The highly pathogenic avian influenza virus (HPAI) H5N1 clade 2.3.4.4B has significantly affected the U.S. Poultry industry, resulting in >168 million bird losses since 2022, driving EGG prices to…

The Department of Agriculture Animal and Plant Health Inspection Service awarded a cooperative agreement to Louisiana State University on February 2, 2026, totaling $1.922 million to develop novel mucosal vaccines against highly pathogenic avian influenza (HPAI) H5N1 in poultry under the Plant and Animal Disease, Pest Control, and Animal Care program (CFDA 10.025).

LSU will develop M-cell-directed self-amplifying RNA and recombinant vesicular stomatitis virus-vectored HPAI H5N1 vaccines using nanobodies as single-domain antibodies to target specific cells for antigen delivery. The project encompasses three objectives: developing M-cell-directed vaccine candidates administered via in ovo and drinking water routes; assessing safety and immunogenicity following both vaccination methods; and evaluating protective efficacy against HPAI H5N1 challenge in poultry, with challenge work performed at Kansas State University. The vaccines are designed to induce both mucosal and systemic protective immunity and overcome limitations of current U.S. vaccines, which lack differentiation between vaccinated and infected animals, provide incomplete early protection, and are unsuitable for mass vaccination.

Performance occurs in Louisiana with a period of performance through February 1, 2029. The cooperative agreement is assistance funding under the program's authority to support institutions of higher education in developing and assessing interventions addressing injurious animal diseases that threaten regional or national agriculture.

The highly pathogenic avian influenza virus (HPAI) H5N1 clade 2.3.4.4B has significantly affected the U.S. Poultry industry, resulting in >168 million bird losses since 2022, driving EGG prices to historic highs. Additionally, transmission of HPAI H5N1 to dairy cattle caused severe reduction in daily milk yields. A multiprong approach is urgently needed to address the HPAI H5N1 crisis nationally, with a particular need for safe and effective vaccines. Current U.S. Vaccines available for deployment face critical challenges: they do not easily differentiate between vaccinated and infected animals (DIVA), lack complete and early protection, and are unsuitable for mass vaccination. Therefore, there is a pressing need to develop novel, next-generation vaccines that overcome these limitations. Nanobodies (VHH) are single-domain antibodies that effectively target specific cells to deliver antigens. They present a promising avenue for vaccine delivery, enhancing specific immune responses to the antigen(S) of interest. We hypothesize that a nanobody -directed HPAI H5N1-specific mucosal vaccine targeting M cells (microfold cells; a specialized intestinal epithelial cell involved in priming the GUT-associated lymphoid tissue), administered via in OVO and booster in drinking water will induce both mucosal and systemic protective immunity in chickens against HPAI H5N1. To test this hypothesis, we will develop a novel mucosal vaccine to protect poultry from HPAI. We propose three objectives: (1) develop M-cell-directed self-amplifying RNA and recombinant vesicular stomatitis virus (VSV)-vectored HPAI H5N1 vaccines; (2) assess the safety and immunogenicity of M-cell-targeted self-amplifying RNA and recombinant VSV-vectored vaccines following vaccination via in OVO and drinking water, respectively; and (3) evaluate their protective efficacy following challenge with HPAI H5N1 in poultry (to be performed at kansas state university). This proposal will deliver a novel vaccine approach for the early protection of poultry from HPAI. Specific positive outcomes include: (1) the development of a novel vaccine(S) utilizing a directed mucosal delivery that can enhance immunogenicity and protection; (2) suitability for mass administration; (3) DIVA compatibility and (4) development of a replication-deficient M cell-directed rvsv-based H5 vaccine for poultry. The outcomes of the study will benefit stakeholders (poultry producers overall, both broiler and layer operations), vaccine manufacturers, and animal health authorities.