Influenza vaccine development: immunogenicity and correlates of protection
Bibliographic record
Abstract
Influenza viruses cause significant morbidity and mortality worldwide. Vaccines are the best tools available to reduce the disease burden; however, vaccine effectiveness varies significantly between years, target populations and strains. Medicago Inc. has developed a highly efficient platform to produce plant-derived virus-like particle (VLP) vaccines bearing influenza hemagglutinin (HA) that have been shown to elicit strong humoral and CD4+ T cell responses in both pre-clinical and clinical studies. To better understand the immunogenicity of these vaccines, we studied the early interactions of VLPs with antigen-presenting cells (APC) in vitro. We demonstrated that VLPs bind to human monocytoid U-937 cells and monocyte-derived macrophages (MDMs) in a sialic acid-dependent manner. VLP attachment to the cell surface led to internalization, trafficking to acidic cell compartments and fusion of the VLP lipid envelope with endosomal membranes. Incubation of MDMs with VLPs bearing H1 (HA sequence from A/California/07/2009 (H1N1) strain) but not H5 (HA sequence from A/Indonesia/05/2005 (H5N1) induced proliferation of autologous lymphoid cells suggesting antigen processing by MDMs and stimulation of a memory T cell response. Pulse-exposure of MDMs with H1-VLPs resulted in a rapid and massive intracellular accumulation of HA that was driven by clathrin-mediated and clathrin-independent endocytosis as well as macropinocytosis/phagocytosis. The H1-VLPs endosomal distribution pattern suggested that HA delivered by VLP had entered both high-degradative late (supporting major histocompatibility complex (MHC) II-restricted antigen presentation) and low-degradative static early and/or recycling (favoring MHC I-restricted antigen cross-presentation) endosomal pathways. High-resolution tandem mass spectrometry identified a large number of HA-derived peptides associated with MHC I in the H1-VLP-treated MDMs. In addition, many host-derived MHC I peptides were identified in VLP-treated samples. These peptides were mainly processed by matrix metalloproteinases and cathepsins. The host proteins associated with these peptides were primarily involved in pathways modulating inflammation (i.e. stimulation and attenuation), innate and adaptive immunity, clathrin-mediated endocytosis, protein synthesis and endo-lysosomal degradation. Finally, tools we used while studying endosome-lysosome fusion led to the development of a novel serological assay for influenza based on 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DiD) fluorescence dequenching. This assay measures 'functional' influenza antibody titers, is free from observer bias and has the potential to be fully automated. In summary, we demonstrated that HA delivery to APCs in a form of plant-derived VLPs facilitates antigen uptake, endosomal processing, presentation and cross-presentation. These observations may help to explain the broad and cross-reactive immune responses generated by VLP vaccines. The new DiD fluorescence dequenching assay we developed may give new insights into the spectrum of antibodies produced in response to influenza infection or vaccination.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".