The Dual Role of the Antibody Response Against the Flavivirus Non-structural Protein 1 (NS1) in Protection and Immuno-Pathogenesis

A candidate tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian-Pacific and Latin American countries. We report the results of long-term follow-up interim analyses and integrated efficacy analyses.

For decades, arboviral diseases were considered to be only minor contributors to global mortality and disability. As a result, low priority was given to arbovirus research investment and related public health infrastructure. The past five decades, however, have seen an unprecedented emergence of epidemic arboviral diseases (notably dengue, chikungunya, yellow fever, and Zika virus disease) resulting from the triad of the modern world: urbanisation, globalisation, and international mobility. The public health emergency of Zika virus, and the threat of global spread of yellow fever, combined with the resurgence of dengue and chikungunya, constitute a wake-up call for governments, academia, funders, and WHO to strengthen programmes and enhance research in aedes-transmitted diseases. The common features of these diseases should stimulate similar research themes for diagnostics, vaccines, biological targets and immune responses, environmental determinants, and vector control measures. Combining interventions known to be effective against multiple arboviral diseases will offer the most cost-effective and sustainable strategy for disease reduction. New global alliances are needed to enable the combination of efforts and resources for more effective and timely solutions.

The flavivirus nonstructural glycoprotein NS1 is an enigmatic protein whose structure and mechanistic function have remained somewhat elusive ever since it was first reported in 1970 as a viral antigen circulating in the sera of dengue-infected patients. All flavivirus NS1 genes share a high degree of homology, encoding a 352-amino-acid polypeptide that has a molecular weight of 46-55 kDa, depending on its glycosylation status. NS1 exists in multiple oligomeric forms and is found in different cellular locations: a cell membrane-bound form in association with virus-induced intracellular vesicular compartments, on the cell surface and as a soluble secreted hexameric lipoparticle. Intracellular NS1 co-localizes with dsRNA and other components of the viral replication complex and plays an essential cofactor role in replication. Although this makes NS1 an ideal target for inhibitor design, the precise nature of its cofactor function has yet to be elucidated. A plethora of potential interacting partners have been identified, particularly for the secreted form of NS1, with many being implicated in immune evasion strategies. Secreted and cell-surface-associated NS1 are highly immunogenic and both the proteins themselves and the antibodies they elicit have been implicated in the seemingly contradictory roles of protection and pathogenesis in the infected host. Finally, NS1 is also an important biomarker for early diagnosis of disease. In this article, we provide an overview of these somewhat disparate areas of research, drawing together the wealth of data generated over more than 40 years of study of this fascinating protein. Copyright © 2013 Elsevier B.V. All rights reserved.