Abstract
ABSTRACTAfrican swine fever is a highly contagious viral disease of mandatory declaration to the World Organization for Animal Health (OIE). The lack of available vaccines makes its control difficult; thus, African swine fever virus (ASFV) represents a major threat to the swine industry. Inactivated vaccines do not confer solid protection against ASFV. Conversely, live attenuated viruses (LAV), either naturally isolated or obtained by genetic manipulation, have demonstrated reliable protection against homologous ASFV strains, although little or no protection has been demonstrated against heterologous viruses. Safety concerns are a major issue for the use of ASFV attenuated vaccine candidates and have hampered their implementation in the field so far. While trying to develop safer and efficient ASFV vaccines, we found that the deletion of the viral CD2v (EP402R) gene highly attenuated the virulent BA71 strain in vivo. Inoculation of pigs with the deletion mutant virus BA71ΔCD2 conferred protection not only against lethal challenge with the parental BA71 but also against the heterologous E75 (both genotype I strains). The protection induced was dose dependent, and the cross-protection observed in vivo correlated with the ability of BA71ΔCD2 to induce specific CD8+ T cells capable of recognizing both BA71 and E75 viruses in vitro. Interestingly, 100% of the pigs immunized with BA71ΔCD2 also survived lethal challenge with Georgia 2007/1, the genotype II strain of ASFV currently circulating in continental Europe. These results open new avenues to design ASFV cross-protective vaccines, essential to fight ASFV in areas where the virus is endemic and where multiple viruses are circulating.IMPORTANCE African swine fever virus (ASFV) remains enzootic in most countries of Sub-Saharan Africa, today representing a major threat for the development of their swine industry. The uncontrolled presence of ASFV has favored its periodic exportation to other countries, the last event being in Georgia in 2007. Since then, ASFV has spread toward neighboring countries, reaching the European Union's east border in 2014. The lack of available vaccines against ASFV makes its control difficult; so far, only live attenuated viruses have demonstrated solid protection against homologous experimental challenges, but they have failed at inducing solid cross-protective immunity against heterologous viruses. Here we describe a new LAV candidate with unique cross-protective abilities: BA71ΔCD2. Inoculation of BA71ΔCD2 protected pigs not only against experimental challenge with BA71, the virulent parental strain, but also against heterologous viruses, including Georgia 2007/1, the genotype II strain of ASFV currently circulating in Eastern Europe.
Highlights
African swine fever is a highly contagious viral disease of mandatory declaration to the World Organization for Animal Health (OIE)
We demonstrated the following: first, that deletion of the EP402R open reading frame (ORF) encoding the African swine fever virus (ASFV) hemagglutinin, known as viral CD2 (CD2v) [40, 41], totally attenuated the virulent BA71 ASFV strain; second, that the deletion mutant BA71ΔCD2 was capable of protecting pigs in a dose-dependent manner, against the homologous BA71 virus and against the heterologous E75 virulent challenge; third, that the protection afforded correlated with the ability of BA71ΔCD2 to induce CD8ϩ T cells that recognized both viruses in vitro; and fourth, that BA71ΔCD2 protected against the ASFV challenge with Georgia 2007/1, the virus currently circulating in Eastern Europe and belonging to genotype II (BA71 and E75 belong to genotype I)
The genetic stability observed for BA71ΔCD2 after 20 consecutive passages in COS-1 cells allows us to hypothesize about the future standardization of the large-scale production of this vaccine prototype
Summary
African swine fever is a highly contagious viral disease of mandatory declaration to the World Organization for Animal Health (OIE). 100% of the pigs immunized with BA71ΔCD2 survived lethal challenge with Georgia 2007/1, the genotype II strain of ASFV currently circulating in continental Europe These results open new avenues to design ASFV cross-protective vaccines, essential to fight ASFV in areas where the virus is endemic and where multiple viruses are circulating. The lack of available vaccines against ASFV makes its control difficult; so far, only live attenuated viruses have demonstrated solid protection against homologous experimental challenges, but they have failed at inducing solid cross-protective immunity against heterologous viruses. The most recent incorporation of molecular technologies has allowed the precise manipulation of the ASFV genome by homologous recombination, obtaining ASFV deletion mutants lacking nonessential genes [30] and, more recently, recombinant viruses encoding essential ASFV genes under the control of inducible promoters [31] These methodologies have allowed a better understanding of key aspects of ASFV biology, including ASFV morphogenesis [32], and have opened new avenues for Journal of Virology jvi.asm.org 2
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