Protection of European domestic pigs from virulent African isolates of African swine fever virus by experimental immunisation

143

132

African swine fever virus (ASFV) is IMPORTANCEThe main problem for controlling ASF is the lack of vaccines. Studies on ASFV virulence lead to the production of genetically modified attenuated viruses that induce protection in pigs but only against homologous virus challenges. Here we produced a recombinant ASFV lacking virulence-associated gene 9GL in an attempt to produce a vaccine against virulent ASFV-G, a highly virulent virus isolate detected in the Caucasus region in 2007 and now spreading though the Caucasus region and Eastern Europe. Deletion of 9GL, unlike with other ASFV isolates, did not attenuate completely ASFV-G. However, when delivered once at low dosages, recombinant ASFV-G-⌬9GL induces protection in swine against parental ASFV-G. The protection against ASFV-G is highly effective after 28 days postvaccination, whereas at 21 days postvaccination, animals survived the lethal challenge but showed signs of ASF. Here we report the design and development of an experimental vaccine that induces protection against virulent ASFV-G.A frican swine fever (ASF) is a contagious viral disease of swine. The causative agent, ASF virus (ASFV), is a large enveloped virus containing a double-stranded DNA (dsDNA) genome of approximately 190 kbp. ASFV shares aspects of genome structure and replication strategy with other large dsDNA viruses, including the Poxviridae, Iridoviridae, and Phycodnaviridae (1). ASF causes a spectrum of disease that ranges from highly lethal to subclinical, depending on host characteristics and the virulence of circulating virus strains (2). ASFV infections in domestic pigs are often fatal and are characterized by high fever, hemorrhages, ataxia, and severe depression.Currently, the disease is endemic in more than 20 sub-Saharan African countries. In Europe, ASF is endemic on the island of Sardinia (Italy), and outbreaks of ASF have been recorded in the Caucasus region since 2007, affecting Georgia, Armenia, Azerbaijan, and Russia. Isolated outbreaks have been recently reported in Ukraine, Belarus, Lithuania, Latvia, and Poland, posing the risk of further dissemination into neighboring countries. The epidemic

Section: Discussionsupporting

confidence: 94%

African Swine Fever Virus Georgia 2007 with a Deletion of Virulence-Associated Gene 9GL (B119L), when Administered at Low Doses, Leads to Virus Attenuation in Swine and Induces an Effective Protection against Homologous Challenge

O’Donnell

Holinka

Krug

et al. 2015

143

132

“…In contrast, E75CV1 behaved with surprising virulence in SPF pigs, killing all control animals within 13 days after infection. These results seem to coincide with those previously reported by King et al, although not deeply discussed at the time (12). In that report, the authors describe some unexpected adverse effects while infecting SPF pigs with OURT88/3, an attenuated strain of ASFV, although they are far from the dramatic adverse effects found with E75CV1, most probably due to genetic differences between the two attenuated ASFV strains.…”

Section: Fig 4 Kinetics Of the Detection Of Ifn-␣ (A) And Tnf-␣ (B) Isupporting

confidence: 89%

“…Despite the fact that little is known about the mechanisms involved in protection, seminal evidence has demonstrated the key role that humoral responses (5-7) and specific CD8 ϩ T cells (8,9) can play in protection. Future vaccine designs against African swine fever vi-rus (ASFV) should take lessons from these findings, garnered by using in vivo models of homologous protection with attenuated viruses first described in the 1960s (10)(11)(12). Different attempts to develop an efficient and safe vaccine against ASF have been made, so far with not very consistent results.…”

mentioning

confidence: 99%

Expression Library Immunization Can Confer Protection against Lethal Challenge with African Swine Fever Virus

Lacasta

Ballester

Monteagudo

et al. 2014

Self Cite

101

African swine fever is one of the most devastating pig diseases, against which there is no vaccine available. Recent work from our laboratory has demonstrated the protective potential of DNA vaccines encoding three African swine fever viral antigens (p54, p30, and the hemagglutinin extracellular domain) fused to ubiquitin. Partial protection was afforded in the absence of detectable antibodies prior to virus challenge, and survival correlated with the presence of a large number of hemagglutinin-specific CD8 IMPORTANCEAfrican swine fever is a highly contagious disease of domestic and wild pigs that is endemic in many sub-Saharan countries, where it causes important economic losses and is currently in continuous expansion across Europe. Unfortunately, there is no treatment nor an available vaccine. Early attempts using attenuated vaccines demonstrated their potential to protect pigs against experimental infection. However, their use in the field remains controversial due to safety issues. Although inactive and subunit vaccines did not confer solid protection against experimental ASFV infection, our DNA vaccination results have generated new expectations, confirming the key role of T-cell responses in protection and the existence of multiple ASFV antigens with protective potential, more of which are currently being identified. Thus, the future might bring complex and safe formulations containing more than a single viral determinant to obtain broadly protective vaccines. We believe that obtaining the optimal vaccine formulation it is just a matter of time, investment, and willingness.

“…Recently, a possible correlation between the induction of virus-specific circulating IFN-␥-producing cells and protection in animal vaccinated with attenuated ASFV strains (23) or with experimental DNA vaccines has been reported (24). Our results indicated no close association between virus-specific IFN-␥-producing cells and protection as an independent factor.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous Deletion of the 9GL and UK Genes from the African Swine Fever Virus Georgia 2007 Isolate Offers Increased Safety and Protection against Homologous Challenge

O’Donnell

Risatti

Holinka

et al. 2017

161

155

African swine fever virus (ASFV) is the etiological agent of a contagious and often lethal viral disease of domestic pigs that has significant economic consequences for the swine industry. The control of African swine fever (ASF) has been hampered by the unavailability of vaccines. Successful experimental vaccines have been derived from naturally occurring, cell culture-adapted, or genetically modified live attenuated ASFV. Recombinant viruses harboring engineered deletions of specific virulence-associated genes induce solid protection against challenge with parental viruses. Deletion of the 9GL (B119L) gene in the highly virulent ASFV isolates Malawi Lil-20/1 (Mal) and Pretoriuskop/96/4 (Δ9GL viruses) resulted in complete protection when challenged with parental isolates. When similar deletions were created within the ASFV Georgia 2007 (ASFV-G) genome, attenuation was achieved but the protective and lethal doses were too similar. To enhance attenuation of ASFV-G, we deleted another gene, UK (DP96R), which was previously shown to be involved in attenuation of the ASFV E70 isolate. Here, we report the construction of a double-gene-deletion recombinant virus, ASFV-G-Δ9GL/ΔUK. When administered intramuscularly (i.m.) to swine, there was no induction of disease, even at high doses (106 HAD50). Importantly, animals infected with 104 50% hemadsorbing doses (HAD50) of ASFV-G-Δ9GL/ΔUK were protected as early as 14 days postinoculation when challenged with ASFV-G. The presence of protection correlates with the appearance of serum anti-ASFV antibodies, but not with virus-specific circulating ASFV-specific gamma interferon (IFN-γ)-producing cells. ASFV-G-Δ9GL/ΔUK is the first rationally designed experimental ASFV vaccine that protects against the highly virulent ASFV Georgia 2007 isolate as early as 2 weeks postvaccination. IMPORTANCE Currently, there is no commercially available vaccine against African swine fever. Outbreaks of the disease are devastating to the swine industry and are caused by circulating strains of African swine fever virus. Here, we report a putative vaccine derived from a currently circulating strain but containing two deletions in two separate areas of the virus, allowing increased safety. Using this genetically modified virus, we were able to vaccinate swine and protect them from developing ASF. We were able to achieve protection from disease as early as 2 weeks after vaccination, even when the pigs were exposed to a higher than normal concentration of ASFV.