Proinflammatory cytokines secreted by memory CD8؉ and CD4 ؉ T cells are thought to play a direct role in the pathogenesis of dengue virus infection by increasing vascular permeability and thereby inducing the pathophysiologic events associated with dengue hemorrhagic fever and dengue shock syndrome. Severe disease is frequently observed in the setting of secondary infection with heterologous dengue virus serotypes, suggesting a role for cross-reactive memory T cells in the immunopathogenesis of severe disease. We used a large panel of well-characterized dengue virus-specific CD8 ؉ T-cell clones isolated from Pacific Islanders previously infected with dengue virus 1 to examine effector memory function, focusing on a novel dominant HLA-B*5502-restricted NS5 329-337 epitope, and assessed T-cell responses to stimulation with variant peptides representing heterologous serotypes. Variant peptides were differentially recognized by dengue virus 1-specific effector CD8

We investigated the duration of humoral responses to dengue virus infection in individuals who recalled experiencing dengue fever-like illnesses at the time of the Second World War, when dengue fever epidemics occurred throughout the Pacific and Southeast Asia. In July 1943 dengue fever reappeared in Hawaii following an interval of 31 years. Over the next 12 months a total of 1498 locally transmitted cases were reported, and at least 46 imported cases were identified, most of which were among members of the military returning from the Pacific Theatre of the war. Serum samples collected in 2005, more than 60 years after onset of symptoms, were tested for the presence of dengue-specific antibodies using a rapid ELISA test, and by plaque reduction neutralization test. Four of seven samples were positive for dengue-specific IgG and demonstrated neutralization titers ≥160 to dengue 1. We describe the existence of dengue-specific antibodies in the serum of people infected more than 60 years earlier. BRIEF REPORTDengue Viruses Are mosquito-borne single-stranded RNA viruses that belong to the family Flaviviridae. Infection with any of the four dengue serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) can cause a spectrum of illnesses ranging from asymptomatic infection to severe hemorrhagic disease and shock syndrome, which can be fatal. Immunity to one dengue serotype following a first, or primary, infection does not protect against subsequent infection with any of the other three serotypes, and indeed, epidemiological observations suggest that severe disease occurs more frequently in the setting of secondary infection with heterologous virus (reviewed in 6 , 7). The pathogenesis of the severe forms of disease is not fully understood, but one hypothesis is based on the idea of antibody-dependent enhancement, in which preexisting non-neutralizing antibodies induced during the first dengue infection enhance infection of mononuclear cells during the second infection via cell surface FcγR (9, reviewed in 13). Thus, persistence of dengue-specific antibody may be a significant risk factor for development of severe disease in countries where dengue is hyperendemic.

Author contributions: Wen-Ming Chu conceived and directed the project and performed a large body of experiments.

dWe evaluated the FDA-cleared InBios dengue virus (DENV) IgM capture enzyme-linked immunosorbent assay (ELISA) for qualitative detection of anti-DENV IgM antibodies from 79 serum samples obtained from dengue virus-infected patients or suspected dengue cases. The agreement, sensitivity, and specificity of the InBios assay compared to the gold standard in-house DENV IgM capture ELISA were 94, 92, and 94%, respectively. We conclude that the InBios DENV IgM capture ELISA can be effectively used for rapid diagnosis of acute or recent DENV infection. Dengue virus (DENV) a mosquito-borne flavivirus, is a significant human pathogen of global importance (1). Dengue, an acute viral disease, is caused by any one of the four DENV serotypes, DENV-1, -2, -3, and -4 (2). Although most of the reported dengue cases in the United States are acquired by travelers or immigrants (3), autochthonous dengue fever outbreaks have occurred in Brownsville, TX (2005), and southern Florida (2009 to 2011) and Hawaii (2011) (4). To date, there is no vaccine or specific antiviral treatment for dengue virus infection in humans, and effective management of severe dengue virus disease can be augmented by rapid diagnosis during the acute stage of infection (5, 6).In the majority of DENV infections, immunoglobulin M (IgM) antibodies can be detected within 3 to 5 days following the onset of fever (7). In secondary DENV infection, IgM antibody titers are usually lower than those in primary DENV infection but follow similar kinetics (8). An ideal IgM serologic test should have sufficient sensitivity to detect low DENV IgM antibody titers and be specific enough to discriminate DENV infection in areas where multiple flaviviruses and other pathogens cocirculate (9). Several rapid diagnostic tests are commercially available for detection of anti-DENV IgM antibodies (9). Therefore, it is important to evaluate the performance characteristics of these kits in terms of sensitivity and specificity in order to ensure accurate and rapid diagnosis of dengue virus infection (5). Recently, the U.S. Food and Drug Administration (FDA) cleared the InBios DENV Detect IgM capture enzyme-linked immunosorbent assay (ELISA) (InBios International, Inc., Seattle, WA) for qualitative detection of anti-DENV IgM antibodies (4). This test can detect acute or recent DENV infections and can be used by public health laboratories for rapid confirmation of dengue cases during dengue outbreaks (4).(These research data are part of the master's thesis of M.N. submitted to the University of Hawaii.)In this study, we evaluated the InBios DENV IgM capture ELISA in comparison with the in-house DENV IgM antibody capture (MAC) ELISA using 79 well-characterized clinical serum samples collected from Hawaii, Vietnam, Niue, Singapore, and American Samoa, where dengue outbreaks have occurred in the past. Samples were coded and collected in compliance with the University of Hawaii Institutional Review Board guidelines (CHS 16857 and 16873). All serum samples were frozen at Ϫ70°C prior to assay.The I...

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