The immune response elicited by LC16m8, a candidate smallpox vaccine that was developed in Japan by cold selection during serial passage of the Lister vaccine virus in primary rabbit kidney cells, was compared to Dryvax in a mouse model. LC16m8 carries a mutation resulting in the truncation of the B5 protein, an important neutralizing target of the extracellular envelope form of vaccinia virus (EV). LC16m8 elicited a broad-spectrum immunoglobulin G (IgG) response that neutralized both EV and the intracellular mature form of vaccinia virus and provoked cell-mediated immune responses, including the activation of CD4 ؉ and CD8 The last naturally occurring case of smallpox was reported in 1977. Following the successful containment of a laboratoryacquired case in Birmingham, England, in 1978, smallpox was officially declared eradicated by the World Health Organization in 1980, after the disease had claimed millions of human lives across the globe during a pandemic that lasted several millennia. Despite the eradication of smallpox, the potential for a reemergence of smallpox and a prevailing threat of clinical infections by other poxviruses associated with smallpoxlike symptoms in humans make a sustained supply of smallpox vaccines imperative. For example, outbreaks of zoonotic monkeypox virus infection of humans have been reported in different parts of the world in the past four decades (4, 17), including a 2003 outbreak in the United States (5, 31).Adverse events associated with traditional smallpox vaccines necessitated the quest for new vaccines with less reactogenicity. Two attenuated smallpox vaccines, modified vaccinia virus Ankara (MVA) (25) and a Lister virus derivative (LC16m8), underwent considerable development near the end of the smallpox eradication campaign. LC16m8 was developed as an attenuated smallpox vaccine in Japan in the early 1970s by about 45 serial passages and cold selection of the Lister/Elstree vaccine virus in primary rabbit kidney cells (13). Unlike MVA, LC16m8 does not carry large deletions of gene blocks in its genome and can replicate productively in mammalian cells. Similar to its parent virus strain (Lister/Elstree), for instance, inoculation of LC16m8 by scarification on the skin surface results in a "take" that manifests as a pock lesion that is characteristic of replication-competent smallpox vaccines. In a number of animal models (mice, rabbits, and monkeys), vaccination with LC16m8 conferred protection against lethal poxvirus challenge (7, 32; reviewed in reference 20). LC16m8 was used as a smallpox vaccine in Japanese children at the end of the smallpox eradication campaign in the 1970s, but its efficacy against smallpox is unknown, since smallpox was no longer endemic at the time of its use. A major genetic difference between LC16m8 and the parent Lister vaccine strain used in the campaign to eradicate smallpox has been mapped to a single-base-pair deletion within the open reading frame that encodes the vaccinia virus B5 protein (28,38). This mutation creates a stop codon in B...
