Anti-pA137R antibodies exacerbate the pathogenicity of African swine fever virus in pigs.

African swine fever virus (ASFV) is the causative agent of African swine fever (ASF), a highly contagious disease with a mortality of up to 100% in pigs. Currently, no safe and effective vaccines are available globally, except for two licensed vaccines in Vietnam. One of the factors impeding the development of vaccines is antibody-dependent enhancement (ADE). Our previous study showed that the antibodies against the ASFV protein A137R (pA137R) could promote ADE of ASFV infection in primary porcine alveolar macrophages. However, direct evidence of ADE in target animals remains limited. Here, we investigated whether anti-pA137R antibodies exacerbate ASFV pathogenicity in pigs. The immunization-challenge experiment showed that the pigs immunized with pA137R exhibited more severe clinical signs and died earlier than the unimmunized ones. Meanwhile, the examination of viral replication in the blood and various tissues revealed that the anti-pA137R antibodies promoted the infectivity of ASFV. Notably, the production of interferon alpha was significantly upregulated in the blood of the immunized piglets, while the level of interferon beta, tumor necrosis factor alpha, and interleukin 1beta remained unchanged. Mechanistically, the Fc gamma receptor (FcR) II and FcRIII facilitated ADE of ASFV infection in the PK-15 cells overexpressing the receptors. Taken together, our study demonstrates for the first time that the anti-pA137R antibodies enhance ASFV pathogenicity in pigs, providing novel insights into the role of anti-ASFV antibodies in the pathogenesis of ASFV and the rational design of innovative ASF vaccines.IMPORTANCEThe antibody-dependent enhancement (ADE) effect can augment viral replication or elicit aberrant immune responses, ultimately aggravating the disease progression. Recently, we have shown that the antibodies against A137R protein (pA137R) of African swine fever virus (ASFV) can drive ADE . The present study shows that the anti-pA137R antibodies can enhance viral infection and exacerbate clinical signs in pigs. Importantly, the aberration in interferon alpha production might be related to the pathogenicity of ASFV mediated by ADE. Mechanistically, Fc gamma receptor (FcR) II and FcRIII are shown to facilitate ASFV infection. This study is the first to demonstrate that the anti-pA137R antibodies enhance the pathogenicity of ASFV in pigs, offering novel insights into the pathophysiology of ASFV and the development of African swine fever vaccines.