Dengue Virus Infections and Maternal Antibody Decay in a Prospective Birth Cohort Study of Vietnamese Infants

Oxford University Clinical Research Unit, Hong Vuong Hospital, Ho Chi Minh City, Vietnam.
The Journal of Infectious Diseases (Impact Factor: 6). 11/2009; 200(12):1893-900. DOI: 10.1086/648407
Source: PubMed


Dengue hemorrhagic fever can occur in primary dengue virus (DENV) infection of infants. The decay of maternally derived DENV
immunoglobulin (Ig) G and the incidence of DENV infection were determined in a prospectively studied cohort of 1244 Vietnamese
infants. Higher concentrations of total IgG and DENV-reactive IgG were found in cord plasma relative to maternal plasma. Maternally
derived DENV-neutralizing and E protein–reactive IgG titers declined to below measurable levels in >90% of infants by 6 months
of age. In contrast, IgG reactive with whole DENV virions persisted until 12 months of age in 20% of infants. Serological
surveillance identified 10 infants with asymptomatic DENV infection for an incidence of 1.7 cases per 100 person-years. DENV-neutralizing
antibodies remained measurable for ⩾1 year after infection. These results suggest that whereas DENV infection in infants is
frequently subclinical, there is a window between 4 and 12 months of age where virion-binding but nonneutralizing IgG could
facilitate antibody-dependent enhancement

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    • "Clinical evidence for a role of antibodies in dengue pathogenesis comes from observations of the increased risk of DHF / DSS in 5 – 9 month - old infants , when maternal antibodies against DENV have waned to sub - neutralizing levels ( Chau et al . , 2009 , 2008 ; Duangchinda et al . , 2010 ; Kliks et al . , 1988 ; Simmons et al . , 2007 ) . While infection with a heterologous DENV serotype in young children or adults would trigger anamnestic , cross - reactive responses from both B and T cells ( Chau et al . , 2008 ; Duangchinda et al . , 2010 ) , only maternal antibodies cross the pla "
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    ABSTRACT: Development of a suitable animal model for dengue virus disease is critical for understanding pathogenesis and for preclinical testing of antiviral drugs and vaccines. Many laboratory animal models of dengue virus infection have been investigated, but the challenges of recapitulating the complete disease still remain. In this review, we provide a comprehensive coverage of existing models, from man to mouse, with a specific focus on recent advances in mouse models for addressing the mechanistic aspects of severe dengue in humans. This article forms part of a symposium in Antiviral Research on flavivirus drug discovery. Copyright © 2015. Published by Elsevier B.V.
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    • "Pre-existing non-neutralising antibodies are thought to drive the observed increased incidence of severe disease following secondary, heterotypic dengue virus infections, through a mechanism of antibody-dependent enhancement [16]. Indirect evidence suggests that the same mechanism may explain the age-related epidemiology of dengue in infants in endemic countries, where symptomatic dengue cases occur most frequently between the ages of 4 to 10 months, coinciding with the time at which maternally derived neutralising antibodies to DENV become undetectable but non-neutralising viron-binding antibodies remain detectable [6,7]. However the degree to which in vitro neutralizing antibody activity, or enhancing antibody activity, correlates with dengue immunity or disease is still uncertain [17-19]. "
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    ABSTRACT: In Ho Chi Minh City, Vietnam, more than one-third of admissions to the two paediatric hospitals are attributable to four infectious syndromes: dengue, diarrhoeal disease, acute respiratory infection, and hand, foot and mouth disease. We have established a large prospective birth cohort study to investigate individual, environmental, virological, and immunological determinants of infection and disease in infants. Specific research questions are focused on the role of maternal antibody in protection against infection in infancy, and the adaptive immune response to vaccination and natural infection. This paper presents the cohort design, methods, and baseline characteristics of the participants enrolled in the first two years.Methods/designWomen are enrolled prior to delivery at one hospital in each of two catchment areas: an urban district in central HCMC, and a mixed urban/rural district in the Mekong Delta 150 km southwest of HCMC. Infants are enrolled within 3 days of birth, and maternal and cord blood samples are collected. Routine blood samples and data on growth, health status and vaccinations are collected from infants at scheduled visits at 4, 9 and 12 months. Clinical data and specimens are collected from infants presenting at a study clinic, or admitted to hospital, with any of the the four infectious syndromes of interest. In four years since since the study began in July 2009, >6400 infants have been enrolled, and enrolment is ongoing. Attrition is low: 84% of participants have completed the full 12-month follow-up period. Baseline characteristics of the first 4300 enrollees are presented here. We have demonstrated the feasibility of establishing a large prospective study of infectious diseases in infancy in a resource-limited setting, with minimal loss to follow-up. Our linked socio-demographic, clinical and laboratory data will help elucidate the viral aetiology and epidemiology of common infectious diseases of infancy, and can inform the implemention of existing and future vaccines. This study furthermore provides a platform to which additional endpoints could be added in the future.
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    • "It has also been suggested that anti-prM antibodies could render essentially non-infectious imDENV highly infectious [24,27,28]. Recent studies in infants have also implicated that anti-prM antibodies could lead to severe disease upon primary infection [29]. These studies on human and mouse anti- prM mAbs [30-32] suggest that this class of antibodies have a significant role to enhance DENV infection in humans. "
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    ABSTRACT: Dengue virus (DENV) infection is the most important arthropod- borne viral disease in human, but antiviral therapy and approved vaccines remain unavailable due to antibody-dependent enhancement (ADE) phenomenon. Many studies showed that pre-membrane (prM)-specific antibodies do not efficiently neutralize DENV infection but potently promote ADE infection. However, most of the binding epitopes of these antibodies remain unknown. In the present study, we characterized a DENV cross-reactive monoclonal antibody (mAb), 4D10, that neutralized poorly but potently enhanced infection of four standard DENV serotypes and immature DENV (imDENV) over a broad range of concentration. In addition, the epitope of 4D10 was successfully mapped to amino acid residues 14 to18 of DENV1-4 prM protein using a phage-displayed peptide library and comprehensive bioinformatics analysis. We found that the epitope was DENV serocomplex cross-reactive and showed to be highly immunogenic in Balb/c mice. Furthermore, antibody against epitope peptide PL10, like 4D10, showed broad cross-reactivity and weak neutralizing activtity with four standard DENV serotypes and imDENV but significantly promoted ADE infection. These results suggested 4D10 and anti-PL10 sera were infection-enhancing antibodies and PL10 was infection-enhancing epitope. We mapped the epitope of 4D10 to amino acid residues 14 to18 of DENV1-4 prM and found that this epitope was infection-enhancing. These findings may provide significant implications for future vaccine design and facilitate understanding the pathogenesis of DENV infection.
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