TY - JOUR
T1 - Adjuvant-mediated epitope specificity and enhanced neutralizing activity of antibodies targeting dengue virus envelope protein
AU - Maeda, Denicar Lina Nascimento Fabris
AU - Batista, Milene Tavares
AU - Pereira, Lennon Ramos
AU - de Jesus Cintra, Mariana
AU - Amorim, Jaime Henrique
AU - Mathias-Santos, Camila
AU - Pereira, Sara Araújo
AU - Boscardin, Silvia Beatriz
AU - dos Ramos Silva, Sandriana
AU - Faquim-Mauro, Eliana L.
AU - Silveira, Vanessa Barbosa
AU - Oliveira, Danielle Bruna Leal
AU - Johnston, Stephen
AU - de Souza Ferreira, Luís Carlos
AU - Rodrigues, Juliana Falcão
N1 - Publisher Copyright:
© 2017 Maeda, Batista, Pereira, de Jesus Cintra, Amorim, Mathias-Santos, Pereira, Boscardin, Silva, Faquim-Mauro, Silveira, Oliveira, Johnston, Ferreira and Rodrigues.
PY - 2017/9/25
Y1 - 2017/9/25
N2 - 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.
AB - 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.
KW - Adjuvants
KW - Antibodies
KW - Dengue virus
KW - Envelope protein
KW - Heat-labile toxins
KW - Immunosignature
KW - Labile toxins
KW - Vaccines
UR - http://www.scopus.com/inward/record.url?scp=85029816498&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029816498&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2017.01175
DO - 10.3389/fimmu.2017.01175
M3 - Article
AN - SCOPUS:85029816498
SN - 1664-3224
VL - 8
JO - Frontiers in Immunology
JF - Frontiers in Immunology
IS - SEP
M1 - 1175
ER -