This study evaluated whether immunity from seasonal influenza induces cross-reactive antibodies against recent avian and bovine H5N1 strains in serum from retail workers. Despite strong neutralizing activity against seasonal strains, no cross-reactivity against H5N1 was detected, emphasizing the need to assess broader immune responses and targeted vaccines for H5N1 viruses.

Highly pathogenic avian influenza (HPAI) H5N1 has been a global concern since its emergence in 1997, causing widespread outbreaks in birds and sporadic human infections. The clade 2.3.4.4b H5N1 virus has rapidly expanded across continents, infecting numerous mammalian species. In 2024, it was detected in dairy cattle for the first time in the U.S., along with human cases following exposure. In Canada, the first human case of this avian influenza was reported in a critically ill adolescent in late 2024. No human-to-human transmission has been documented, but concerns persist regarding mutations associated with enhanced virulence and human adaptation. Although seasonal influenza vaccines are not directed against H5N1, studies suggest that pre-existing immunity from prior infections or vaccinations may provide partial protection against severe H5N1 infections through cross-reactive immune response. Given the ongoing circulation of avian influenza and the rise in human infections, this study evaluated the effectiveness of neutralizing antibodies developed against seasonal influenza viruses and their cross-reactivity with recent H5N1 strains. Serum samples from 194 retail sector workers in Quebec, collected between late 2021 and 2022, were analyzed using a microneutralization assay. While strong neutralizing activity was found against seasonal influenza viruses, no neutralizing antibodies were detected against H5N1 strains in either vaccinated or unvaccinated individuals. These findings emphasize the need to evaluate cross-reactive antibodies against the neuraminidase protein of H5N1, assess cellular immune responses potentially linked to protection against severe HPAI H5N1 infections and targeted vaccine strategies against recently emerged H5N1 influenza viruses.

Background/Objectives: Chronic inflammation underlies many immune-mediated conditions, yet current anti-inflammatory therapies are often limited by incomplete efficacy or safety concerns. Small molecules inspired by soluble epoxide hydrolase (sEH) inhibitors represent a promising scaffold for early-stage exploration. This study describes the design, synthesis, and preliminary biological evaluation of three series of arylurea derivatives (ACBUs) to establish structure–activity relationships and guide chemical optimization. Methods: The compounds were assessed for effects on keratinocyte proliferation, human sEH activity, and the expression of selected inflammatory markers using IL-17A/TNF-α-stimulated HaCaT cells, a relevant in vitro model for preliminary anti-inflammatory profiling. Results: A total of 23 novel ACBU derivatives were synthesized and evaluated. Most compounds showed low antiproliferative activity, allowing selection based on cytotoxicity and solubility. Compounds 4b, 10b, and 16b consistently displayed the most favorable profiles in these preliminary assays. Docking studies provided structural rationales supporting the observed trends and guided further optimization within the series. Conclusions: Compound 4b emerged as the most active candidate in preliminary screening, serving as a reference for ongoing SAR studies. These results highlight the potential of the arylurea scaffold for further chemical optimization and demonstrate the value of early-stage biological profiling in guiding our further studies.

Highly pathogenic avian influenza A/H5N1 viruses continue to spread among multiple mammalian species, including humans, raising concerns about zoonotic transmission and pandemic preparedness. Immunocompromised individuals often develop severe and prolonged disease, yet evidence guiding antiviral therapy in these patients remains limited. We investigated pathogenesis, transmissibility, and antiviral efficacy of oseltamivir, baloxavir, and molnupiravir against a human A/H5N1 clade 2.3.4.4b genotype D1.1 virus isolated in Canada using a cyclophosphamide-immunosuppressed hamster model. A/H5N1 infection caused severe disease in immunosuppressed hamsters with no contact transmission. Baloxavir conferred complete survival, markedly reduced viral burden, and prevented neuroinvasion, while high-dose molnupiravir and combination therapy with oseltamivir and low-dose molnupiravir improved outcomes and achieved viral clearance in lung and brain tissues. These findings support baloxavir as an effective therapeutic option for severe A/H5N1 infection in immunocompromised hosts and identify molnupiravir as a promising antiviral candidate, with implications for pandemic preparedness strategies targeting vulnerable populations.