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The poxvirus lumpy skin disease virus (LSDV) is the causative agent of the vexatious lumpy skin disease, which predominantly affects cattle and water buffalo. It has been endemic to South Africa since the 1950s, and in 1960, a live attenuated vaccine was commercially released for use in the country to mitigate the spread of this transboundary disease. This vaccine (Neethling/vaccine/LW-1959) was generated from serial passages of the prototype lumpy skin disease virus strain Neethling-WC/RSA/1957, which was isolated in 1957 from an outbreak in the Western Cape province of South Africa and was subsequently used to prove the infectious nature of the virus and the resulting disease in cattle. In this study, we determined the complete genome sequence of the LSDV prototype strain Neethling-WC/RSA/1957, as well as three other LSDV isolates from the 1950s, one wild-type isolate from the 1970s, and a commercial vaccine produced in 1988 (LW-1959). Phylogenomic analysis showed that all six sequences were in cluster 1.1, along with previous sequences of the vaccine strain, the oldest known isolate (LSDV/Haden/RSA/1954), and virulent viruses isolated in the 1990s from South Africa. Seven single-nucleotide polymorphisms were identified between the Neethling-WC/RSA/1957 strain and the vaccine strain (LW-1959), providing new insights into virus attenuation and possible markers for DIVA assays. [ABSTRACT FROM AUTHOR]