Adjuvant-mediated epitope specificity and enhanced neutralizing activity of antibodies targeting dengue virus envelope protein

Denicar Lina Nascimento Fabris Maeda, Milene Tavares Batista, Lennon Ramos Pereira, Mariana de Jesus Cintra, Jaime Henrique Amorim, Camila Mathias-Santos, Sara Araújo Pereira, Silvia Beatriz Boscardin, Sandriana dos Ramos Silva, Eliana L. Faquim-Mauro, Vanessa Barbosa Silveira, Danielle Bruna Leal Oliveira, Stephen Johnston, Luís Carlos de Souza Ferreira, Juliana Falcão Rodrigues

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The heat-labile toxins (LT) produced by enterotoxigenic Escherichia coli display adjuvant effects to coadministered antigens, leading to enhanced production of serum antibodies. Despite extensive knowledge of the adjuvant properties of LT derivatives, including in vitro-generated non-toxic mutant forms, little is known about the capacity of these adjuvants to modulate the epitope specificity of antibodies directed against antigens. This study characterizes the role of LT and its non-toxic B subunit (LTB) in the modulation of antibody responses to a coadministered antigen, the dengue virus (DENV) envelope glycoprotein domain III (EDIII), which binds to surface receptors and mediates virus entry into host cells. In contrast to non-adjuvanted or alum-adjuvanted formulations, antibodies induced in mice immunized with LT or LTB showed enhanced virus-neutralization effects that were not ascribed to a subclass shift or antigen affinity. Nonetheless, immunosignature analyses revealed that purified LT-adjuvanted EDIII-specific antibodies display distinct epitope-binding patterns with regard to antibodies raised in mice immunized with EDIII or the alum-adjuvanted vaccine. Notably, the analyses led to the identification of a specific EDIII epitope located in the EF to FG loop, which is involved in the entry of DENV into eukaryotic cells. The present results demonstrate that LT and LTB modulate the epitope specificity of antibodies generated after immunization with coadministered antigens that, in the case of EDIII, was associated with the induction of neutralizing antibody responses. These results open perspectives for the more rational development of vaccines with enhanced protective effects against DENV infections.

Original languageEnglish (US)
Article number1175
JournalFrontiers in Immunology
Volume8
Issue numberSEP
DOIs
StatePublished - Sep 25 2017

Keywords

  • Adjuvants
  • Antibodies
  • Dengue virus
  • Envelope protein
  • Heat-labile toxins
  • Immunosignature
  • Labile toxins
  • Vaccines

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Maeda, D. L. N. F., Batista, M. T., Pereira, L. R., de Jesus Cintra, M., Amorim, J. H., Mathias-Santos, C., Pereira, S. A., Boscardin, S. B., dos Ramos Silva, S., Faquim-Mauro, E. L., Silveira, V. B., Oliveira, D. B. L., Johnston, S., de Souza Ferreira, L. C., & Rodrigues, J. F. (2017). Adjuvant-mediated epitope specificity and enhanced neutralizing activity of antibodies targeting dengue virus envelope protein. Frontiers in Immunology, 8(SEP), [1175]. https://doi.org/10.3389/fimmu.2017.01175