Deletion of the Gene for the Type I Interferon Inhibitor I329L from the Attenuated African Swine Fever Virus OURT88/3 Strain Reduces Protection Induced in Pigs

Abstract

Live attenuated vaccines are considered to be the fastest route to the development of a safe and efficacious African swine fever (ASF) vaccine. Infection with the naturally attenuated OURT88/3 strain induces protection against challenge with virulent isolates from the same or closely related genotypes. However, adverse clinical signs following immunisation have been observed. Here, we attempted to increase the OURT88/3 safety profile by deleting I329L, a gene previously shown to inhibit the host innate immune response. The resulting virus, OURT88/3ΔI329L, was tested in vitro to evaluate the replication and expression of type I interferon (IFN) and in vivo by immunisation and lethal challenge experiments in pigs. No differences were observed regarding replication; however, increased amounts of both IFN-β and IFN-α were observed in macrophages infected with the deletion mutant virus. Unexpectedly, the deletion of I329L markedly reduced protection against challenge with the virulent OURT88/1 isolate. This was associated with a decrease in both antibody levels against VP72 and the number of IFN-γ-producing cells in the blood of non-protected animals. Furthermore, a significant increase in IL-10 levels in serum was observed in pigs immunised with OURT88/3ΔI329L following challenge. Interestingly, the deletion of the I329L gene failed to attenuate the virulent Georgia/2007 isolate.

Current State of Global African Swine Fever Vaccine Development under the Prevalence and Transmission of ASF in China

“…In the latest study in May 2020, an attempt was made to increase the safety of the naturally attenuated strain OURT88/3 by deleting I329L, a gene previously shown to inhibit the innate immune response of the host. Unexpectedly, the OURT88/3∆I329L strain significantly reduced protection against virulent stains OURT 88/1 attacks [ 50 ]. To date, the hinge to immune protection of naturally LAVs still needs to be further elucidated.…”

African Swine Fever Virus as a Difficult Opponent in the Fight for a Vaccine—Current Data

“…For example, infection with a naturally attenuated OURT88/3 strain induced protection against the same or closely related strains but simultaneously caused side effects. Reis et al [ 60 ] attempted to increase the vaccine’s safety by deleting the I329L gene. Surprisingly, the protection induced by the OURT88/3ΔI329L deletion mutant was significantly reduced against challenge with the virulent OURT88/1 isolate.…”

“…A decrease in the level of antibodies against ASFV protein VP72/B646L and the number of IFN-γ-producing cells in the blood was observed in unprotected animals, while the concentration of IL-10 in the serum of animals immunized with OURT88/3ΔI329L was increased. The same study also showed that the deletion of the I329L gene fails to attenuate the virulent Georgia/2007 isolate [ 60 ]. Previous studies showed that the deletion of another IFN inhibitor (A276R) from the NH/P68 isolate resulted in a complete loss of protection against Arm07 challenge, as opposed to the complete protection provided by vaccination with wild-type NH/P68 [ 67 ].…”

“…By avoiding detection and inhibiting host defense mechanisms, ASFV replicates rapidly and causes clinical disease in pigs. Inhibition of the induction of IFN type I in response to infection with virulent ASFV is essential to rapid viral replication [ 60 , 62 ]. It is suggested that the deletion of genes that inhibit the induction of IFN type I may debilitate the virus [ 60 ].…”

“…Inhibition of the induction of IFN type I in response to infection with virulent ASFV is essential to rapid viral replication [ 60 , 62 ]. It is suggested that the deletion of genes that inhibit the induction of IFN type I may debilitate the virus [ 60 ]. ASFV, similarly to numerous other viruses, encodes anti-apoptotic proteins that prevent the destruction of infected cells.…”