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1.
Nano Lett ; 18(12): 7832-7838, 2018 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-30461280

RESUMEN

Elicitation of neutralizing antibody responses against hepatitis C virus (HCV) has been a challenging goal. While the E2 subunit of the HCV envelope glycoprotein complex is a promising target for generating cross-genotype neutralizing antibodies, vaccinations with soluble E2 immunogens generally induce weak neutralizing antibody responses. Here, E2 immunogens (i.e., E2.661 and E2c.661) were loaded into lipid-based nanovaccines and examined for induction of neutralizing antibody responses. Compared with soluble E2 immunogens, E2 nanoparticles elicited 6- to 20-fold higher E2-specific serum IgG titers in mice. Importantly, E2 vaccine nanoparticles analyzed at a single particle level with a flow cytometry-based method revealed interesting dynamics between epitope display on the surfaces of nanoparticles in vitro and induction of neutralizing antibody responses in vivo. E2c.661 nanoparticles that are preferentially bound by a broadly neutralizing antibody, HCV1, in vitro elicit neutralizing antibody responses against both autologous and heterologous HCV virions in vivo. In stark contrast, E2.661 nanoparticles with reduced HCV1-antibody binding in vitro mainly induce autologous neutralizing antibody responses in vivo. These results show that rationale antigen design coupled with interrogation of epitope display on vaccine nanoparticles at a single particle level may aid in vaccine development toward achieving neutralizing antibody responses in vivo.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Portadores de Fármacos/química , Hepacivirus/inmunología , Hepatitis C/prevención & control , Nanopartículas/química , Proteínas del Envoltorio Viral/administración & dosificación , Vacunas contra Hepatitis Viral/administración & dosificación , Animales , Formación de Anticuerpos , Hepatitis C/inmunología , Humanos , Inmunoglobulina G/inmunología , Ratones , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/farmacología , Vacunas contra Hepatitis Viral/inmunología , Vacunas contra Hepatitis Viral/farmacología
2.
Sci Adv ; 5(1): eaav1882, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30613781

RESUMEN

An effective vaccine to the antigenically diverse hepatitis C virus (HCV) must target conserved immune epitopes. Here, we investigate cross-neutralization of HCV genotypes by broadly neutralizing antibodies (bNAbs) encoded by the relatively abundant human gene family V H 1-69. We have deciphered the molecular requirements for cross-neutralization by this unique class of human antibodies from crystal structures of HCV E2 in complex with bNAbs. An unusually high binding affinity is found for germ line-reverted versions of VH1-69 precursor antibodies, and neutralization breadth is acquired during affinity maturation. Deep sequencing analysis of an HCV-immune B cell repertoire further demonstrates the importance of the V H 1-69 gene family in the generation of HCV bNAbs. This study therefore provides critical insights into immune recognition of HCV with important implications for rational vaccine design.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/inmunología , Hepacivirus/inmunología , Anticuerpos contra la Hepatitis C/inmunología , Hepatitis C/inmunología , Afinidad de Anticuerpos/inmunología , Sitios de Unión , Donantes de Sangre , Línea Celular Tumoral , Reacciones Cruzadas/inmunología , Epítopos/química , Hepatitis C/virología , Humanos , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/metabolismo , Vacunas contra Hepatitis Viral/genética , Vacunas contra Hepatitis Viral/inmunología
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