The Potential of Disabled Infectious Single Cycle (DISC) Virus Platforms for Next Generation African Swine Fever Vaccine Development

Abstract

African swine fever (ASF) is an emergency animal disease causing significant socio-economic impacts in affected areas on a global scale. While the first generation of ASF live-attenuated virus (LAV) vaccines to be recently approved for use in some countries offer potential to kerb the spread of ASF, non-live next-generation vaccines offer a safer alternative that can also be administered to animals in ASF-free zones. Among the next-generation vaccine platforms, disabled infectious single cycle (DISC) viruses are a promising replication-incompetent viral vaccine approach. In this review, we evaluate potential ASF virus gene targets that have been shown to have essential roles in the replication cycle and could be selected as deletion targets for producing DISC vaccines. We also summarise ASF virus genes for which there is evidence for a role in replication but have not yet been examined for their essential functions. Anticipated challenges for the development of an ASF DISC vaccine include limited cell substrates for development and manufacturing, genomic and phenotypic diversity of ASFV and potential for recombination events with co-infecting field viruses leading to reversion to virulence.

Keywords: African swine fever; disabled infectious single cycle; essential ASFV genes; vaccine development and challenges.

Figure 1

Replication cycle of African swine fever virus. The ASFV replication cycle starts with entry into the host cell by dynamin- and clathrin-mediated endocytosis via unknown virus-specific binding receptors or non-specific micropinocytosis [55, 56], followed by internalisation via the endocytic pathway, where sequential viral uncoating occurs. The uncoated ASFV particle reaches the perinuclear area in the cytoplasm and releases viral genome for replication [57]. At the early phase of genome replication, the ASFV DNA briefly transports into and out of the nucleus with the help of ASFV proteins p14 and p37 [9, 58]. Transcription of ASFV genes is initiated before viral genome replication, with both chains of the double-stranded ASFV genome able to alternatively serve as the coding template [59, 60]. The assembly process of ASFV virions occurs in the cytoplasm in viral factories which are held together by a network of microtubules, located near the nucleus and surrounded by ER membranes [61, 62]. Viral proteins and nucleic acids are retained in the viral factories where they interact to form the nucleoid (p10 and pA104R), inner core shell (p35, p15, p8, p150, p37, p34, p14 and p5), inner envelope (p12, p17, pE183L, pE248R, pH108R, pE199L and p22), outer capsid (p72, pE120R and pB438L) and outer envelope (p12 and pE402R) structures that are eventually assembled into a mature virion [63, 64]. At the end of the replication cycle, mature ASFV virions are transported from the viral assembly sites to the plasma membrane by microtubules, then exit the host cell by budding [61]. This diagram was created with bioRENDER.