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Vaccine Delivery Platforms Affect Heterologous Protection by Hemagglutinin-Based Influenza Vaccines in Pigs

ABSTRACT: Vaccine-associated enhanced disease (VAED) poses a significant challenge in vaccine development for certain diseases. Vaccine-associated enhanced respiratory disease (VAERD), a form of VAED, has been observed in pigs vaccinated with whole-inactivated vaccine against influenza A virus (IAV) vaccines, followed by an exposure to antigenically mismatched virus strains. Similar outcomes have been reported in pigs vaccinated with a protein-based vaccine containing hemagglutinin (HA), a key viral surface antigen of IAV. We recently developed a lipid nanoparticle encapsulated DNA vaccine encoding the HA gene of IAV, which induced robust immune responses after a single immunization and protected pigs against homologous IAV challenges. This study compared the immunogenicity and efficacy of HA-protein-based and HA-DNA-based vaccines against an antigenically mismatched IAV strain in pigs. While the HA protein-based vaccine exacerbated lung consolidation compared to non-vaccinated controls, the HA-based DNA vaccine prevented gross lung lesion development. Transcriptome analysis revealed distinct gene expression profiles, highlighting differences in host immune responses. These findings provide direct evidence that the same vaccine antigen, when delivered through different platforms, can result in different outcomes: protection versus disease enhancement. This underscores the importance of selecting appropriate delivery platforms for vaccine development. Furthermore, the IAV vaccine in pigs could be a valuable model for studying the immunological mechanisms underlying vaccine-enhanced diseases.

ORGANISM(S): Sus scrofa

PROVIDER: GSE285002 | GEO | 2025/12/19

REPOSITORIES: GEO

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Project description:Influenza B virus (FLUBV) is a major respiratory pathogen of humans. Seasonal influenza vaccines include either one or both FLUBV lineage strains, Victoria, and Yamagata. Vaccine mismatch occurs frequently, particularly in countries where vaccines contain only one of the lineages. We have previously described the safety and efficacy of modified live attenuated FLUBV vaccines based on either virus with rearranged genomes (FluB-RAM and FluB-RANS) or carrying a PB1 segment with a combination of temperature sensitive mutations and a C-terminal HA tag (FluB-att). We compared side by side the immunological responses in female and male DBA/2J mice vaccinated with either one of these vaccines and those with isogenic backgrounds encoding a chimeric HA segment carrying an N-terminal peptide encoding the IgA inducing peptide (IGIP). Recombinant viruses with or without the IGIP modification were genetically stable over multiple passages in eggs. In mice, introduction of IGIP improved attenuation of the vaccine candidates, particularly for the FluB-RAM/IGIP compared with the non-IGIP FluB-RAM counterpart. In a prime-boost regime, mice were completely protected against lethal challenge with a homologous FLUBV strain. Recombinant viruses induced antibodies against HA considered of protective value. Antibodies against NA and NP were readily detected. Compared to male mice and regardless of the vaccine used, female mice showed a clear trend towards enhanced humoral and cross-reactive IgG and IgA anti-HA responses as well as against NA and NP. The presence of IGIP in the vaccine resulted in an overall trend towards reduced anti-HA responses but enhanced anti-NA and anti-NP responses, particularly of the IgA isotype. Mucosal and serological responses two weeks after challenge showed similar trends with clear differences observed based on sex, vaccine backbone, and whether the vaccine carried the IGIP modification. These findings are significant for the development of universal influenza vaccines.

Project description:The amino acid sequences of immunodominant domains of hemagglutinin (HA) on the surface of influenza A virus (IAV) evolve rapidly, producing viral variants. HA mediates receptor recognition, binding and cell entry, and serves as the target for IAV vaccines. Glycosylation, a post-translational modification that places large, branched polysaccharide molecules on proteins, can modulate the function of HA, and can shield antigenic regions allowing for viral evasion from immune responses. Our previous work showed that subtle changes in the HA protein sequence can have a measurable change in glycosylation. Thus, being able to measure quantitatively how glycosylation changes in viral variants is critical for understanding how HA function may change throughout viral evolution. Moreover, understanding quantitatively how the choice of viral expression systems affects glycosylation can help in the process of vaccine design and manufacture. Although IAV vaccines are most commonly expressed in chicken eggs, cell-based vaccines have many advantages and the adoption of more cell-based vaccines would be an important step in mitigating seasonal influenza and protecting against future pandemics. Here, we have investigated the use of data-independent acquisition (DIA) mass spectrometry for quantitative glycoproteomics. We found that DIA improved the sensitivity of glycopeptide detection for four variants of A/Switzerland/9715293/2013 IAV: WT and mutant, each expressed in chicken eggs and MDCK cells. We used the Tanimoto similarity metric to quantify changes in glycosylation between WT and mutant, and between egg-expressed and cell-expressed virus. Our DIA site-specific glycosylation similarity comparison of WT and mutant expressed in eggs confirmed our previous analysis while achieving greater depth of coverage. We found that sequence changes resulting from different viral expression systems affected distinct glycosylation sites of HA. Our methods can be applied to track glycosylation changes in circulating IAV variants to bolster the genomic surveillance already being done, for a more complete understanding of IAV evolution.

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Vaccine Delivery Platforms Affect Heterologous Protection by Hemagglutinin-Based Influenza Vaccines in Pigs

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