Antibodies Targeting the CCHFV Nucleocapsid Protein Require TRIM21 for Protection

Abstract

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a negative-sense RNA virus spread by Hyalomma genus ticks across Europe, Asia, and Africa. CCHF disease begins as a non-specific febrile illness which may progress into a severe hemorrhagic disease and there are currently no widely approved or highly efficacious interventions available. Recently, we reported a self-replicating, alphavirus-based RNA vaccine which expresses the CCHFV nucleoprotein and is protective against lethal CCHFV disease in mice. This vaccine induces high titers of non-neutralizing anti-NP antibodies and is protective even in mice with constitutive knock-out of Fc-gamma receptors or complement, indicating these mechanisms are not required for protection. Instead, vaccinated mice deficient in the intracellular Fc-receptor TRIM21 despite having robust CCHFV-specific immunity, were unable to control the infection. We also show that passive transfer of NP-immune sera confers significant and TRIM21-dependent protection against lethal CCHFV challenge. Together our data identifies TRIM21 as the Fc effector function of protective antibodies against the CCHFV NP and provides mechanistic insight into how vaccines against CCHFV confer protection.

A replicating RNA vaccine confers protection in a rhesus macaque model of Crimean-Congo hemorrhagic fever

“…3c). As we have previously shown that humoral immunity is the primary correlate of protection 5,22,23 , we hypothesized that antibody titer would correlate with viral loads. Indeed, we found that CCHFV-specific antibody titer significantly and inversely correlated with viral load in multiple tissues, including the heart, liver, kidney, and adrenal gland (Fig.…”

“…CCHFV has substantial genetic diversity, differing by >5% in the NP and over 25% in the GPC 38 , and thus, an effective vaccine will need to protect against diverse strains of CCHFV. We have shown in mice that our repNP vaccine and passive transfer of NPimmune serum can protect against a highly divergent strain of CCHFV 5,22,23 , making the more conserved NP a promising vaccine-encoded antigen. Fourthly, we did not evaluate the durability of immune responses to CCHFV following repRNA vaccination.…”