MUTATION IN A 17D-204 VACCINE SUBSTRAIN-SPECIFIC ENVELOPE PROTEIN EPITOPE ALTERS THE PATHOGENESIS OF YELLOW-FEVER VIRUS IN MICE

The heterogeneous nature of the yellow fever (YF) 17D-204 vaccine viru s population was exploited in this study to isolate virus variants abl e to escape neutralization by the 17D-204 vaccine-specific MAb 864. Th e conformational change on the virus surface that resulted in the loss of the MAb 864-defined epitope was effected in each variant by a sing le amino acid mutation in the envelope (E) protein at either position E-305 or E-325. Interestingly, both positions were mutated during atte nuation of the 170-204 vaccine substrain from the wildtype Asibi strai n. The mutations in several of the variants represented reversion to t he wildtype Asibi virus sequence consistent with loss of a 17D-204 sub strain-specific epitope, The majority of the variant viruses were show n to have altered mouse neurovirulence phenotypes, ranging from comple te avirulence through to increased virulence. The avirulent variants a re the first flavivirus MAb-neutralization-resistant variants to be at tenuated for neurovirulence in the adult mouse model. Overall, the res ults indicate that the E protein epitope recognized by MAb 864 defines a functionally important region that encodes major molecular determin ants of YF virus pathogenesis in vivo. (C) 1998 Academic Press.