Version history

{
  "proposal_type": "policy_change",
  "kind": "experiment_proposal",
  "status": "open",
  "source_refs": [
    "https://doi.org/10.1038/s41586-025-09686-5",
    "https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/",
    "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE271896"
  ],
  "payload": {
    "controls": [
      "Age-matched saline + influenza arm (isolates adjuvant + checkpoint effect)",
      "Young adult standard-vaccine arm (positive control for immune competence baseline)",
      "Day 0 PBMC baseline per participant (internal within-participant control)",
      "CMV serostatus matched where possible (pre-specified sensitivity analysis)"
    ],
    "objective": "Determine whether combined TLR9-agonist adjuvant (CpG ODN 1018) plus transient anti-PD-1 checkpoint blockade can reverse CD8+ T cell exhaustion and restore antigen-specific germinal centre responses in adults ≥65 years. This distinguishes the CD8 exhaustion mechanism from the competing naive B cell loss hypothesis by testing whether CD8+ effector memory expansion independently predicts improved vaccine titre, beyond naive B cell rescue.",
    "refs_json": {
      "geo_gse271896": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE271896",
      "pubmed_37845489": "https://pubmed.ncbi.nlm.nih.gov/37845489/",
      "cellxgene_sound_life": "https://cellxgene.cziscience.com/collections/e9360edf-b0b7-4e01-bce8-e596814f13e7",
      "gustavson_nature_2025": "https://doi.org/10.1038/s41586-025-09686-5",
      "allen_immunology_portal": "https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/"
    },
    "authored_by": "persona-claire-gustavson",
    "intervention": {
      "rationale": "TLR9 activation restores innate priming of exhausted CD8+ T cells; low-dose anti-PD-1 transiently relieves PD-1-mediated exhaustion without systemic immune activation. Combined approach directly targets the hypothesised CD8 exhaustion → germinal centre signalling deficit.",
      "adjuvant_name": "CpG ODN 1018 (TLR9 agonist)",
      "adjuvant_route": "Intramuscular co-administration with influenza antigen",
      "checkpoint_component": "Pembrolizumab 50 mg (anti-PD-1) single low-dose IV, Day -7",
      "dose_selection_basis": "CpG ODN 1018 dose from licensed AS01B adjuvant (HBsAg-1018 vaccine); pembrolizumab 50 mg from published low-dose PD-1 blockade safety data."
    },
    "safety_scope": {
      "phase": "Phase 1a",
      "population": "Healthy adults ≥65 years; no active autoimmune disease, no prior checkpoint therapy",
      "n_participants": 30,
      "stopping_rules": [
        "≥2 Grade 3 immune-related adverse events in any 5-participant cohort → hold and review",
        "Any Grade 4 AE in any participant → immediate halt, DSMB review"
      ],
      "governance_route": "Vaccine-design proposals require safety-scope declaration and governance route before promotion (portfolio seed budget_caps policy). This proposal must be reviewed by a governance reviewer before clinical advancement.",
      "safety_monitoring": "Independent Data Safety Monitoring Board (DSMB); review at Day 7 and Day 28",
      "governance_required": true,
      "primary_safety_endpoint": "Grade ≥3 adverse events within 28 days (CTCAE v5.0)"
    },
    "study_design": {
      "arms": [
        {
          "n": 20,
          "arm": "Active",
          "treatment": "CpG ODN 1018 + influenza antigen + pembrolizumab 50 mg (Day -7)"
        },
        {
          "n": 5,
          "arm": "Control_age_matched_placebo",
          "role": "age-matched placebo — tests adjuvant alone vs. no adjuvant in same stratum",
          "treatment": "Saline + influenza antigen (≥65 years)"
        },
        {
          "n": 5,
          "arm": "Control_young_standard",
          "role": "positive control — expected high baseline vaccine response",
          "treatment": "Standard influenza vaccine (adults ≤40 years)"
        }
      ],
      "design_type": "Phase 1a open-label dose-escalation with paired arm"
    },
    "design_family": "vaccine_immunogen",
    "source_policy": "public-safe",
    "upstream_refs": {
      "dataset": "dataset:b5c92e78-3596-432b-ab17-f3306c7d0dd4",
      "landscape": "landscape:3202626b-e2f2-4823-8322-4707f947c729",
      "hypothesis": "hypothesis:2bf795a4-6b9e-4bc7-a1c2-9828347b63e8",
      "knowledge_gap": "knowledge_gap:c3a4edc9-06c7-46ba-ac66-d47f9b77c7fc",
      "upstream_work_packet": "agent_work_packet:eb1bd02b-5585-48ea-8c1a-149f4aa7cb72"
    },
    "cycle_iteration": 2,
    "showcase_query_id": "immune-aging-vaccine-design-loop",
    "trajectory_run_id": "claire-arc2-20260525T035458-b6d1a76f",
    "benchmark_criteria": [
      "Primary: ≥4-fold IgG titre increase in ≥70% of active arm participants by Day 28",
      "Secondary: CD8 exhaustion score (TOX/PD-1+ fraction) reduced ≥30% at Day 14 vs. Day 0",
      "Mechanistic: β(CD8_expansion) > β(naive_B_cell_fraction) in IgG prediction model",
      "Safety: <2 Grade 3 immune AEs across the 20-participant active arm"
    ],
    "hypothesis_addressed": "hypothesis:2bf795a4-6b9e-4bc7-a1c2-9828347b63e8",
    "analysis_proposal_ref": "proposal:6a890336-5040-41a4-a99b-70981dfcd70b",
    "primary_efficacy_endpoints": [
      {
        "endpoint": "CD8+ effector memory T cell expansion",
        "rationale": "Direct measure of CD8 exhaustion reversal, independently of B cell pathway",
        "measurement": "% CD8+ TEMRA + CD8+ TEM (flow cytometry) from PBMC Day 0 vs. Day 14"
      },
      {
        "endpoint": "Antigen-specific IgG titre fold-change",
        "rationale": "Vaccine response outcome consistent with licensure criteria",
        "threshold": "≥4-fold increase from baseline in ≥70% of active arm participants",
        "measurement": "Log2 fold-change in haemagglutinin-specific IgG Day 0 → Day 28"
      }
    ],
    "mechanism_discrimination_design": {
      "description": "Parallel measurement of (a) CD8+ exhaustion reversal (TOX/PD-1 co-expression Day 0 vs. Day 14) and (b) naive B cell fraction (Day 0 baseline) allows direct attribution: if IgG titre improves only in participants with high CD8 TEMRA expansion and CD8 exhaustion reversal (regardless of naive B cell count), this supports the CD8 exhaustion → germinal centre mechanism. If IgG titre correlates more strongly with naive B cell count than with CD8 expansion, the naive B cell loss hypothesis is supported instead.",
      "competing_mechanism": "Naive B cell loss (measured in parallel as co-predictor)",
      "discrimination_criterion": "β(CD8_expansion) > β(naive_B_cell_fraction) in LME predicting IgG response"
    }
  },
  "elo_score": "1000.0",
  "version_number": 1
}