An attenuated LC16m8 smallpox vaccine: analysis of full-genome sequence and induction of immune protection.
The potential threat of smallpox bioterrorism has made urgent the development of lower-virulence vaccinia virus vaccines. An attenuated LC16m8 (m8) vaccine was developed in 1975 from the Lister strain used in the World Health Organization smallpox eradication program but was not used against endemic smallpox. Today, no vaccines can be tested with variola virus for efficacy in humans, and the mechanisms of immune protection against the major intracellular mature virion (IMV) and minor extracellular enveloped virion (EEV) populations of poxviruses are poorly understood. Here, we determined the full-genome sequences of the m8, parental LC16mO (mO), and grandparental Lister (LO) strains and analyzed their evolutionary relationships. Sequence data and PCR analysis indicated that m8 was a progeny of LO and that m8 preserved almost all of the open reading frames of vaccinia virus except for the disrupted EEV envelope gene B5R. In accordance with this genomic background, m8 induced 100% protection against a highly pathogenic vaccinia WR virus in mice by a single vaccination, despite the lack of anti-B5R and anti-EEV antibodies. The immunogenicity and priming efficacy with the m8 vaccine consisting mainly of IMV were as high as those with the intact-EEV parental mO and grandparental LO vaccines. Thus, mice vaccinated with 10(7) PFU of m8 produced low levels of anti-B5R antibodies after WR challenge, probably because of quick clearance of B5R-expressing WR EEV by strong immunity induced by the vaccination. These results suggest that priming with m8 IMV provides efficient protection despite undetectable levels of immunity against EEV.
Morikawa
Shigeru
S
Department of Virology, National Institute of Infectious Diseases, Toyama, Tokyo, Japan.
Sakiyama
Tokuki
T
Hasegawa
Hideki
H
Saijo
Masayuki
M
Maeda
Akihiko
A
Kurane
Ichiro
I
Maeno
Go
G
Kimura
Junko
J
Hirama
Chie
C
Yoshida
Teruhiko
T
Asahi-Ozaki
Yasuko
Y
Sata
Tetsutaro
T
Kurata
Takeshi
T
Kojima
Asato
A
D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D001483:Base Sequence; D023482:Bioterrorism; D002460:Cell Line; D002874:Chromosome Mapping; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D015752:Genes, env; D016679:Genome, Viral; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D017354:Point Mutation; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D012899:Smallpox / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D012900:Smallpox Vaccine / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D012901:Variola virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity
D000914:Antibodies, Viral; D004279:DNA, Viral; D012900:Smallpox Vaccine; D014613:Vaccines, Attenuated