Immune correlates of protection for dengue: State of the art and research agenda

Abstract

Dengue viruses (DENV1-4) are mosquito-borne flaviviruses estimated to cause up to ∼400 million infections and ∼100 million dengue cases each year. Factors that contribute to protection from and risk of dengue and severe dengue disease have been studied extensively but are still not fully understood. Results from Phase 3 vaccine efficacy trials have recently become available for one vaccine candidate, now licensed for use in several countries, and more Phase 2 and 3 studies of additional vaccine candidates are ongoing, making these issues all the more urgent and timely. At the "Summit on Dengue Immune Correlates of Protection", held in Annecy, France, on March 8-9, 2016, dengue experts from diverse fields came together to discuss the current understanding of the immune response to and protection from DENV infection and disease, identify key unanswered questions, discuss data on immune correlates and plans for comparison of results across assays/consortia, and propose a research agenda for investigation of dengue immune correlates, all in the context of both natural infection studies and vaccine trials.

Keywords: Dengue virus; Immune correlates of protection; Immune correlates of risk; Natural infection; Vaccine.

Conflict of interest statement

Conflicts of Interest

The Partnership for Dengue Control has multiple operating partners, including Fondation Mérieux, Dengue Vaccine Initiative (DVI), National Institutes of Health (NIH), and Sabin Vaccine Institute, as well as funding partners, including Bill & Melinda Gates Foundation, Sanofi Pasteur, Takeda, Bayer, GSK, and bioMérieux. Ralph Baric has financial relationships with several dengue tetravalent virus vaccine manufacturers. Beth-Ann Coller is an employee, shareholder, and patent inventor for Merck & Co., Inc., Kenilworth, NJ, USA. James E. Crowe, Jr. is a consultant for Sanofi; is on the Scientific Advisory Boards of PaxVax, CompuVax, GigaGen, Meissa Vaccines, and Rensavir; and is a recipient of research grants from Moderna and Sanofi. Derek Cummings, Neil Ferguson, and Isabel Rodriguez-Barraquer advised Sanofi Pasteur Ltd., without payment, on modeling the potential impact of their dengue vaccine. Hansi Dean an employee of Takeda Pharmaceuticals Vaccine Business Unit. Aravinda de Silva has consulted for Takeda Vaccines, GSK and Merck Pharmaceuticals and is an inventor on patents related to dengue vaccines that have been filed by the University of North Carolina. Michael S. Diamond is a consultant for Inbios, Visterra, and Takeda Pharmaceuticals and on the Scientific Advisory Boards of Moderna and OvaGene. Peter B. Gilbert received a contract from Sanofi Pasteur to analyze data from its clinical trials. Duane J. Gubler is a patent holder on the Takeda dengue vaccine, has Investment in Takeda Pharmaceuticals, and has consulting activities to Sanofi, Takeda, and Merck on dengue. M. Elizabeth Halloran is in the Modelling Consortium with Sanofi, but did not receive payment and is involved in the development of the Phase IV evaluation of Dengvaxia in the Yucatan. Eva Harris served on the Scientific Advisory Board of Sanofi Pasteur during the Phase 3 vaccine trials, and her laboratory received research funds from Takeda Vaccines, Inc. to analyze samples from vaccine recipients. Nicholas Jackson, Bruno Guy, and Athanasios Papadopoulos are Sanofi Pasteur employees. Stanley Plotkin is a consultant to many manufacturers, including Sanofi Pasteur, manufacturer of a dengue vaccine. Alexander R. Precioso is the Director of the Clinical Trials and Pharmacovigilance Division and coordinator of the phase III Butantan dengue vaccine clinical trial for Instituto Butantan, a public owned Institution of the Government of Sao Paulo State, Brazil, which has a development and manufacturing program for an attenuated tetravalent dengue vaccine. Alan Rothman has served as a Consultant for Sanofi and Takeda. Alexander Schmidt is an employee of the GSK group of companies and holds shares in GSK. Gavin Screaton and Felix A. Rey are named inventors on a patent application by Imperial College and Institut Pasteur for EDE antibodies and epitope. Cameron Simmons is a principal investigator in the Eliminate Dengue program – this entity is evaluating a technology for arbovirus disease control that competes with dengue vaccines. Joseph Torresi has had speaker honoraria and consultancies with Sanofi Pasteur, GSK, and Bristol Myers Squibb and an unrestricted research grant with SanofiPasteur. Kirsten Vannice is a staff member of the World Health Organization. Leah Katzelnick, Josefina Coloma, Anna Durbin, Aubree Gordon, Scott Halstead, Richard Jarman, Shee-mei Lok, Nelson Michael, Robert Reiner, Alessandro Sette, Ashley St. John, Wellington Sun, Stephen Thomas, John Tsang, Stephen Whitehead, Annelies Wilder-Smith, and In Kyu Yoon do not report conflicts of interest.

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