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D. Kobasa

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Open access Jul 2026

Antigen clade matching enhances protective efficacy of H5N1 DNA vaccines delivered by electroporation or lipid nanoparticles 2267127

Highly pathogenic avian influenza viruses (HPAIs) continue to threaten both agriculture and human health. Recent H5N1 clades have caused zoonotic infections in humans with mortality rates approaching 50%. However, currently licensed H5 vaccines are based on ancestral strains and may provide suboptimal protection against circulating variants. Rapidly adaptable DNA vaccine platforms offer a promising approach for clade-specific protection. Codon-optimized plasmid DNA vaccines expressing hemagglutinin (HA) from two recently circulating H5N1 clades (2.3.2.1c and 2.3.4.4b) were generated and delivered by either intramuscular electroporation (EP) or a lipid nanoparticle (LNP) formulation. Cellular and humoral responses were evaluated by multiparameter flow cytometry and ELISpot and by ELISA and pseudovirus neutralization, respectively. Protective efficacy was evaluated in lethal H5N1 murine challenge models. EP delivery of clade 2.3.2.1c HA (pCamb) elicited strong humoral and cellular responses and achieved complete protection against homologous viral challenge, but only partial protection against heterologous 2.3.4.4b challenge. In contrast, vaccination with clade 2.3.4.4b HA (pMich) DNA supported robust immune responses and full protection against contemporary clade challenge. Co-immunization with both plasmids via EP induced broad binding and neutralizing antibodies and conferred complete protection from clade 2.3.4.4b challenge. Moreover, formulation of the pMich plasmid optimized LNPs generated durable, protective immunity following a single dose, effective at both acute and memory timepoints. These studies demonstrate that antigenic clade-matching is likely critical for protection against H5N1 and suggest that currently stockpiled H5N1 vaccines may not protect against contemporary viruses. Further this data suggests that DNA vaccine platforms including EP or LNP formulations can provide a flexible approach for rapid adaptation to evolving influenza strains. NIH NIAID CIVICs Vaccines and Immunotherapy (VAC)

Ebony N. Gary, Nicholas J. Tursi, Casey E. Hojecki et al. · 0 citations
Open access Jul 2026

Characterization of oseltamivir-resistant A(H5N1) clade 2.3.4.4b, genotype D1.1 variants identified in poultry farms of British Columbia, Canada

ABSTRACT Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b, genotype D1.1, are responsible for widespread outbreaks in poultry and continue to cause sporadic, sometimes severe, human infections. Herein, we characterized a wild-type (WT) influenza A(H5N1) D1.1 isolate (BC-H5N1-WT) and its H275Y neuraminidase (NA) variant (BC-H5N1-H275Y), both of which emerged on farms in British Columbia, Canada, during the fall 2024 outbreak. In vitro analysis assessed replication kinetics in MDCK cells, with supernatants collected at different days post-infection (p.i.) and titrated by TCID50 and qRT-PCR. Neuraminidase inhibitor (NAI) susceptibility was determined by NA inhibition assays, whereas susceptibility to baloxavir acid (BXA) was evaluated by plaque reduction assay. In vivo virulence was evaluated in BALB/c mice infected with serial 10-fold dilutions of each virus to monitor weight loss and mortality. Viral titers in lungs, brain, nose, kidney, spleen, and heart were quantified at day 4 p.i. The BC-H5N1-WT virus was susceptible to the four antivirals tested, whereas BC-H5N1-H275Y displayed resistance to oseltamivir and peramivir but remained susceptible to zanamivir and BXA. The BC-H5N1-WT exhibited significantly higher viral replication titers than BC-H5N1-H275Y at all tested time points and showed larger plaque sizes. In mice, BC-H5N1-WT was more virulent with LD50 values of 1.78 × 103 PFUs compared to 8.71 × 104 PFUs for BC-H5N1-H275Y, and produced higher viral titers in lungs and other organs. Despite the reduced fitness of the resistant H5N1 D1.1 variant, its emergence in the absence of viral selection pressure underscores the need for continued surveillance.

Maxime Cochin, Yacine Abed, Robert Vendramelli et al. · 0 citations