Neutralizing and non-neutralizing monoclonal antibodies against dengue virus E protein derived from a naturally infected patient

Schieffelin, John S.; Costin, Joshua M.; Nicholson, Cindo O.; Orgeron, Nicole M; Fontaine, Krystal A.; Isern, Sharon; Michael, Scott F.; Robinson, James E.

doi:10.1186/1743-422x-7-28

Cited by 92 publications

(92 citation statements)

References 31 publications

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“…50 Likewise, other studies that detected neutralizing antibodies in primary and secondary infections observed that, in the presence of an infection caused by serotype 1, the serotypes with the highest antibody titers corresponded to serotypes 1 and 3. 13,51,52 The multitypic response was positively associated with age because of the diversity of antibodies generated as a result of ongoing exposure in addition to triggering an increase in the titer against the others as a result of a cross-reaction response.…”

Section: Discussionmentioning

confidence: 99%

Seroprevalence of Neutralizing Antibodies Against Dengue Virus in Two Localities in the State of Morelos, Mexico

Amaya-Larios¹,

Martínez-Vega²,

Mayer³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Abstract. Humoral immune response against dengue virus (DENV) is an important component in dengue-endemic transmission. We conducted a cross-sectional nested cohort study to determine the seroprevalence and frequency of neutralizing antibodies against DENV serotypes in two endemic localities in the state of Morelos, Mexico. The cohort participants (N = 1,196) were screened to determine previous exposure to DENV. Overall seroprevalence was 76.6% (95% confidence interval [95% CI] = 73.6-79.2), and prevalence of neutralizing antibodies in the 5-to 9-year-old group was 82.5% (95% CI = 67.2-92.7), 45% (95% CI = 29.3-61.5), and 65% (95% CI = 48.3-79.4) for DENV-1, DENV-2, and DENV-3, respectively. For participants older than 10 years, the observed seroprevalence was above 60% for each serotype, except DENV-4 in the 10-to 25-year-old group (42.9%); 81% of humoral responses were multitypic. The outcomes of our study contribute to understanding the immune component of dengue transmission and provide focal information for the evaluation of vaccine candidates under development.

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Section: Discussionmentioning

confidence: 99%

Seroprevalence of Neutralizing Antibodies Against Dengue Virus in Two Localities in the State of Morelos, Mexico

Amaya-Larios¹,

Martínez-Vega²,

Mayer³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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“…Viruses were propagated in LLC-MK 2 as previously described (30). LLC-MK 2 cells were inoculated with DENV stock at 70% to 80% confluence and cultured in DMEM and 10% (vol/vol) FBS.…”

Section: Methodsmentioning

confidence: 99%

“…In the work of Schieffelin et al, three antibodies that targeted the E protein were isolated from a single donor (30). All three antibodies were cross-reactive with at least two DENV serotypes, one was neutralizing, and all were able to enhance DENV infection.…”

mentioning

confidence: 99%

Mechanistic Study of Broadly Neutralizing Human Monoclonal Antibodies against Dengue Virus That Target the Fusion Loop

Costin

Зайцева

Kahle

et al. 2013

J Virol

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117

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There are no available vaccines for dengue, the most important mosquito-transmitted viral disease. Mechanistic studies with anti-dengue virus (DENV) human monoclonal antibodies (hMAbs) provide a rational approach to identify and characterize neutralizing epitopes on DENV structural proteins that can serve to inform vaccine strategies. Here, we report a class of hMAbs that is likely to be an important determinant in the human humoral response to DENV infection. In this study, we identified and characterized three broadly neutralizing anti-DENV hMAbs: 4.8A, D11C, and 1.6D. These antibodies were isolated from three different convalescent patients with distinct histories of DENV infection yet demonstrated remarkable similarities. All three hMAbs recognized the E glycoprotein with high affinity, neutralized all four serotypes of DENV, and mediated antibody-dependent enhancement of infection in Fc receptor-bearing cells at subneutralizing concentrations. The neutralization activities of these hMAbs correlated with a strong inhibition of virus-liposome and intracellular fusion, not virus-cell binding. We mapped epitopes of these antibodies to the highly conserved fusion loop region of E domain II. Mutations at fusion loop residues W101, L107, and/or G109 significantly reduced the binding of the hMAbs to E protein. The results show that hMAbs directed against the highly conserved E protein fusion loop block viral entry downstream of virus-cell binding by inhibiting E protein-mediated fusion. Characterization of hMAbs targeting this region may provide new insights into DENV vaccine and therapeutic strategies.

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“…Previous reports described the specificity of MBCs isolated several weeks after acute infection with a known dengue serotype, followed by clone immortalization using EBV, screening of the secreted Abs, and cloning of Ab genes (13)(14)(15)(16). Most Abs isolated in this way were found to react with conserved epitopes in the prM and E domain of the virus or with nonstructural proteins and, therefore, were largely serotype cross-reactive.…”

mentioning

confidence: 99%

Plasmablasts Generated during Repeated Dengue Infection Are Virus Glycoprotein–Specific and Bind to Multiple Virus Serotypes

Hadinoto

Appanna

et al. 2012

The Journal of Immunology

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Dengue virus immune protection is specific to the serotype encountered and is thought to persist throughout one’s lifetime. Many serotype cross-reactive memory B cells isolated from humans with previous dengue infection are specific for the nonstructural and the prM structural viral proteins, and they can enhance infection in vitro. However, plasmablasts circulating in enormous numbers during acute secondary infection have not been studied. In this study, we analyzed single plasmablasts from two patients by sorting the cells for Ig sequence analysis and for recombinant expression of Abs. In contrast to memory B cells, most plasmablast-derived Abs bound to the structural E protein of dengue, and protection experiments in mice revealed that virus serotypes encountered during past infections were neutralized more efficiently than were the serotypes of the current infection. Together with genetic analyses, we show evidence that plasmablasts in dengue patients are a polyclonal pool of activated E protein–specific memory B cells and that their specificity is not representative of the serum Abs secreted by long-lived plasma cells in the memory phase. These results contribute to the understanding of the phenomenon of original antigenic sin in dengue.

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Neutralizing and non-neutralizing monoclonal antibodies against dengue virus E protein derived from a naturally infected patient

Cited by 92 publications

References 31 publications

Seroprevalence of Neutralizing Antibodies Against Dengue Virus in Two Localities in the State of Morelos, Mexico

Seroprevalence of Neutralizing Antibodies Against Dengue Virus in Two Localities in the State of Morelos, Mexico

Mechanistic Study of Broadly Neutralizing Human Monoclonal Antibodies against Dengue Virus That Target the Fusion Loop

Plasmablasts Generated during Repeated Dengue Infection Are Virus Glycoprotein–Specific and Bind to Multiple Virus Serotypes

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