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1.
Vaccine ; 28(51): 8085-94, 2010 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-20959154

RESUMEN

Dengue viruses co-circulate as four serologically distinct viruses (DENV1-4) that commonly infect individuals sequentially. Current DENV candidate vaccines incorporate the entire virion envelope E protein (E) ectodomain thereby stimulating both DENV serotype-specific and cross-reactive antibodies. Because the latter may enhance naturally acquired infection, such vaccine formulations must be tetravalent. We evaluated the neutralizing and enhancing antibody response to E domain III (dIII) proteins, in which serotype-specific neutralizing determinants are concentrated. Mice immunized with insect cell-secreted recombinant DENV-dIII proteins individually, and in tetravalent combination, produced serotype-specific IgG1 neutralizing antibodies that nevertheless exhibited measurable DENV enhancing activity in FcγR-bearing cells. Vaccine strategies directed to DENV-dIII-targeted neutralizing antibody production remain attractive but will likely require further modifications to induce safe, protective immunity.


Asunto(s)
Anticuerpos Bloqueadores/sangre , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Vacunas contra el Dengue/inmunología , Animales , Virus del Dengue/inmunología , Femenino , Inmunoglobulina G/sangre , Ratones , Ratones Endogámicos BALB C , Vacunas de Subunidad/inmunología , Proteínas del Envoltorio Viral/inmunología
2.
Virology ; 394(2): 175-82, 2009 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-19833371

RESUMEN

Severe dengue virus (DENV) infection is epidemiologically linked to pre-existing anti-DENV antibodies acquired by maternal transfer or primary infection. A possible explanation is that DENV immune complexes evade neutralization by engaging Fcgamma receptors (FcgammaR) on monocytes, natural targets for DENV in humans. Using epitope-matched humanized monoclonal antibodies (mAbs) and stable FcgammaR-transfected CV-1 cells, we found that DENV neutralization by IgG1, IgG3, and IgG4 mAbs was enhanced in high-affinity FcgammaRIA transfectants and diminished in low-affinity FcgammaRIIA transfectants, whereas neutralization by IgG2 mAbs (low-affinity ligands for both FcgammaRs) was diminished equally. In FcgammaR-negative Vero cells, IgG3 mAbs exhibited the strongest neutralizing activity and IgG2, the weakest. Our results demonstrate that DENV neutralization is modulated by the Fc region in an IgG subclass manner, likely through effects on virion and FcgammaR binding. Thus, the IgG antibody subclass profile generated by DENV infection or vaccination may independently influence the magnitude of the neutralizing response.


Asunto(s)
Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Virus del Dengue/inmunología , Inmunoglobulina G/metabolismo , Receptores de IgG/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Anticuerpos Neutralizantes/clasificación , Anticuerpos Antivirales/clasificación , Línea Celular , Chlorocebus aethiops , Dengue/inmunología , Dengue/virología , Humanos , Inmunoglobulina G/clasificación , Técnicas In Vitro , Ratones , Pruebas de Neutralización , Pan troglodytes , Receptores de IgG/clasificación , Proteínas Recombinantes de Fusión/inmunología , Células Vero
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