The Deletion of the MGF360-10L/505-7R Genes of African Swine Fever Virus Results in High Attenuation but No Protection Against Homologous Challenge in Pigs

African swine fever virus (ASFV) is the causative agent of African swine fever (ASF), a severe hemorrhagic disease with a mortality rate reaching 100%. Despite extensive research on ASFV mechanisms, no safe and effective vaccines or antiviral treatments have been developed. Live attenuated vaccines generated via gene deletion are considered to be highly promising. We developed a novel recombinant ASFV strain by deleting <i>MGF360-10L</i> and <i>MGF505-7R</i>, significantly reducing virulence in pigs. In the inoculation experiment, pigs were infected with 10⁴ 50% hemadsorption doses (HAD₅₀) of the mutant strain. All the animals survived the observation period without showing ASF-related clinical signs. Importantly, no significant viral infections were detected in the cohabitating pigs. In the virus challenge experiment, all pigs succumbed after being challenged with the parent strain. RNA-seq analysis showed that the recombinant virus induced slightly higher expression of natural immune factors than the parent ASFV; however, this level was insufficient to provide immune protection. In conclusion, our study demonstrates that deleting <i>MGF360-10L</i> and <i>MGF505-7R</i> from ASFV CN/GS/2018 significantly reduces virulence but fails to provide protection against the parent strain.