<b>Novel Bovine Adenoviral Vector-Based Platform for Designing Universal Influenza Vaccines</b>

<p dir="ltr">Seasonal influenza vaccines provide only strain-specific protection, leaving populations vulnerable to mismatched and emerging pandemic strains. To address this limitation, universal influenza vaccine strategies are increasingly focused on conserved viral antigens and novel vaccine delivery platforms. Adenoviral (Ad) vector–based systems, including both human and nonhuman serotypes, have been used as versatile candidates capable of eliciting robust humoral and cellular immune responses, particularly when delivered intranasally to induce local mucosal immunity.</p><p dir="ltr">In these studies, bovine and human adenoviral vectors were engineered to express combinations of influenza antigens, such as the hemagglutinin (HA) stem, matrix protein 2 ectodomain, and nucleoprotein (NP). Heterologous prime–boost immunizations with HA stem–expressing vector enhanced HA stem–specific antibody and humoral responses, and conferred cross-protection against both group 1 and group 2 influenza A viruses. Similarly, bovine adenoviral vectors expressing NP from influenza A and B viruses fused to the autophagy-inducing peptide C5 (AIP-C5) induced strong systemic and mucosal immunity after a single intranasal dose. Notably, the bivalent formulation provided protection against broad-spectrum influenza A and B viruses in both mice and ferrets.</p><p dir="ltr">Mechanistic analyses revealed that protection induced by adenoviral vectors expressing NP was mediated not only by antibodies but also by robust cellular immunity. Vaccine-induced CD8⁺ effector memory and lung-resident T cells, along with memory B cells, contributed to heterosubtypic protection, with passive transfer experiments underscoring the critical role of local lung T cells. These findings highlight the promise of adenoviral vector–based vaccines, particularly NP- and HA stem–targeted formulations, as broadly protective and clinically relevant candidates for the development of a universal influenza vaccine.</p>