Background. Despite the strong association between secondary dengue virus (DENV) infections and dengue hemorrhagic fever (DHF), the majority of secondary infections are subclinical or mild. The determinants of clinical severity remain unclear, though studies indicate a titer-dependent and time-dependent role of cross-protective anti-DENV antibodies.Methods. Data from 2 sequential prospective cohort studies were analyzed for subclinical and symptomatic DENV infections in schoolchildren in Kamphaeng Phet, Thailand (1998-2002 and 2004-2007). Children experiencing ≥1 DENV infection were selected as the population for analysis (contributing 2169 person-years of follow-up).Results. In total, 1696 children had ≥1 DENV infection detected during their enrollment; 268 experienced 2 or more infections. A shorter time interval between infections was associated with subclinical infection in children seronegative for DENV at enrollment, for whom a second-detected DENV infection is more likely to reflect a true second infection (average of 2.6 years between infections for DHF, 1.9 for DF, and 1.6 for subclinical infections).Conclusions. These findings support a pathogenesis model where cross-reactive antibodies wane from higher-titer, protective levels to lower-titer, detrimental levels. This is one of the first studies of human subjects to suggest a window of cross-protection following DENV infection since Sabin's challenge studies in the 1940s.
Bibliographical noteFunding Information:
Acknowledgments. We thank Alan Rothman, John McGowan, Ruth Berkelman, and Dana Flanders for their careful review and helpful comments on the analysis and the article. We thank the staff at the Department of Virology, Armed Forces Research Institute of Medical Science (Bangkok, Thailand) for their careful diagnostic testing and data collection and entry. We acknowledge the support of the Office of the Provincial Public Health, Kamphaeng Phet province, and the clinical research nurses at AFRIMS and the support staff at the Kamphaeng Phet Field Station for all their efforts. This project and publication was made possible by Dissertation grant 1R36CK00104 from the Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH) grant P01 AI034533, the Military Infectious Diseases Research Program (MIDRP) and the United States Army Medical Research and Materiel Command, Ft Detrick, MD, USA. The opinions expressed in this manuscript do not necessarily represent the official views of the US NIH, the US Department of Defense, or the US Department of the Army.
Financial support. The clinical trial was supported by the United States Army Medical Research and Materiel Command, Ft Detrick, MD, USA. The analysis was supported by Dissertation grant 1R36CK00104 from the CDC, NIH Grant P01 AI034533, and the Military Infectious Diseases Research Program (MIDRP). The opinions expressed in this manuscript do not necessarily represent the official views of the US Department of Defense, or the US Department of the Army.
- prospective cohort study