BA71ΔCD2: a New Recombinant Live Attenuated African Swine Fever Virus with Cross-Protective Capabilities

Abstract

African 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.

Current status and evolving approaches to African swine fever vaccine development

“…Hence, specific gene‐deleted ASFV mutants have unlocked new possibilities for rational vaccine development (Table ). Having noted the drawbacks of in vitro attenuated ASFVs, target gene‐deleted live attenuated and subunit vaccines become attractive options, and as a result, several gene‐deleted ASF vaccines have been attempted (Gallardo, Sánchez, et al, ; Monteagudo et al, ; O’Donnell et al, , ; Reis et al, ). By targeted deletion of virulence‐related genes, it has been shown that it would be possible to define the balance between attenuation and immunogenicity (Reis et al, ; Sánchez‐Cordón, Jabbar, et al, ).…”

“…To date, several virulence‐associated ASFV genes such as 9GL, UK, CD2v, DP148R and MGFs have been deleted to generate attenuated ASF vaccines. Despite these achievements, safety concerns remain to be challenging, and attenuated ASF vaccines are still at the experimental levels (Monteagudo et al, ; O’Donnell et al, , ; Reis et al, ).…”

“…This information might be used to design rationally attenuated vaccine strains that fulfil the right balance between attenuation and immunogenicity. The current data suggest that the main challenge to generate safe and effective attenuated ASF vaccine is the uncertain genetic window for attenuation (Monteagudo et al, ; O’Donnell et al, , ; Reis et al, ). These challenges and drawbacks of live attenuated ASF vaccines like the retained residual pathogenicity would be addressed by targeting multifoci.…”

ASFVdb: An integrative resource for genomics and proteomics analyses of African swine fever

“…CD2v (EP402R) is an ASFV gene related to hemadsorption (Rodriguez et al, 1993). CD2v (EP402R) plays a key role in viral attenuation and may be involved in the generation of immune protection from the host against ASFV infection (Monteagudo et al, 2017). Through searching for “EP402R” in the strain China_AnhuiXCGQ_2018, we found that this gene encodes a single-Pass membrane protein in the transmembrane region from 207 AA to 229 AA (Figure S2A).…”

African swine fever: Etiology, epidemiological status in Korea, and perspective on control

“…Discrepancies do exist, attenuated non-HAD viruses, which presumably lack CD2v/C-type lectin proteins, can protect pigs from a virulent challenge. Similarly, DNA vaccination of animals with an entire ASFV genomic library that is lacking CD2v, p54, and p30 genes indicates additional viral proteins are needed for protection because only 60% of the vaccines protected against the challenge [57]. Several ASFV proteins have been associated with protection, but no specific viral protein has been shown to induce robust protective immunity.…”