Category: Publications

Anderson KB, Gibbons RV, Thomas SJ, Rothman AL, Nisalak A, Berkelman RL, Libraty DH, Endy TP

PLoS Negl Trop Dis 2011 Oct;5(10):e1311

PMID: 21991398

Abstract

BACKGROUND: Dengue viruses (DENVs) and Japanese encephalitis virus (JEV) have significant cross-reactivity in serological assays; the clinical implications of this remain undefined. An improved understanding of whether and how JEV immunity modulates the clinical outcome of DENV infection is important as large-scale DENV vaccine trials will commence in areas where JEV is co-endemic and/or JEV immunization is routine.

METHODS AND FINDINGS: The association between preexisting JEV neutralizing antibodies (NAbs) and the clinical severity of DENV infection was evaluated in a prospective school-based cohort in Thailand that captured asymptomatic, non-hospitalized, and hospitalized DENV infections. Covariates considered included age, baseline DENV antibody status, school of attendance, epidemic year, and infecting DENV serotype. 942 children experienced at least one DENV infection between 1998 and 2002, out of 3,687 children who were enrolled for at least one full year. In crude analysis, the presence of JEV NAbs was associated with an increased occurrence of symptomatic versus asymptomatic infection (odds ratio [OR]= 1.55, 95% CI: 1.08-2.23) but not hospitalized illness or dengue hemorrhagic fever (DHF). The association was strongest in children with negative DENV serology (DENV-naive) (OR=2.75, 95% CI: 1.12-6.72), for whom the presence of JEV NAbs was also associated with a symptomatic illness of longer duration (5.4 days for JEV NAb+ versus 2.6 days for JEV NAb-, p=0.048). JEV NAbs were associated with increased DHF in younger children with multitypic DENV NAb profiles (OR=4.05, 95% CI: 1.18 to 13.87). Among those with JEV NAbs, the association with symptomatic illness did not vary by antibody titer.

INTERPRETATION: The prior existence of JEV NAbs was associated with an increased probability of symptomatic as compared to asymptomatic DENV illness. These findings are in contrast to previous studies suggesting an attenuating effect of heterologous flavivirus immunity on DENV disease severity.

Mathew A, West K, Kalayanarooj S, Gibbons RV, Srikiatkhachorn A, Green S, Libraty D, Jaiswal S, Rothman AL

J. Infect. Dis. 2011 Nov;204(10):1514-22

PMID: 21930609

Abstract

Low-avidity serotype-cross-reactive antibodies are hypothesized to play a key role in triggering severe disease in patients with secondary dengue virus (DENV) infection. However, there is little systematic information about the frequency, avidity, and cross-reactivity of DENV-specific B cells in individuals experiencing primary instead of secondary infection. We compared DENV-specific B-cell responses in a cohort of Thai children with primary or secondary DENV infection. B cells specific for DENV precursor membrane protein, envelope (E) protein, and nonstructural protein 1 were detectable in immune peripheral blood mononuclear cells with the highest frequencies of DENV E-specific B cells detected in patients experiencing primary DENV-1 infections. DENV E-specific B cells were highly serotype-specific after primary DENV infections, whereas most E-specific B cells in patients with secondary infection were serotype-cross-reactive and secreted antibodies with higher avidity to heterologous DENV serotypes. Our data suggest that the minor populations of serotype-cross-reactive B cells generated by primary DENV infection are preferentially expanded during secondary DENV infection.

Srikiatkhachorn A, Rothman AL, Gibbons RV, Sittisombut N, Malasit P, Ennis FA, Nimmannitya S, Kalayanarooj S

Clin. Infect. Dis. 2011 Sep;53(6):563-7

PMID: 21832264

Abstract

Dengue has emerged as a major public health problem worldwide. Dengue virus infection causes a wide range of clinical manifestations. Since the 1970s, clinical dengue has been classified according to the World Health Organization guideline as dengue fever and dengue hemorrhagic fever. The classification has been criticized with regard to its usefulness and its applicability. In 2009, the World Health Organization issued a new guideline that classifies clinical dengue as dengue and severe dengue. The 2009 classification differs significantly from the previous classification in both conceptual and practical levels. The impacts of the new classification on clinical practice, dengue research, and public health policy are discussed.

Friberg H, Bashyam H, Toyosaki-Maeda T, Potts JA, Greenough T, Kalayanarooj S, Gibbons RV, Nisalak A, Srikiatkhachorn A, Green S, Stephens HA, Rothman AL, Mathew A

Sci Rep 2011;1:51

PMID: 22355570

Abstract

Serotype-cross-reactive memory T cells responding to secondary dengue virus (DENV) infection are thought to contribute to disease. However, epitope-specific T cell responses have not been thoroughly compared between subjects with primary versus secondary DENV infection. We studied CD8(+) T cells specific for the HLA-A*1101-restricted NS3(133) epitope in a cohort of A11(+) DENV-infected patients throughout acute illness and convalescence. We compared the expansion, serotype-cross-reactivity, and activation of these cells in PBMC from patients experiencing primary or secondary infection and mild or severe disease by flow cytometry. Our results show expansion and activation of DENV-specific CD8(+) T cells during acute infection, which are predominantly serotype-cross-reactive regardless of DENV infection history. These data confirm marked T cell activation and serotype-cross-reactivity during the febrile phase of dengue; however, A11-NS3(133)-specific responses did not correlate with prior antigenic exposure or current disease severity.

Wichmann O, Yoon IK, Vong S, Limkittikul K, Gibbons RV, Mammen MP, Ly S, Buchy P, Sirivichayakul C, Buathong R, Huy R, Letson GW, Sabchareon A

PLoS Negl Trop Dis 2011;5(3):e996

PMID: 21468308

Abstract

BACKGROUND: Disease incidence data are needed to guide decision-making for public health interventions. Although dengue is a reportable disease in Thailand and Cambodia, the degree that reported incidence underrecognizes true disease burden is unknown. We utilized dengue incidence calculated from laboratory-confirmed outpatient and inpatient cases in prospective cohort studies to estimate the magnitude of dengue underrecognition and to establish more accurate disease burden estimates for these countries.

METHODS AND FINDINGS: Cohort studies were conducted among children aged <15 years by members of a dengue field site consortium over at least 2 dengue seasons. Age-group specific multiplication factors (MFs) were computed by comparing data from three cohort studies to national surveillance data in the same province and year. In Thailand, 14,627 person-years of prospective cohort data were obtained in two provinces and 14,493 person-years from one province in Cambodia. Average annual incidence of laboratory-confirmed dengue was 23/1,000 and 25/1,000 in Thailand, and 41/1,000 in Cambodia. Calculated MFs in these provinces varied by age-group and year (range 0.4-29). Average age-group specific MFs were then applied to country-level reporting data and indicated that in Thailand a median 229,886 (range 210,612-331,236) dengue cases occurred annually during 2003-2007 and a median 111,178 (range 80,452-357,135) cases occurred in Cambodia in children <15 years of age. Average underrecognition of total and inpatient dengue cases was 8.7 and 2.6-fold in Thailand, and 9.1 and 1.4-fold in Cambodia, respectively. During the high-incidence year 2007, >95,000 children in Thailand and >58,000 children in Cambodia were estimated to be hospitalized due to dengue.

CONCLUSION: Calculating MFs by comparing prospective cohort study data to locally-reported national surveillance data is one approach to more accurately assess disease burden. These data indicate that although dengue is regularly reported in many countries, national surveillance data significantly underrecognize the true burden of disease.