{
 "generated": "2026-10-09",
 "method": "#14 GRADE-style certainty in each vaccine page's \"Evidence state\" table, from the curated\nratings in analysis/grade_curated.py (editorial judgments with stated reasons; a mechanical\nversion produced misleading results — subgroup-specific effects read as \"inconsistency\" — and\nwas discarded). Outcomes without a curated rating stay \"Not searched\". Idempotent.",
 "ratings": {
  "covid": [
   {
    "outcome": "Myocarditis or pericarditis",
    "question": "mRNA COVID-19 vaccines; highest risk in males 12–29 after dose 2",
    "finding": "increased risk",
    "certainty": "High",
    "rationale": "Start low (observational). +2 very large effect in young males (IRR/RR 5–19 for dose 2) replicated in Israel, the Nordic countries, the US VSD and England; +1 gradient (dose 2 > dose 1, mRNA-1273 > BNT162b2, young males > others). Smaller or null estimates in older groups reflect effect modification, not inconsistency.",
    "studies": [
     "Mevorach 2021",
     "Witberg 2021",
     "Karlstad 2022",
     "Husby 2021",
     "Goddard 2022",
     "Patone 2022"
    ]
   },
   {
    "outcome": "Guillain-Barré syndrome",
    "question": "Janssen Ad26.COV2.S vs mRNA vaccines",
    "finding": "increased risk with Janssen (adenovirus-vector) vaccine; no increase detected with mRNA vaccines",
    "certainty": "Moderate (Janssen) · Low (mRNA)",
    "rationale": "Janssen: start low; +2 very large effect (RR 20.6 vs mRNA); −1 single data source in this table. mRNA: start low; null with a wide interval (RR 0.56, 0.21–1.48), single source.",
    "studies": [
     "Hanson 2022"
    ]
   },
   {
    "outcome": "Anaphylaxis",
    "question": "mRNA COVID-19 vaccines",
    "finding": "increased risk (about 5 per million doses, chart-confirmed)",
    "certainty": "Moderate",
    "rationale": "Start low; +2 very large effect (background anaphylaxis in the minutes after an injection is near zero); −1 single data source.",
    "studies": [
     "Klein 2021"
    ]
   },
   {
    "outcome": "Thrombosis with thrombocytopenia",
    "question": "Janssen Ad26.COV2.S",
    "finding": "increased risk (about 4 confirmed cases per million doses)",
    "certainty": "Low",
    "rationale": "Case series with confirmed cases and a reporting-rate denominator (passive surveillance); very large relative to background but without a comparison group in this table.",
    "studies": [
     "See 2022"
    ]
   }
  ],
  "influenza": [
   {
    "outcome": "Guillain-Barré syndrome",
    "question": "2009 H1N1 monovalent vaccines vs seasonal vaccines",
    "finding": "increased risk with 2009 H1N1 vaccines (about 1–3 extra cases per million doses); no increase detected for seasonal vaccines",
    "certainty": "Moderate (H1N1) · Low (seasonal)",
    "rationale": "H1N1: start low; +1 effect RR > 2 in two independent analyses, consistent across four US systems. Seasonal: start low; nulls with wide intervals.",
    "studies": [
     "Salmon 2013",
     "Greene 2012",
     "Polakowski 2013",
     "Wise 2012",
     "Baxter 2013"
    ]
   },
   {
    "outcome": "Febrile seizure",
    "question": "Inactivated influenza vaccine given the same day as PCV13 or DTaP, children 6–59 months",
    "finding": "increased risk with same-day co-administration (about 1 extra seizure per 2,000–8,000 children); influenza vaccine alone: inconsistent",
    "certainty": "Moderate (co-administration) · Very low (alone)",
    "rationale": "Co-administration: start low; +1 RR > 2 in two independent VSD studies. A small randomized trial of simultaneous vs staggered vaccination found no difference in fever. Alone: studies disagree (IRR 2.4 vs 0.46).",
    "studies": [
     "Tse 2012",
     "Duffy 2016",
     "Walter 2020"
    ]
   },
   {
    "outcome": "Narcolepsy",
    "question": "Pandemrix (AS03-adjuvanted H1N1, used in Europe, never licensed in the US) vs US vaccines",
    "finding": "increased risk with Pandemrix in children and adolescents; no increase detected with US 2009–11 vaccines",
    "certainty": "High (Pandemrix) · Low (US vaccines)",
    "rationale": "Pandemrix: start low; +2 very large effect (RR 10–13) replicated in Finland, England and a meta-analysis. US vaccines: single observed-vs-expected analysis.",
    "studies": [
     "Nohynek 2012",
     "Miller 2013",
     "Sarkanen 2018",
     "Duffy 2014"
    ]
   },
   {
    "outcome": "Anaphylaxis",
    "question": "Trivalent inactivated influenza vaccine",
    "finding": "increased risk (about 1.4 per million doses)",
    "certainty": "Moderate",
    "rationale": "Start low; +2 very large effect relative to background; −1 single source.",
    "studies": [
     "McNeil 2016"
    ]
   },
   {
    "outcome": "Pregnancy outcomes",
    "question": "Inactivated influenza vaccine in pregnancy",
    "finding": "no increased risk of preterm birth or spontaneous abortion detected",
    "certainty": "Low",
    "rationale": "Large cohort with a precise null for preterm birth (OR 0.97, 0.93–1.02); one case-control study of consecutive pandemic-strain seasons was inconclusive.",
    "studies": [
     "Nordin 2014",
     "Donahue 2019",
     "Donahue 2017"
    ]
   }
  ],
  "mmr": [
   {
    "outcome": "Febrile seizure",
    "question": "First dose of MMR (and MMRV vs separate MMR + varicella) at 12–23 months",
    "finding": "increased risk 7–10 days after the first dose (about 1 extra per 3,000–4,000 doses; MMRV adds about 4 per 10,000 vs separate shots); no increase at the 4–6-year dose",
    "certainty": "High",
    "rationale": "Start low; +1 RR > 2 replicated in US and Danish cohorts; +1 age/dose gradient (first dose in toddlers, not the 4–6-year dose). IOM 2011: evidence convincingly supports.",
    "studies": [
     "Barlow 2001",
     "Vestergaard 2004",
     "Klein 2010",
     "Klein 2012",
     "IOM 2011"
    ]
   },
   {
    "outcome": "Immune thrombocytopenia",
    "question": "MMR at 12–15 months",
    "finding": "increased risk (about 1 case per 40,000 doses), usually mild and self-limited",
    "certainty": "Moderate",
    "rationale": "Start low; +2 very large effect (IRR ≈ 7); −1 imprecision (interval not reported in the abstract; one main estimate).",
    "studies": [
     "France 2008",
     "O'Leary 2012"
    ]
   },
   {
    "outcome": "Autism",
    "question": "MMR vaccine",
    "finding": "no increased risk",
    "certainty": "Moderate",
    "rationale": "Start low; +1 because plausible residual confounding (more health-care contact among vaccinated children) would tend to create a spurious association, and none was found in national cohorts of 537,000 and 657,000 children with tight intervals (HR 0.93, 0.85–1.02), a sibling-design study and a meta-analysis.",
    "studies": [
     "Hviid 2019",
     "Madsen 2002",
     "Jain 2015",
     "Taylor 2014",
     "IOM 2011"
    ]
   },
   {
    "outcome": "Type 1 diabetes",
    "question": "MMR vaccine",
    "finding": "no increased risk detected",
    "certainty": "Low",
    "rationale": "One case-control study with a wide interval; IOM 2011 favours rejection.",
    "studies": [
     "DeStefano 2001",
     "IOM 2011"
    ]
   }
  ],
  "rotavirus": [
   {
    "outcome": "Intussusception",
    "question": "RotaTeq (RV5) and Rotarix (RV1), week after dose 1",
    "finding": "increased risk (about 1–5 extra cases per 100,000 vaccinated infants, mostly in the week after the first dose)",
    "certainty": "High",
    "rationale": "Start low; +2 very large effect after dose 1 (relative incidence ≈ 5) replicated in the US, Mexico and Brazil. Randomized trials were too small for an event this rare (pooled RR 1.14, 0.49–2.64): imprecise, not contradictory.",
    "studies": [
     "Yih 2014",
     "Weintraub 2014",
     "Patel 2011",
     "Shui 2012",
     "Lu 2019"
    ]
   }
  ],
  "hpv": [
   {
    "outcome": "Syncope",
    "question": "Any injected vaccine; HPV vaccine in adolescents",
    "finding": "increased risk of fainting on the day of vaccination",
    "certainty": "High",
    "rationale": "Start low; +2 very large effect (OR 6.0) with an immediate, mechanistically clear time course; IOM 2011: convincingly supports for injection-related syncope.",
    "studies": [
     "Klein 2012",
     "IOM 2011"
    ]
   },
   {
    "outcome": "Guillain-Barré syndrome",
    "question": "HPV vaccines",
    "finding": "uncertain: one French cohort found an increase, US surveillance did not",
    "certainty": "Very low",
    "rationale": "Start low; −1 inconsistency (HR 3.78 in France vs 0.36 per million doses, no excess, in US VSD).",
    "studies": [
     "Miranda 2017",
     "Gee 2017"
    ]
   },
   {
    "outcome": "Venous thromboembolism",
    "question": "Gardasil (4vHPV)",
    "finding": "no increased risk detected",
    "certainty": "Low",
    "rationale": "Two cohorts with consistent nulls (upper limits 1.36–1.57).",
    "studies": [
     "Naleway 2016",
     "Arnheim-Dahlström 2013"
    ]
   },
   {
    "outcome": "Multiple sclerosis / demyelination",
    "question": "Gardasil (4vHPV)",
    "finding": "no increased risk",
    "certainty": "Moderate",
    "rationale": "Start low; +1 because more health-care contact among vaccinated women would tend to create a spurious association, and none was found in a 3.9-million-woman Nordic cohort with a precise estimate (IRR 0.90, 0.70–1.15), replicated in a US case-control study.",
    "studies": [
     "Scheller 2015",
     "Langer-Gould 2014"
    ]
   },
   {
    "outcome": "Autoimmune conditions",
    "question": "HPV vaccines",
    "finding": "no increased risk for autoimmune disease overall; a celiac-disease association was judged likely due to earlier diagnosis (unmasking)",
    "certainty": "Moderate",
    "rationale": "Start low; +1 plausible confounding toward a spurious association, none found across several national cohorts and case-control studies; the remaining celiac finding was inconclusive.",
    "studies": [
     "Arnheim-Dahlström 2013",
     "Grimaldi-Bensouda 2014",
     "Grimaldi-Bensouda 2017",
     "Miranda 2017",
     "Hviid 2018"
    ]
   }
  ],
  "hepatitis-b": [
   {
    "outcome": "Anaphylaxis",
    "question": "Hepatitis B and other childhood vaccines",
    "finding": "increased risk, very rare (about 1 per million doses)",
    "certainty": "Moderate",
    "rationale": "Start low; +2 very large effect relative to background; −1 rarity limits precision; IOM 2011 supports (yeast-sensitive individuals).",
    "studies": [
     "Bohlke 2003",
     "McNeil 2016",
     "IOM 2011"
    ]
   },
   {
    "outcome": "Multiple sclerosis / demyelination",
    "question": "Hepatitis B vaccine",
    "finding": "no increased risk detected (including relapse in people with MS)",
    "certainty": "Low",
    "rationale": "Three consistent nulls with moderately wide intervals.",
    "studies": [
     "Ascherio 2001",
     "Confavreux 2001",
     "Langer-Gould 2014"
    ]
   },
   {
    "outcome": "Type 1 diabetes",
    "question": "Hepatitis B vaccine",
    "finding": "no increased risk detected",
    "certainty": "Low",
    "rationale": "One case-control study, wide interval.",
    "studies": [
     "DeStefano 2001"
    ]
   }
  ],
  "dtap": [
   {
    "outcome": "Febrile seizure",
    "question": "DTaP (acellular) vs whole-cell DTP (no longer used in the US)",
    "finding": "no increase detected with DTaP; increased with whole-cell DTP",
    "certainty": "Low (DTaP) · Moderate (whole-cell DTP)",
    "rationale": "DTaP: one large risk-interval study. Whole-cell DTP: start low; +2 very large effect (RR 5.7) in a large VSD cohort.",
    "studies": [
     "Huang 2010",
     "Barlow 2001"
    ]
   },
   {
    "outcome": "Pregnancy outcomes",
    "question": "Tdap during pregnancy",
    "finding": "no increase in preterm birth, small-for-gestational-age, hypertensive disorders or neonatal sepsis; a small rise in coded chorioamnionitis in early studies was not confirmed later",
    "certainty": "Low",
    "rationale": "Large VSD cohorts with precise nulls for birth outcomes; chorioamnionitis inconsistent (RR 1.19–1.23 coded diagnosis vs HR 0.96 in a later cohort).",
    "studies": [
     "Kharbanda 2014",
     "DeSilva 2017",
     "Greenberg 2023"
    ]
   },
   {
    "outcome": "Guillain-Barré syndrome",
    "question": "Td",
    "finding": "no increased risk detected",
    "certainty": "Very low",
    "rationale": "Single case-centered study with a wide interval.",
    "studies": [
     "Baxter 2013"
    ]
   },
   {
    "outcome": "Type 1 diabetes",
    "question": "Pertussis-containing vaccines",
    "finding": "no increased risk detected",
    "certainty": "Low",
    "rationale": "Case-control study; IOM 2011 favours rejection.",
    "studies": [
     "DeStefano 2001",
     "IOM 2011"
    ]
   }
  ],
  "pcv": [
   {
    "outcome": "Febrile seizure",
    "question": "PCV13 (especially same day as influenza vaccine), children 6–59 months",
    "finding": "increased risk (about 1 extra per 7,000 doses)",
    "certainty": "Moderate",
    "rationale": "Start low; +1 RR ≈ 2–2.5 in two independent VSD studies.",
    "studies": [
     "Tse 2012",
     "Duffy 2016"
    ]
   },
   {
    "outcome": "Kawasaki disease",
    "question": "PCV13",
    "finding": "no increased risk detected",
    "certainty": "Low",
    "rationale": "One self-controlled study, interval to 1.21.",
    "studies": [
     "Kamidani 2022"
    ]
   },
   {
    "outcome": "Guillain-Barré syndrome",
    "question": "PPSV23 (adults)",
    "finding": "no increased risk detected",
    "certainty": "Very low",
    "rationale": "Single study, wide interval.",
    "studies": [
     "Baxter 2013"
    ]
   }
  ],
  "meningococcal": [
   {
    "outcome": "Guillain-Barré syndrome",
    "question": "Menactra (MenACWY-D), adolescents",
    "finding": "no increased risk detected (excess at most 1.5 per million doses)",
    "certainty": "Low",
    "rationale": "Large retrospective cohort; the 2005 signal from passive reports was not confirmed.",
    "studies": [
     "Velentgas 2012"
    ]
   },
   {
    "outcome": "Bell's palsy",
    "question": "Menveo (MenACWY-CRM)",
    "finding": "inconclusive (relative incidence 2.9 only with concomitant vaccines)",
    "certainty": "Very low",
    "rationale": "Single study; finding sensitive to co-administration.",
    "studies": [
     "Tseng 2017"
    ]
   }
  ],
  "shingles": [
   {
    "outcome": "Guillain-Barré syndrome",
    "question": "Shingrix (RZV), adults 65+",
    "finding": "increased risk (about 3 extra cases per million doses)",
    "certainty": "Low",
    "rationale": "Start low; +1 RR 2.3–2.8 in two designs; −1 both from one Medicare data source.",
    "studies": [
     "Goud 2021"
    ]
   }
  ],
  "rsv": [
   {
    "outcome": "Guillain-Barré syndrome",
    "question": "Abrysvo and Arexvy, adults 60+",
    "finding": "increased risk (about 5–18 extra cases per million doses)",
    "certainty": "Low",
    "rationale": "Two independent US analyses (FDA/CMS Medicare; EHR platform) agree on an excess; estimates imprecise.",
    "studies": [
     "FDA 2025",
     "Fry 2025"
    ]
   },
   {
    "outcome": "Pregnancy outcomes",
    "question": "Abrysvo (RSVpreF) in pregnancy",
    "finding": "no increase in preterm birth detected in the licensure trial or a US cohort; a different (unlicensed) GSK maternal candidate increased preterm birth in its trial",
    "certainty": "Moderate",
    "rationale": "Randomized evidence starts high; −1 imprecision (trial not powered for preterm birth; numerical imbalance). FDA licensed maternal use only at 32–36 weeks of gestation.",
    "studies": [
     "Kampmann 2023",
     "Son 2024",
     "Dieussaert 2024"
    ]
   },
   {
    "outcome": "Immune thrombocytopenia",
    "question": "Abrysvo and Arexvy",
    "finding": "no increased risk detected",
    "certainty": "Low",
    "rationale": "One large self-controlled analysis.",
    "studies": [
     "Fry 2025"
    ]
   }
  ],
  "varicella": [
   {
    "outcome": "Herpes zoster",
    "question": "Varicella vaccine in children",
    "finding": "lower risk of shingles in vaccinated children than after natural chickenpox",
    "certainty": "Moderate",
    "rationale": "Start low; +1 large protective effect: incidence 38 vs 170 per 100,000 person-years in vaccinated vs unvaccinated children (ratio 0.22) in the largest cohort, RR 0.61 in a second cohort, and a 69% population decline in an ecological study.",
    "studies": [
     "Weinmann 2019",
     "Baxter 2013",
     "Civen 2016"
    ]
   },
   {
    "outcome": "Immune thrombocytopenia",
    "question": "Varicella vaccine, adolescents",
    "finding": "inconclusive",
    "certainty": "Very low",
    "rationale": "Single study with too few events.",
    "studies": [
     "O'Leary 2012"
    ]
   }
  ],
  "hib": [
   {
    "outcome": "Type 1 diabetes",
    "question": "Hib conjugate vaccine",
    "finding": "no increased risk detected",
    "certainty": "Low",
    "rationale": "Finnish trial-cohort comparison and a US case-control study, consistent nulls.",
    "studies": [
     "Karvonen 1999",
     "DeStefano 2001"
    ]
   }
  ],
  "hepatitis-a": [
   {
    "outcome": "Immune thrombocytopenia",
    "question": "Hepatitis A vaccine, children 7–17",
    "finding": "inconclusive",
    "certainty": "Very low",
    "rationale": "Single study with too few events.",
    "studies": [
     "O'Leary 2012"
    ]
   }
  ],
  "polio": [
   {
    "outcome": "Neurological events (meningitis, encephalitis, seizure)",
    "question": "IPV-containing combinations (Kinrix, Pentacel)",
    "finding": "no increased risk detected",
    "certainty": "Low",
    "rationale": "Two sequential-surveillance studies vs historical comparators.",
    "studies": [
     "Daley 2014",
     "Nelson 2013"
    ]
   }
  ],
  "yellow-fever": [
   {
    "outcome": "Serious neurologic / viscerotropic disease",
    "question": "Yellow fever 17D vaccine",
    "finding": "increased risk, rare (about 0.8 and 0.3 per 100,000 doses)",
    "certainty": "Low",
    "rationale": "Passive reporting rates with confirmed case series; no comparison group in this table, but the events are not otherwise seen in healthy travellers.",
    "studies": [
     "Lindsey 2016"
    ]
   }
  ]
 }
}