Virus-like particles of Macrobrachium rosenbergii nodavirus displaying M2e of Influenza A viruses protect White Leghorn chickens against heterologous H9N2 and H5N2 challenges

H9N2 and H5N2 avian influenza A viruses (IAVs) are two of the most widespread and economically damaging subtypes affecting the poultry industry. Controlling these viruses in poultry remains challenging, highlighting the need for a vaccine that can confer broad and effective protection across multiple avian IAV subtypes. Previously, we fused two copies of the matrix 2 ectodomain (M2e) of human and avian IAV (2xhuM2e-2xavM2e) at the C-terminus of Macrobrachium rosenbergii nodavirus capsid protein (NvC). This chimeric protein (NvC-2xhuM2e-2xavM2e) self-assembled into virus-like particles (VLPs), which elicited broad immune responses and activated humoral and cellular immune responses in chickens. In this study, we evaluated the protective efficacy of these chimeric VLPs in White Leghorn chickens against H9N2 and H5N2 infections. Chickens immunized with the chimeric VLPs produced a significant level of M2e antibodies that reacted with the M2e of H9N2 and H5N2 IAVs. Following viral infections, the chimeric VLPs mitigated weight loss in H9N2-infected chickens and alleviated delayed weight gain in H5N2-infected chickens. Furthermore, the chimeric VLPs reduced the clinical signs in immunized chickens challenged with either H9N2 or H5N2 avian IAV. Viral loads in the lung tissues of the immunized chickens were significantly lower compared to the negative control group. The chimeric VLPs also enhanced H9N2 and H5N2 viral clearance, showing a significant reduction in viral shedding in the oropharynges and cloacae of the immunized chickens. Furthermore, the VLPs activated both inflammatory and anti-inflammatory cytokines, which were associated with enhanced viral clearance while reducing lung and tracheal immunopathology. Collectively, these findings demonstrate the potential of the chimeric VLPs as a cross-protective vaccine against both H9N2 and H5N2 infections in poultry.

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