Monoclonal antibodies (MAbs) prepared against the yellow fever virus (YF) vaccine strain 17D (17D YF) envelope E protein were used to investigate Fc piece involvement in antibody-mediated protection against YF encephalitis in mice. 17D YF passaged either in Vero cells or in mouse brain (P-YF) to increase neurovirulence was used. To avoid uncertainty concerning antibody clearance and blood-brain barrier penetration, and to directly compare protective activity with neutralization , pre-formed antibody-virus complexes were injected intracerebrally or assayed for plaque formation in parallel. F(ab′) fragments of an IgG2a MAb that strongly neutralized both YF strains retained molar equivalent neutralizing activity , but did not protect. However, further incubation of such F(ab′)-virus antibody complexes with rabbit IgG, but not F(ab′) anti-mouse IgG resulted in protection. To unambiguously test for Fc piece involvement in this model we derived an IgG2a isotype switch variant from a protective IgG1 MAb-secreting hybridoma and prepared F(ab′) fragments of the derivative. Intact and fragmented antibodies exhibited weak neutralizing activity. The variant antibody failed to protect against P-YF, but against considerably less neurovirulent 17D YF its protective capacity was 10-fold higher than that of its IgG1 parent. F(ab′) fragments of the variant did not protect. Together, these results provide strong evidence of an protective function for the anti-virion antibody Fc piece and indicate that neutralizing activity as a predictor of antibody protective capacity is dependent on Fc piece integrity and isotype.


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