Genetic basis of attenuation of the Sabin type 2 vaccine strain of poliovirus in primates.
The type 2 live-attenuated vaccine strain of poliovirus (P2/Sabin) is associated with rare cases of poliomyelitis in vaccinees or their contacts. Recombinants were generated between infectious clones of a neurovirulent isolate from one such case (P2/117) and P2/Sabin and neurovirulence assays suggested that a maximum of six nucleotide differences between the two strains were responsible for their phenotypic difference. Site-directed mutagenesis of P2/Sabin showed that mutations at just two positions, at 481 in the 5' non-coding region and at VP1-143 in the capsid proteins, resulted in a highly neurovirulent virus. Other nucleotide changes may have weaker phenotypic effects. These results are consistent with those reported in the mouse model by Ren et al. [J. Virol. 65, 1377, (1991)] indicating that, for P2/Sabin at least, the same determinants of attenuation are important in both primates and transgenic mice expressing the poliovirus receptor. Sequence analysis of isolates from other vaccine-associated cases of poliomyelitis and from healthy vaccinees showed that both major determinants of attenuation are unstable on human passage, although selection pressures against an A at 481 are stronger than those against an Ile at 1143.
National Institute for Biological Standards and Control, Potters Bar, Herts, United Kingdom.
A J
AJ
Macadam
S R
SR
Pollard
G
G
Ferguson
R
R
Skuce
D
D
Wood
J W
JW
Almond
P D
PD
Minor
D002213:Capsid / Q000235:genetics / Q000276:immunology; D036022:Capsid Proteins; D002478:Cells, Cultured; D003062:Codon; D004252:DNA Mutational Analysis; D006801:Humans; D066298:In Vitro Techniques; D016297:Mutagenesis, Site-Directed; D009422:Nervous System Diseases / Q000382:microbiology; D017955:Poliovirus / Q000235:genetics / Q000472:pathogenicity*; D011055:Poliovirus Vaccine, Oral / Q000235:genetics*; D014613:Vaccines, Attenuated / Q000235:genetics*; D014765:Viral Vaccines / Q000235:genetics*
D036022:Capsid Proteins; D003062:Codon; D011055:Poliovirus Vaccine, Oral; C442540:VP1 protein, Poliovirus; D014613:Vaccines, Attenuated; D014765:Viral Vaccines