Ontogeny of yellow fever 17D vaccine: RNA oligonucleotide fingerprint and monoclonal antibody analyses of vaccines produced world-wide.

Abstract

Yellow fever 17D vaccines are currently manufactured with approval of the World Health Organization (WHO) in 11 countries. These vaccines have proven highly efficacious and safe. Nevertheless, they have not been fully characterized genetically, a problem for future standardization and modernization of vaccine manufacture now being proposed by WHO. Vaccines in use are derived from two distinct substrains (17D-204 and 17DD) which represent independently maintained passage series from original 17D. In this study, all 17D vaccines produced world-wide were characterized by RNA oligonucleotide fingerprinting. Forty-two large oligonucleotides were compared, and differences from an arbitrarily selected reference strain (produced by Connaught Laboratories in the U.S.A.) were determined. With one exception (vaccine produced in South Africa), fingerprints of vaccines derived from substrain 17D-204 were identical. The South African primary seed differed in position of one oligonucleotide, reflecting a charge shift due to a single base change. This difference occurred within one egg passage; a further change in the South African vaccine occurred within one or two passages from primary seed. No antigenic differences between 17D-204-derived vaccines (including South Africa) were demonstrated by neutralization tests using monoclonal antibody. Vaccines derived from the 17DD substrain consistently differed from 17D-204 vaccines in the absence of one oligonucleotide (No. 37). This change probably occurred during 40 additional egg passages in development of the 17DD vaccines. A clear antigenic difference was shown between 17D-204 and 17DD substrain vaccines using monoclonal antibody. 17DD vaccines showed minor genotypic differences, suggesting a higher degree of genetic instability than 17D-204 vaccines. No oligonucleotide fingerprint differences were found between avian leukosis virus (ALV)-free and ALV-contaminated vaccines. No definite genomic correlate of neurovirulence was defined by fingerprinting strains with a history of encephalitic complications in man or of failure to pass monkey neurovirulence tests. Parent Asibi virus showed several oligonucleotide differences and was serologically distinct from 17D vaccine.