Granzyme B: A Double-Edged Sword in the Response to Influenza Infection in Vaccinated Older Adults
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Background: Influenza-specific cytolytic T lymphocytes (CTL) have a critical role in clearing the virus from the lungs, but are poorly stimulated by current inactivated influenza vaccines. Our previous work suggests that granzyme B (GrB) activity predicts protection against laboratory-confirmed influenza infection (LCII) in older adults. However, basal GrB (bGrB) activity increases with age and the frequency of GrB + CTL that do not co-express perforin increases following influenza infection, thereby acting as a potential contributor to immune pathology. Objectives: Using data from a 4-years randomized trial of standard-versus high-dose influenza vaccination, we sought to determine whether measurements of GrB activity alone indicate a protective vs pathologic response to influenza infection. We compared LCII to No-LCII subsets according to: pre-vaccination bGrB activity; and induced GrB activity in ex vivo influenza-challenged peripheral blood mononuclear cells (PBMC) at four and 20weeks post-vaccination. Results: Over four influenza seasons (2014–2018), 27 of 608 adult participants aged 65 years and older developed influenza A/H3N2-LCII (n = 18) or B-LCII (n = 9). Pre-vaccination, there was a significant correlation between bGrB and ex vivo GrB activity in each of the H3N2-LCII, B-LCII, and No-LCII subsets. Although pre-vaccination ex vivo GrB activity was significantly higher in B-LCII vs No-LCII with a trend for H3N2-LCII vs No-LCII, there was no difference in the response to vaccination. In contrast, there was a trend toward increased pre-vaccination bGrB activity and LCII: Odds Ratio (OR) (95% confidence intervals) OR = 1.46 (0.94, 2.33). By 20-weeks post-vaccination, there were significant fold-increases in ex vivo GrB activity specific for the infecting subtype in H3N2-LCII: OR = 1.63 (1.35, 2.00) and B-LCII: OR = 1.73 (1.34, 2.23). Conclusions: Our results suggest that the poor GrB responses to influenza vaccination that led to development of LCII can be attributed to inactivated formulations rather than the aging immune system since LCII cases generated robust ex vivo GrB responses following natural infection. Further, we identified bGrB as a biomarker of those who remain at risk for LCII following vaccination. Future studies will focus on understanding the mechanisms responsible for the shift in GrB-mediated protection vs potential immune pathology caused by GrB release.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 it