• event

    Dengue Immune Correlates of Protection

March 8-9, 2016 - Annecy (France)

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