title: Protective Capacity of the Human Anamnestic Antibody Response during Acute Dengue Virus Infection.
abstract: Half of the world's population is exposed to the risk of dengue virus infection. Although a vaccine for dengue virus is now available in a few countries, its reported overall efficacy of about 60% is not ideal. Protective immune correlates following natural dengue virus infection remain undefined, which makes it difficult to predict the efficacy of new vaccines. In this study, we address the protective capacity of dengue virus-specific antibodies that are produced by plasmablasts a few days after natural secondary infection. Among a panel of 18 dengue virus-reactive human monoclonal antibodies, four groups of antibodies were identified based on their binding properties. While antibodies targeting the fusion loop of the glycoprotein of dengue virus dominated the antibody response, two smaller groups of antibodies bound to previously undescribed epitopes in domain II of the E protein. The latter, largely serotype-cross-reactive antibodies, demonstrated increased stability of binding at pH 5. These antibodies possessed weak to moderate neutralization capacity in vitro but were the most efficacious in promoting the survival of infected mice. Our data suggest that the cross-reactive anamnestic antibody response has a protective capacity despite moderate neutralization in vitro and a moderate decrease of viremia in vivo IMPORTANCE: Antibodies can protect from symptomatic dengue virus infection. However, it is not easy to assess which classes of antibodies provide protection because in vitro assays are not always predictive of in vivo protection. During a repeat infection, dengue virus-specific immune memory cells are reactivated and large amounts of antibodies are produced. By studying antibodies cloned from patients with heterologous secondary infection, we tested the protective value of the serotype-cross-reactive "recall" or "anamnestic" response. We found that results from in vitro neutralization assays did not always correlate with the ability of the antibodies to reduce viremia in a mouse model. In addition, a decrease of viremia in mice did not necessarily improve survival. The most protective antibodies were stable at pH 5, suggesting that antibody binding in the endosomes, after the antibody-virus complex is internalized, might be important to block virus spread in the organism.
authors.affiliation: Singapore Immunology Network, Agency for Science Technology and Research, Singapore.
authors.forename: Meihui
authors.initials: M
authors.lastname: Xu
authors.affiliation: Singapore Immunology Network, Agency for Science Technology and Research, Singapore.
authors.forename: Roland
authors.initials: R
authors.lastname: Züst
authors.affiliation: Singapore Immunology Network, Agency for Science Technology and Research, Singapore.
authors.forename: Ying Xiu
authors.initials: YX
authors.lastname: Toh
authors.affiliation: Integral Molecular, Philadelphia, Pennsylvania, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Pfaff
authors.affiliation: Integral Molecular, Philadelphia, Pennsylvania, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Kahle
authors.affiliation: Integral Molecular, Philadelphia, Pennsylvania, USA.
authors.forename: Edgar
authors.initials: E
authors.lastname: Davidson
authors.affiliation: Integral Molecular, Philadelphia, Pennsylvania, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
authors.affiliation: Singapore Immunology Network, Agency for Science Technology and Research, Singapore.
authors.forename: Sumathy
authors.initials: S
authors.lastname: Velumani
authors.affiliation: Singapore Immunology Network, Agency for Science Technology and Research, Singapore.|School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Farhana
authors.initials: F
authors.lastname: Tukijan
authors.affiliation: Singapore Immunology Network, Agency for Science Technology and Research, Singapore.
authors.forename: Cheng-I
authors.initials: CI
authors.lastname: Wang
authors.affiliation: Singapore Immunology Network, Agency for Science Technology and Research, Singapore Katja_fink@immunol.a-star.edu.sg.|School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Katja
authors.identifier: http://orcid.org/0000-0002-3571-0390
authors.initials: K
authors.lastname: Fink
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000096:biosynthesis* / Q000737:chemistry; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000096:biosynthesis* / Q000737:chemistry; D000914:Antibodies, Viral / Q000008:administration & dosage / Q000096:biosynthesis* / Q000737:chemistry; D003429:Cross Reactions; D003715:Dengue / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D003716:Dengue Virus / Q000145:classification / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D006863:Hydrogen-Ion Concentration; D056724:Immunity, Humoral / Q000187:drug effects; D007156:Immunologic Memory; D051379:Mice; D009500:Neutralization Tests; D011485:Protein Binding; D055550:Protein Stability; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D014759:Viral Envelope Proteins; C072281:E protein TH Sman, Dengue virus