Elsevier

Vaccine

Volume 35, Issue 36, 24 August 2017, Pages 4659-4669
Vaccine

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

https://doi.org/10.1016/j.vaccine.2017.07.045Get rights and content

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.

Introduction

Dengue is the most prevalent arthropod-borne viral disease globally. The four serotypes of dengue virus (DENV1-4) cause up to approximately 400 million infections annually [1] ranging from asymptomatic infection to severe disease manifested by vascular leak, hemorrhagic manifestations, and shock [2]. A major goal of dengue research is to identify and understand immune correlates of protection and risk (Box 1) of DENV infection, dengue illness, and severe disease, particularly in the context of vaccines (Box 2).

Here we summarize insights from the “Summit on Dengue Immune Correlates of Protection”, sponsored by the Partnership for Dengue Control. This summit focused on research on dengue immunology and pathogenesis in relation to correlates of protection and risk. The goal of the summit was to review the state-of-the-art regarding immunity to DENV natural infections and vaccines (Box 3) and to generate a research agenda of key unanswered questions (Box 4). We also addressed methods for measuring dengue immune correlates, measurement of safety and efficacy in vaccine trials, and a framework for comparing results across consortia, vaccines, and research sites (Box 5).

Section snippets

Dynamics of immunity following natural infection

The dynamics of immunity derived from natural DENV infections provide important insights into the appropriate time-point(s) to measure immune correlates of protection for vaccines. After natural primary DENV infection, the antibody response against the homologous infecting serotype is potently neutralizing and thought to be life-long; however, individuals also generate a large quantity of less-neutralizing cross-reactive antibodies that initially protect against but may later enhance infection

Antibodies induced by vaccination

The strategy for dengue vaccination has been to immunize simultaneously with antigens from DENV1-4 in an effort to induce balanced type-specific neutralizing responses to each serotype [39]. There are currently multiple dengue vaccine candidates, including live-attenuated vaccines (LAV), whole virus inactivated vaccines, protein-based vaccines, and more recently mRNA-based vaccines; all are tetravalent [40]. The magnitude of the vaccine-mediated immune response is generally lower than in

The virus

Dengue virions display on their surface a lattice of pre-membrane/membrane (prM/M) and envelope (E) proteins. DENV strains vary in temperature sensitivity and maturation state, in part due to laboratory-adapted mutations in prototype and some vaccine strains, which may not be representative of circulating strains [65]. Such amino acid differences can also lead to differences in virion “breathing”, which allows cryptic epitopes to be revealed during temperature- and time-dependent changes in the

Age, serostatus, and disease severity in vaccine trials

Given the differences observed in all vaccine trials to date between flavivirus- and/or DENV-seropositive and -seronegative vaccine recipients, vaccine efficacy must be assessed separately according to prior baseline serostatus; whether studies should be powered to evaluate vaccine efficacy by baseline serostatus was also discussed. An exploratory analysis of a recent Phase 3 trial showed a significant increase in risk of hospitalization with dengue disease in vaccinated 2–5 year olds 1–2 years

Conclusions

The Summit on Dengue Immune Correlates of Protection highlighted recent advances in research toward identifying DENV immune correlates in the context of natural DENV infections and vaccines, as well as remaining research questions and challenges to be addressed in the future.

Acknowledgments

We thank the Scientific Committee for developing and guiding the agenda of the Summit: Aravinda de Silva, Derek Cummings (co-Chair), Neil Ferguson, Duane Gubler, Eva Harris (co-Chair), and Cameron Simmons. We thank Remy Teyssou, Benjamin D’Hont and other members of the Organizing Committee of the PDC and Les Pensières for their work supporting and organizing Summit. We are grateful to the Rapporteurs for their valuable contributions: Leah Katzelnick, Josefina Coloma, Aubree Gordon, Isabel

Funding sources

The “Summit on Dengue Immune Correlates of Protection” was sponsored by the Partnership for Dengue Control. Writing this report was supported by National Institutes of Health (NIH), National Institute for Allergy and Infectious Diseases grant P01 AI106695 (EH).

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

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