Abstract
ABSTRACTHalf 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.
Highlights
Half of the world’s population is exposed to the risk of dengue virus infection
We described the generation of a panel of human monoclonal antibodies from the plasmablasts of two naturally infected dengue patients by single B cell PCR cloning
We further characterized a subset of clonally distinct antibodies that were selected based on good binding to both E protein and virus particles (Fig. 1A and B)
Summary
Half of the world’s population is exposed to the risk of dengue virus infection. a vaccine for dengue virus is available in a few countries, its reported overall efficacy of about 60% is not ideal. 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. 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. Antibody-associated correlates of protection and mechanisms of neutralization that prevent or reduce the spread of the virus in the organism are still poorly understood This was best illustrated by the recent clinical trials of the leading vaccine from Sanofi-Pasteur, for which the overall efficacy across all four DENV serotypes was only 60.3% despite generally high neutralizing titers in vaccinees [8]. Antibodies against the E glycoprotein have been shown to inhibit virus attachment and infection in vitro, 11122 jvi.asm.org
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