Adjuvant-Mediated Epitope Specificity and Enhanced Neutralizing Activity of Antibodies Targeting Dengue Virus Envelope Protein

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

• Document type: Journal article
• Source: FRONTIERS IN IMMUNOLOGY; v. 8, SEP 25 2017.
• Web of Science Citations: 4

Abstract

The heat-labile toxins (LT) produced by enterotoxigenic Escherichia coil 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. (AU)

• FAPESP's process: 12/51204-2 - A new way for the rational pursuit of an effective vaccine against dengue
• Grantee: Jaime Henrique Amorim Santos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/17595-0 - New vaccine research based on recombinant proteins of dengue virus
• Grantee: Luis Carlos de Souza Ferreira
• Support Opportunities: Regular Research Grants