Genomic differences of Vaccinia virus clones from Dryvax smallpox vaccine: the Dryvax-like ACAM2000 and the mouse neurovirulent Clone-3.
Conventional vaccines used for smallpox eradication were often denoted one or another strain of Vaccinia virus (VACV), even though seed virus was sub-cultured multifariously, which rendered the virion population genetically heterogeneous. ACAM2000 cell culture vaccine, recently licensed in the U.S., consists of a biologically vaccine-like VACV homogeneous-sequence clone from the conventional smallpox vaccine Dryvax, which we verified from Dryvax sequence chromatograms is genetically heterogeneous. ACAM2000 VACV and CL3, a mouse-neurovirulent clone from Dryvax, differ by 572 single nucleotide polymorphisms and 53 insertions-deletions of varied size, including a 4.5-kbp deletion in ACAM2000 and a 6.2-kbp deletion in CL3. The sequence diversity between the two clones precludes precisely defining why CL3 is more pathogenic; however, four genes appear significantly dissimilar to account for virulence differences. CL3 encodes intact immunomodulators interferon-alpha/beta and tumor necrosis factor receptors, which are truncated in ACAM2000. CL3 specifies a Cowpox and Variola virus-like ankyrin-repeat protein that might be associated with proteolysis via ubiquitination. And, CL3 shows an elongated thymidylate kinase, similar to the enzyme of the mouse-neurovirulent VACV-WR, a derivative of the New York City Board of Health vaccine, the origin vaccine of Dryvax. Although ACAM2000 encodes most proteins associated with immunization protection, the cloning probably delimited the variant epitopes and other motifs produced by Dryvax due to its VACV genetic heterogeneity. The sequence information for ACAM2000 and CL3 could be significant for resolving the dynamics of their different proteomes and thereby aid development of safer, more effective vaccines.
Biotechnology Core Facility Branch, Division of Scientific Resources, National Center for Preparedness, Detection, and Control of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30329, United States.
John D
JD
Osborne
Melissa
M
Da Silva
A Michael
AM
Frace
Scott A
SA
Sammons
Melissa
M
Olsen-Rasmussen
Chris
C
Upton
R Mark L
RM
Buller
Nanhai
N
Chen
Zehua
Z
Feng
Rachel L
RL
Roper
Jonathan
J
Liu
Svetlana
S
Pougatcheva
Weiping
W
Chen
Robert M
RM
Wohlhueter
Joseph J
JJ
Esposito
D000818:Animals; D023061:Gene Order; D016679:Genome, Viral; D051379:Mice; D008969:Molecular Sequence Data; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D012900:Smallpox Vaccine / Q000235:genetics*; D026801:Synteny; D014481:United States; D014616:Vaccinia virus / Q000235:genetics* / Q000472:pathogenicity*; D014764:Viral Proteins / Q000235:genetics
C078786:DryVax vaccine; D012900:Smallpox Vaccine; D014764:Viral Proteins