Prophylactic treatment with PEGylated bovine FN-lambda3 effectively bridges the gap in vaccine-induced immunity against FMD in cattle

Authors: Attreed, Sarah; Silva, Christina; RODRIGUEZ-CALZADA, MONICA - Oak Ridge Institute For Science And Education (ORISE); MOGULOTHU, AISHWARYA - University Of Connecticut; Abbot, Sophia; Azzinaro, Paul; CANNING, PETER - Vetbio Partners, Llc; SKIDMORE, LILLIAN - Ambryx; NELSON, JAY - Ambryx; KNUDSEN, NICK - Ambryx; Medina, Gisselle; DE LOS SANTOS, TERESA - Retired ARS Employee; DIAZ-SAN SEGUNDO, FAYNA - Nih, National Institutes Of Allergy And Infectious Diseases

Submitted to: Frontiers in Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/11/2024
Publication Date: 4/4/2024
Citation: Attreed, S.E., Silva, C.M., Rodriguez-Calzada, M., Mogulothu, A., Abbott, S.T., Azzinaro, P.A., Canning, P., Skidmore, L., Nelson, J., Knudsen, N., Medina, G.N., De Los Santos, T., Diaz-San Segundo, F. 2024. Prophylactic treatment with PEGylated bovine FN-lambda3 effectively bridges the gap in vaccine-induced immunity against FMD in cattle. Frontiers in Microbiology. 15. https://doi.org/10.3389/fmicb.2024.1360397.
DOI: https://doi.org/10.3389/fmicb.2024.1360397

Interpretive Summary: Problem: Following vaccination, it takes 7 days for susceptible animals to develop protective immunity against foot-and-mouth disease (FMD). Novel biotherapeutics with a long half-life in the body are needed for application in FMD outbreak scenarios to help bridge the gap in immunity and prevent the spread of this costly livestock disease. Accomplishment: We have developed a novel biotherapeutic with increased half-life and tested in cattle resulting in successful protection of cows against infection with FMD virus (FMDV) at both 3 and 5 days following treatment, with and without co-administration of an FMD vaccine. Contribution to field: This biotherapeutic has the potential to be applied in FMD outbreak scenarios to help prevent the spread of this disease.

Technical Abstract: Foot-and-mouth disease (FMD) is a vesicular disease of cloven-hoofed animals with devastating economic implications. The current FMD vaccine is routinely used in enzootic countries and requires at least 7 days to induce protection. However, FMD vaccination is typically not recommended for use in non-enzootic areas, underscoring the need to develop new fast-acting therapies for FMD control during outbreaks. Interferons (IFNs) are among the immune system’s first line of defense against viral infections. Bovine type III IFN delivered by a replication defective adenovirus (Ad) vector has effectively blocked FMD in cattle. However, the limited duration of protection—usually only 1-3 days post-treatment (dpt)—diminishes its utility as a field-use therapeutic. Here we test whether polyethylene glycosylation (PEGylation) of recombinant bovine IFN-lambda3 (PEGboIFN-lambda3) can extend the duration of interferon-induced prevention of FMDV infection in both vaccinated and unvaccinated cattle. We treated groups of Holstein heifers with PEGboIFN-lambda3 alone or in combination with an adenovirus-based FMD O1Manisa vaccine (Adt-O1M) at either 3 or 5 days prior to challenge with homologous wild type FMDV. We found that pre-treatment with PEGboIFN-lambda3 was highly effective at preventing clinical FMD when administered at either time point, with and without co-administration of Adt-O1M vaccine. PEGboIFN-lambda3 protein was detectable systemically for >10 days and antiviral activity for 4 days following administration. Furthermore, in combination with Adt-O1M vaccine, we observed a strong induction of FMDV-specific IFN-lambda3+ T cell response, evincing its adjuvanticity when formulated with vaccine. Our results demonstrate the promise of this modified IFN as a pre-exposure prophylactic therapy for use in emergency outbreak scenarios.