dengue disease and, ultimately, to improving its control. The mission of the Partnership for Dengue Control (PDC) is to promote development and implementation of innovative, integrated, synergistic approaches for the prevention and control of dengue. The purpose of this 2-day meeting was to bring together a diverse group of experts, with representatives from universities, non-governmental organizations (NGOs), health agencies, and private sector companies, to discuss and address key issues related to dengue surveillance in the context of the limitations of the current systems and the future introduction of new tools for dengue control.

Taking integrated action to improve surveillance

This workshop looked at ways to improve both disease and vector surveillance. Vaccine, vector, laboratory, epidemiology and public health specialists reviewed the current dengue control situation and laboratory diagnostic techniques. The participants discussed areas for future development, such as more robust surveillance systems and new intervention tools, as well as the idea of introducing surveillance to areas that do not currently have systems in place, with a focus on Africa.

Advancing the research agenda

Experts at the workshop discussed potential items for the operational research agenda in the fields of vector control, surveillance and diagnostics. They agreed on a general need to design key messages and initiatives for targeted audiences. In the context of the introduction of a dengue vaccine and the emergence of new tools, they emphasized the importance of developing advocacy and communication roadmaps.

Workshop outcomes

Experts at the workshop discussed potential items for the operational research agenda in the fields of vector control, surveillance and diagnostics. They agreed on a general need to design key messages and initiatives for targeted audiences. In the context of the introduction of a dengue vaccine and the emergence of new tools, they emphasized the importance of developing advocacy and communication roadmaps.

Workshop outcomes

Several recommendations were developed in support of a global strategy for dengue control:

• Adopt a combined approach to disease surveillance to improve data quality;
• Focus more on adult mosquitoes (rather than larvae and pupae);
• Ensure standardized laboratory methods for diagnostic testing supported by robust quality controls, guidance and training;
• Harness new technologies to detect dengue outbreaks and febrile illness faster;
• Increase awareness through training programs for the healthcare community and the public;
• Build on existing polio and influenza infrastructure to improve surveillance;
• Fully engage all stakeholders by collecting, analyzing and presenting high quality data;
• Organize regular meetings between experts in the vaccine, pesticide and vector control communities;
• Make developing and implementing sound training programs a key priority.

Supporting PDC’s integrated approach and long-term strategy

PDC is ready to engage with several partners to improve integration of laboratory and disease surveillance, in particular focusing on more sensitive and rapid diagnostic tests. Another key factor to improve dengue surveillance is enhanced data and information sharing.

Speakers & Participants

• Kwasi Amfo, Takeda
• Miguel Betancourt, Carlos Slim Foundation
• Ana Carvalho, Sabin Vaccine Institute
• José Ramos Castañeda, Instituto Nacional de Salud Publica
• Catherine Dutel, PDC
• Héctor Gomez-Dantes, Instituto Nacional de Salud Publica
• Duane Gubler, PDC / Duke University
• Maria Guzman, PAHO/ WHO, Tropical Medicine Institute ‘Pedro Kouri’
• Scott Halstead, Dengue Vaccine Initiative
• Eva Harris, University of Berkeley
• Elizabeth Hunsperger, CDC
• Dennis Israelsky, Stanford University
• Jacqueline Kyung Ah Lim, IVI
• Andrew Lane, LANE medical writing services
• Arturo Losoya, Bayer
• Aurélie Malecot-Chabanel, PDC / Alcimed
• Harold Margolis, CDC
• Amy Morrison, University of California
• Ricardo Palacios, Instituto Butantan
• Scott Ritchie, James Cook University
• Elsa Sarti, Sanofi Pasteur
• Tom W. Scott, University of California
• Donald Shepard, Brandeis University
• João Bosco Siqueira, Federal University of Goias
• Mark Smolinsky, Skoll Global Threats
• Rémy Teyssou, PDC
• Georges Thiry, DVI
• Eduardo Andres Undurraga, Brandeis University
• Steve Waterman, CDC

Program – Day 1

08h30 – 14h30	Topic 1: Changes in dengue surveillance in the context of the introduction of new tools for control
	Plenary: State of the art disease surveillance (H. Margolis)
	Plenary: State of the art vector surveillance (S. Ritchie)
	Plenary: Key issues that could affect surveillance results for an integrated disease and vector surveillance system in a country where an integrated control program has been initiated. (S. Ritchie and G. Thiry)
	Workshop A: Disease surveillance in the context of vaccine introduction (D. Gubler)
	Workshop B: How to perform integrated surveillance (H. Gomez)
	Discussion of Topic 1 (H. Gomez)
14h30 – 18h00	Topic 2: Laboratory techniques and surveillance
	Plenary: State of the art currently available laboratory methods and new approaches for diagnosis and surveillance (E. Harris)
	Workshop C: How do we currently use available technology to support disease and vector surveillance? (M. Guzman)
	Workshop D: New and innovative technology (E. Harris)
	Discussion of Topic 2 (E. Harris)

Program – Day 2

09h00 – 14h30	Topic 3: New technologies
	Plenary: How new technologies may improve surveillance in areas with and without capacity (M. Smolinski)
	Plenary: New technologies for surveillance mapping (T. Scott)
	Workshop E: How could social networks help to improve the current surveillance of dengue? (M. Smolinski)
	Workshop F: Can we use new technologies (such as specific software for cell phones), for surveillance in remote areas? What are the implications in terms of lay public involvement, but also in terms of sensitivity and specificity? (M. Betancourt)
	Discussion of Topic 3 (M. Smolinski)
14h30 – 17h00	Topic 4: Surveillance in countries that do not have any system in place
	Plenary: State of the art issues in specific contexts – focus on Africa (H. Margolis)
	Workshop G: What methodology/indicators should be put in place in countries where nothing exists? (J. Lim and H. Margolis)
	Discussion of Topic 4 (H. Margolis)
17h00 – 18h00	Consensus on conclusions from the meeting