{ "index": { "schema_version": "1.0.0", "last_compiled": "2026-09-21", "compiled_by": "Open Source Medicine Foundation (draft — corrections welcome)", "status": "draft-for-review", "title": "Post-Acute Vaccination Syndromes (PAVS) Dashboard", "vaccine_order": [ "covid19", "hpv", "anthrax", "hepatitis-b", "asia-aluminum" ], "global_disclaimers": [ "Database counts and case-series frequencies are unverified reports, not proven injury rates. Not medical advice.", "A temporal association between vaccination and symptom onset does not establish causation.", "Symptom percentages come from small, self-selected or clinic-referred case series with no control group; they cannot be compared to population incidence.", "Large registry and self-controlled case series (SCCS) studies are shown alongside case series so that both signals and non-signals are visible. Neither type alone settles the question.", "'PAVS' is a descriptive umbrella term used on this dashboard for chronic illnesses reported after vaccination; it is not a recognised diagnosis." ], "symptom_domains": [ { "id": "fatigue", "label": "Fatigue" }, { "id": "pem", "label": "Exercise intolerance / PEM" }, { "id": "autonomic", "label": "Autonomic / POTS" }, { "id": "pain", "label": "Pain" }, { "id": "cognitive", "label": "Cognitive" }, { "id": "gi", "label": "Gastrointestinal" }, { "id": "other", "label": "Other reported" } ], "evidence_types": [ { "id": "case_series", "label": "Case series / patient survey", "group": "reported", "note": "Clinic-referred or self-selected patients; no unexposed comparison." }, { "id": "spontaneous_reports", "label": "Spontaneous reports", "group": "reported", "note": "Passive surveillance (e.g., VAERS, national AE registers); unverified, subject to stimulated reporting." }, { "id": "registry_sccs", "label": "Registry / SCCS / cohort / case-control", "group": "population", "note": "Compares vaccinated with unvaccinated persons or risk vs. control windows." }, { "id": "mechanistic", "label": "Mechanistic / biomarker", "group": "mechanistic", "note": "Biomarker, in-silico or animal work; hypothesis-generating." }, { "id": "review", "label": "Narrative / systematic review", "group": "review", "note": "Secondary synthesis; check whether authors advocate a position." }, { "id": "regulator_review", "label": "Regulator / expert-committee review", "group": "regulator", "note": "EMA, WHO GACVS, IOM/NASEM and similar." } ], "directions": [ { "id": "reports_association", "label": "Reports association" }, { "id": "no_association", "label": "No association found" }, { "id": "mixed", "label": "Mixed / qualified" }, { "id": "descriptive", "label": "Descriptive (no causal test)" } ], "grade_levels": [ { "id": "very_low", "label": "Very low" }, { "id": "low", "label": "Low" }, { "id": "moderate", "label": "Moderate" }, { "id": "n/a", "label": "Not graded" } ], "definitions": [ { "term": "PAVS", "expansion": "Post-acute vaccination syndromes", "text": "Umbrella label used on this dashboard for chronic, multi-system illnesses that patients or clinicians report beginning after vaccination. It is not a diagnosis recognised by regulators.", "source_ids": [] }, { "term": "PACVS / PVS", "expansion": "Post-acute COVID-19 vaccination syndrome / post-vaccination syndrome", "text": "Terms used by researchers for chronic fatigue and dysautonomia-type symptoms reported after COVID-19 vaccination. Semmler et al. 2023 define PACVS operationally as three or more symptoms lasting at least five months after the last mRNA vaccination, not attributable to SARS-CoV-2 infection or confounding disease. Krumholz et al. 2023 use 'post-vaccination syndrome' for a self-reported online cohort.", "source_ids": [ "semmler-2023", "krumholz-2023" ] }, { "term": "GWI / CMI", "expansion": "Gulf War Illness / chronic multisymptom illness", "text": "A chronic multisymptom illness reported by veterans of the 1990–91 Gulf War. Its causes are debated; vaccines, including anthrax vaccine, are one of several proposed exposures.", "source_ids": [ "hotopf-2000", "james-2024" ] }, { "term": "ASIA", "expansion": "Autoimmune/inflammatory syndrome induced by adjuvants", "text": "A proposed umbrella syndrome (2011) grouping immune-mediated conditions attributed to adjuvants such as aluminium salts. Its diagnostic criteria have been criticised as too broad to exclude alternative explanations.", "source_ids": [ "cohen-tervaert-2023", "hawkes-2015" ] }, { "term": "MMF", "expansion": "Macrophagic myofasciitis", "text": "A histological finding of aluminium-containing macrophage infiltrates at a prior injection site, proposed by some authors as a marker of adjuvant persistence.", "source_ids": [ "gherardi-2019" ] } ], "methodology": { "summary": "Each entry is scored on study design, sample size, comparison group and whether the authors themselves claim causation. Grades are GRADE-style editorial ratings for orientation only, not formal GRADE assessments.", "steps": [ "Studies are found via PubMed and regulator/committee websites and are added only if their key figures can be traced to an abstract, table or official page.", "Every statistic in the data files sits inside a study record with a PMID, DOI or official URL. The build fails if a record is missing a citation.", "Reported symptom frequencies (case series) are kept separate from population rate ratios (registry / SCCS). They answer different questions and are never pooled.", "Unreported values are left blank, never filled with zero.", "Regulator positions are quoted from the regulator's own page and dated. If none was located, the record says so." ], "grade_rubric": [ { "design": "Case series, patient survey, spontaneous reports", "default_grade": "very_low", "why": "No comparison group; selection and recall bias; cannot estimate risk." }, { "design": "Registry / SCCS / cohort / case-control", "default_grade": "low", "why": "Comparison group present, but outcome coding, healthy-vaccinee effects, diagnostic delay and confounding remain." }, { "design": "Mechanistic / biomarker / in-silico", "default_grade": "very_low", "why": "Hypothesis-generating; does not test whether the vaccine causes illness." }, { "design": "Narrative review", "default_grade": "n/a", "why": "Depends on the sources reviewed and the authors' stated position." }, { "design": "Regulator / expert-committee review", "default_grade": "n/a", "why": "Not a study; reflects the committee's reading of evidence available at the time." } ] }, "hub": { "nav_label": "Post-acute syndromes", "url": "https://vaccinedatanavigator.org/pavs.html", "definition": "Post-acute vaccination syndromes (PAVS) is an umbrella label used on this site for persistent, multi-system illness that patients or clinicians report beginning after vaccination and lasting weeks, months or longer. It is a research category, not a diagnosis, and the clusters below are not assumed to be the same disease. Evidence comes mainly from case series and patient surveys; for some clusters, large registry studies have not found increased rates of coded diagnoses. This hub maps the clusters and points to the evidence. It does not decide whether any vaccine caused any person's illness.", "reading_guide": [ "Case series and patient surveys describe who is ill and how, but cannot show how often it happens or whether the vaccine caused it.", "Registry and self-controlled case series studies compare vaccinated with unvaccinated people or risk windows, but rely on coded diagnoses that may not capture the reported syndrome.", "Regulator and committee reviews reflect the evidence available on their date; several predate the newest patient series and biomarker papers.", "The detailed dashboard separates these evidence types for every cluster and grades each study on a GRADE-style scale." ], "clusters": [ { "syndrome_id": "covid19", "name": "COVID-19 / PACVS", "status": "Active research program", "blurb": "Chronic fatigue, exercise intolerance, brain fog and dysautonomia-type symptoms reported after COVID-19 vaccination. Evidence so far: a self-selected online cohort (n=241), a German biomarker study (191 affected, 89 controls) and registry analyses of POTS diagnoses. We did not locate a regulator assessment of PACVS as a defined syndrome.", "links": [ { "label": "COVID-19 vaccine summary", "href": "/covid-vaccine.html" }, { "label": "Detailed evidence", "href": "/pavs-dashboard.html#covid19" }, { "label": "Long COVID treatment", "href": "/long-covid-treatment.html" }, { "label": "OSMF Research Tracker", "href": "https://research.opensourcemed.info", "external": true }, { "label": "OSMF Evidence Desk", "href": "https://desk.opensourcemed.info/", "external": true }, { "label": "PACVS Research Summit", "href": "https://pacvsresearchsummit.com", "external": true } ], "osmf_depth": "Tracker, Desk and Summit programs", "dossier_coverage": "COVID-19 dossiers exist; none is specific to PACVS" }, { "syndrome_id": "hepatitis-b", "name": "Hepatitis B–associated", "status": "Case series; contested framework", "blurb": "Two US records-based series (19 and 93 patients) describe fatigue, musculoskeletal, neuro-psychiatric and autoimmune manifestations a mean of about six weeks after the last dose, interpreted by the authors within the ASIA framework. The 93-patient series consisted of people who sought legal consultation. Registry data address multiple sclerosis, not this phenotype.", "links": [ { "label": "Hepatitis B vaccine summary", "href": "/hepatitis-b-vaccine.html" }, { "label": "Detailed evidence", "href": "/pavs-dashboard.html#hepatitis-b" }, { "label": "Dossier: hepatitis B autoimmune disorder", "href": "/evidence-dossiers/cand-hepatitis-b-autoimmune-disorder.html" } ], "osmf_depth": "Via this hub only", "dossier_coverage": "One related dossier (autoimmune disorder)" }, { "syndrome_id": "hpv", "name": "HPV-associated", "status": "Contested", "blurb": "Clinic series in Japan (87 patients) and Denmark (35 and 53) describe fatigue, headache, pain, orthostatic intolerance and cognitive symptoms in adolescent girls and young women; median onset was 199 days in the Japanese series. Danish (1.38 million females) and Norwegian (176,453 girls) registry studies found no increased rate of CFS, CRPS or POTS, and EMA and WHO GACVS found no causal link. The disagreement is unresolved.", "links": [ { "label": "HPV vaccine summary", "href": "/hpv-vaccine.html" }, { "label": "Detailed evidence", "href": "/pavs-dashboard.html#hpv" }, { "label": "Evidence dossiers index", "href": "/evidence-dossiers/index.html" } ], "osmf_depth": "Via this hub only", "dossier_coverage": "No dossier specific to this cluster" }, { "syndrome_id": "anthrax", "name": "Anthrax vaccine–associated (Gulf War Illness–adjacent)", "status": "Nascent — no VDN vaccine page yet", "blurb": "Small US veteran samples report more Gulf War Illness among anthrax-vaccinated veterans (47.1% vs 17.2%, n=111) and propose an HLA-based mechanism. A US Army cohort of 716,833 soldiers found no increase in disability evaluation, and an IOM 2002 review found no convincing evidence of raised later-onset risk. Gulf War Illness has several proposed exposures; it is related to, not the same as, this cluster. A full VDN anthrax page is not yet built.", "links": [ { "label": "Detailed evidence", "href": "/pavs-dashboard.html#anthrax" }, { "label": "OSMF Research Tracker", "href": "https://research.opensourcemed.info", "external": true } ], "osmf_depth": "Related Gulf War Illness biomarker work in OSMF Tracker", "dossier_coverage": "None" } ], "cross_cutting": { "syndrome_id": "asia-aluminum", "blurb": "The ASIA and aluminium-adjuvant hypothesis cuts across the HPV, hepatitis B and other clusters. The dashboard includes both proponent reviews and a critical systematic review, and a 2025 Danish cohort of 1.22 million children." }, "cite_text": "Open Source Medicine Foundation. Post-Acute Vaccination Syndromes (PAVS) Hub. Vaccine Data Navigator. https://vaccinedatanavigator.org/pavs.html. Last compiled 2026-09-21.", "license_note": "Content available under CC BY 4.0 unless otherwise noted (matches the site footer)." }, "cross_vaccine_research_gaps": [ "A single biomarker panel (functional GPCR autoantibodies, IL-6, HLA typing) run on the same assay across HPV-symptomatic, PACVS, long-COVID, ME/CFS and healthy-vaccinated cohorts.", "Case-control studies with matched vaccinated-but-well controls, pre-specified symptom definitions and blinded biomarker assays.", "Case definitions: the Japanese HPV criteria, the PACVS criteria and the ASIA criteria were each proposed by the groups studying them; none has been independently validated.", "Registry studies use ICD-coded CFS, CRPS or POTS. Patients in case series often carry different or no such diagnoses, so coded outcomes may miss the reported syndrome and vice versa.", "Post-exertional malaise (PEM) is rarely reported in a standardised way; only one compiled study reports an exercise-intolerance item.", "Prospective follow-up of symptomatic patients to describe natural history and recovery." ] }, "syndromes": [ { "id": "covid19", "vaccine": "COVID-19 (mRNA)", "site_pages": [ { "label": "COVID-19 vaccine summary", "href": "/covid-vaccine.html" }, { "label": "Long COVID treatment", "href": "/long-covid-treatment.html" } ], "syndrome_name": "Post-acute COVID-19 vaccination syndrome (PACVS) / post-vaccination syndrome (PVS)", "aliases": [ "PACVS", "PVS", "long-vax syndrome (used in some reviews)" ], "key_symptom_clusters": [ "Exercise intolerance", "Excessive fatigue", "Numbness / neuropathy", "Brain fog / cognitive", "Dysautonomia / POTS-type" ], "onset_window": { "text": "Median 3 days (IQR 1–8) from index vaccination to symptom onset in the Yale LISTEN self-reported cohort (n=241). Onset is self-reported and the cohort is self-selected; other cohorts are not compiled.", "source_ids": [ "krumholz-2023" ] }, "case_series_summary": "Self-selected online cohort (Yale LISTEN, n=241, 80% female) reports high symptom burden, led by exercise intolerance, fatigue, numbness, brain fog and neuropathy. A German cohort (191 affected vs 89 vaccinated controls) reports altered receptor-autoantibody and IL-6 markers.", "registry_summary": "A sequence-symmetry analysis (284,592 vaccinated persons) found higher odds of a POTS diagnosis in the 90 days after vaccination than the 90 days before, but about five times higher odds after SARS-CoV-2 infection. A meta-analysis pooled a POTS rate of 3.94 per 10,000 vaccinated (CI 0–16.39; 2 studies) versus 107.75 per 10,000 after infection (5 studies). No large SCCS or registry study of a PACVS-defined syndrome was compiled.", "regulator_position": "No regulator or expert-committee assessment of PACVS as a defined syndrome was located during this compile. A Sept 2026 web search for an EMA PRAC assessment of POTS after mRNA vaccines returned only myocarditis/pericarditis assessments. This describes our search, not a regulator conclusion; verify before citing.", "regulator_position_ids": [], "regulator_position_status": "not_located", "proposed_mechanisms": [ { "text": "Altered functional receptor autoantibody pattern with elevated IL-6 (hypothesis; observational association in one German cohort).", "evidence_level": "hypothesis", "source_ids": [ "semmler-2023" ] } ], "alternative_explanations": [ { "text": "Symptoms overlap with post-infection long COVID and ME/CFS; unrecognised prior infection is a possible confounder unless excluded by testing.", "source_ids": [ "semmler-2023", "yong-2023" ] }, { "text": "Self-selected online recruitment can over-represent severely affected people and cannot estimate incidence.", "source_ids": [ "krumholz-2023" ] } ], "biomarkers": [ { "marker": "Angiotensin II type 1 receptor (AT1R) autoantibody", "finding": "Altered in PACVS vs. healthy vaccinated controls; ROC-AUC 0.824 ± 0.027.", "source_ids": [ "semmler-2023" ] }, { "marker": "Alpha-2B adrenergic receptor autoantibody", "finding": "Altered in PACVS vs. controls; ROC-AUC 0.828 ± 0.025.", "source_ids": [ "semmler-2023" ] }, { "marker": "Interleukin-6 (IL-6)", "finding": "Increased in PACVS; ROC-AUC 0.850 ± 0.022. Combined markers reported sensitivity 90% for discriminating PACVS from normal post-vaccination state.", "source_ids": [ "semmler-2023" ] } ], "key_studies": [ { "id": "krumholz-2023", "citation": "Krumholz et al. 2023 — Yale LISTEN online cohort, 241 people", "authors": "Krumholz HM, Wu Y, Sawano M, Shah R et al.", "year": 2023, "title": "Post-Vaccination Syndrome: A Descriptive Analysis of Reported Symptoms and Patient Experiences After Covid-19 Immunization.", "journal": "medRxiv (preprint)", "pmid": "37986769", "pmc": "PMC10659483", "doi": "10.1101/2023.11.09.23298266", "type": "case_series", "design": "Descriptive analysis of self-reported online cohort (preprint)", "n": 241, "population": "Adults who self-reported PVS after COVID-19 vaccination and joined Yale LISTEN, May 2022–July 2023. Median age 46; 80% female; 55% BNT162b2, 37% mRNA-1273. Median 595 days (IQR 417–661) from vaccination to survey.", "key_finding": "Top symptoms: exercise intolerance 71%, excessive fatigue 69%, numbness 63%, brain fog 63%, neuropathy 63%. Median EQ-VAS 50. Participants reported a median of 20 interventions tried. Median onset 3 days (IQR 1–8).", "direction": "descriptive", "grade": "very_low", "quality_note": "Self-selected, self-reported, no comparison group, no verification of vaccination-symptom sequence or exclusion of infection in the abstract; preprint status at time of compilation. Cannot estimate incidence.", "symptoms": [ { "label": "Exercise intolerance", "domain": "pem", "pct": 71, "proxy": true }, { "label": "Excessive fatigue", "domain": "fatigue", "pct": 69 }, { "label": "Numbness", "domain": "other", "pct": 63 }, { "label": "Brain fog", "domain": "cognitive", "pct": 63 }, { "label": "Neuropathy", "domain": "other", "pct": 63 } ], "symptom_source": "Abstract (five most common symptoms only)", "onset": { "statistic": "median", "days": 3, "iqr_low": 1, "iqr_high": 8, "anchor": "index vaccination" } }, { "id": "semmler-2023", "citation": "Semmler et al. 2023 — PACVS vs. healthy vaccinated controls (autoantibodies, IL-6)", "authors": "Semmler A, Mundorf AK, Kuechler AS, Schulze-Bosse K et al.", "year": 2023, "title": "Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers.", "journal": "Vaccines (Basel) 11(11)", "pmid": "38005974", "pmc": "PMC10674626", "doi": "10.3390/vaccines11111642", "type": "mechanistic", "design": "Case-control biomarker study", "n": 280, "population": "191 PACVS-affected persons (159 female; ≥3 symptoms for ≥5 months after last mRNA vaccination, not due to infection or confounding disease) vs. 89 healthy vaccinated controls (71 female) sampled before and 6 months after first vaccination.", "key_finding": "Normal vaccination response included decreases in 11 receptor antibodies and increases in two. PACVS differed on AT1R and alpha-2B adrenergic receptor antibodies and IL-6 (see biomarker table). Authors conclude PACVS is a somatic syndrome detectable by blood markers.", "direction": "reports_association", "grade": "very_low", "quality_note": "Case-control design; how cases were recruited is not described in the abstract and cases and controls may differ in recruitment; the markers are not validated in independent cohorts; association does not show that vaccination caused the pattern.", "symptoms": [] }, { "id": "kwan-2022", "citation": "Kwan et al. 2022 — POTS diagnoses after vaccination vs infection (sequence-symmetry)", "authors": "Kwan AC, Ebinger JE, Wei J, Le CN et al.", "year": 2022, "title": "Apparent Risks of Postural Orthostatic Tachycardia Syndrome Diagnoses After COVID-19 Vaccination and SARS-Cov-2 Infection.", "journal": "Nat Cardiovasc Res 1", "pmid": "37303827", "pmc": "PMC10254901", "doi": "10.1038/s44161-022-00177-8", "type": "registry_sccs", "design": "Sequence-symmetry analysis, health-system records", "n": 284592, "population": "284,592 COVID-19-vaccinated individuals.", "key_finding": "Odds of a POTS diagnosis were higher in the 90 days after vaccination than the 90 days before, higher than for referent primary-care diagnoses, but lower than after SARS-CoV-2 infection (post-infection odds about five times higher). Authors suggest further study.", "direction": "mixed", "grade": "low", "quality_note": "Diagnosis-based; sequence-symmetry designs can be affected by increased healthcare contact around vaccination and by diagnostic delay. Authors note probable low incidence.", "symptoms": [] }, { "id": "yong-2023", "citation": "Yong et al. 2023 — meta-analysis of POTS after infection vs vaccination", "authors": "Yong SJ, Halim A, Liu S, Halim M et al.", "year": 2023, "title": "Pooled rates and demographics of POTS following SARS-CoV-2 infection versus COVID-19 vaccination: Systematic review and meta-analysis.", "journal": "Auton Neurosci 250", "pmid": "38000119", "doi": "10.1016/j.autneu.2023.103132", "type": "review", "design": "Systematic review and meta-analysis", "n": null, "population": "5 studies of infected and 2 studies of vaccinated individuals (pooled rates); case reports and series for demographics.", "key_finding": "Pooled POTS rate 107.75 per 10,000 (95% CI 9.73–273.52) after infection vs. 3.94 per 10,000 (95% CI 0–16.39) after vaccination. POTS RR 2.12 (1.71–2.62) infected vs. uninfected. Time from exposure to onset was shorter in post-vaccination POTS cases. Evidence for post-vaccination POTS described as limited.", "direction": "mixed", "grade": "n/a", "quality_note": "Vaccination pool rests on only two studies with a very wide interval; heterogeneity high.", "symptoms": [] } ], "disclaimers": [ "PACVS has no regulator-endorsed case definition. The Semmler criteria and the Yale self-report criteria differ.", "Comparison of POTS after vaccination and after infection does not tell any individual whether their illness is vaccine-related." ], "research_gaps": [ "Independent replication of the Semmler receptor-autoantibody and IL-6 pattern, with a pre-registered analysis and blinded assays.", "Head-to-head biomarker comparison of PACVS, post-infection long COVID and ME/CFS on a common platform.", "Population-scale SCCS or registry analysis of a PACVS-like phenotype (fatigue, exercise intolerance, dysautonomia) rather than POTS diagnoses alone.", "Standardised PEM assessment (e.g., validated PEM questionnaire or two-day exercise testing) in vaccinated-symptomatic cohorts.", "Serologic exclusion of prior infection (nucleocapsid antibody) in every PACVS cohort." ] }, { "id": "hpv", "vaccine": "HPV", "site_pages": [ { "label": "HPV vaccine summary", "href": "/hpv-vaccine.html" }, { "label": "Package-insert ingredients", "href": "/hpv-vaccine.html#ingredients" } ], "syndrome_name": "Post-HPV vaccination disorder (Japan) / suspected autonomic dysfunction after HPV vaccination", "aliases": [ "HPV vaccine-related symptoms (Japan)", "HANS (name used in some case-series literature; source not compiled here)", "post-HPV-vaccination POTS / CRPS / ME-CFS presentations" ], "key_symptom_clusters": [ "Fatigue", "Headache", "Widespread pain / CRPS-like", "Orthostatic intolerance / dysautonomia", "Cognitive dysfunction", "Sleep and menstrual disturbance" ], "onset_window": { "text": "Median 199 days (range 0–1,532) from first dose in the 87-patient Japanese series; mean 319.7 days (range 1–1,532) in the earlier 72-patient series.", "source_ids": [ "hineno-2021", "ozawa-2017" ] }, "case_series_summary": "Clinic-based series from Japan and Denmark describe a similar cluster of fatigue, headache, pain, orthostatic intolerance and cognitive symptoms in adolescent girls and young women. Authors of the Japanese series state that a causal link has not been demonstrated and note that symptom onset overlapped with a defined vaccination period and media activity.", "registry_summary": "Danish (SCCS, 1.38 million females) and Norwegian (176,453 girls) registry studies found no increased rate of CFS, CRPS or POTS after HPV vaccination. Authors of the Danish SCCS note that an increase of up to 32% cannot be formally excluded.", "regulator_position": "EMA PRAC (Nov 2015): evidence does not support a causal link between HPV vaccines and CRPS or POTS. WHO GACVS (2015, 2017): no evidence of a causal association with CRPS, POTS or diverse symptoms including pain and motor dysfunction.", "regulator_position_ids": [ "ema-2015", "gacvs-2015", "gacvs-2017" ], "proposed_mechanisms": [ { "text": "Functional autoantibodies against neuroendocrine / autonomic GPCRs (hypothesis; reported in a Danish patient cohort, not established as causal).", "evidence_level": "hypothesis", "source_ids": [ "mehlsen-2022", "blitshteyn-2018" ] }, { "text": "Aluminium-adjuvant persistence within ASIA framework (hypothesis; see ASIA / aluminium entry for critique).", "evidence_level": "hypothesis", "source_ids": [ "cohen-tervaert-2023", "hawkes-2015" ] } ], "alternative_explanations": [ { "text": "Coincidental temporal association: syndromes of this type occur in the unvaccinated adolescent population.", "source_ids": [ "hviid-2020", "ema-2015" ] }, { "text": "Stimulated reporting: a Danish cluster analysis attributed one cluster of serious-AE reports, with a spike in December 2015, to likely media stimulation.", "source_ids": [ "ward-2019" ] } ], "biomarkers": [ { "marker": "Autoantibodies to neuroendocrine receptors (GPCR family)", "finding": "Authors report significant changes in these autoantibodies in patients with long-term complications after HPV vaccination versus comparison. Abstract text was not retrievable during this compile, so group sizes and effect sizes are not recorded here.", "source_ids": [ "mehlsen-2022" ], "verify": true } ], "key_studies": [ { "id": "hineno-2021", "citation": "Hineno & Ikeda 2021 — Japanese clinic series, 87 patients", "authors": "Hineno A, Ikeda SI", "year": 2021, "title": "A Long-Term Observation on the Possible Adverse Effects in Japanese Adolescent Girls after Human Papillomavirus Vaccination.", "journal": "Vaccines (Basel) 9", "pmid": "34451981", "pmc": "PMC8402449", "doi": "10.3390/vaccines9080856", "type": "case_series", "design": "Single-centre retrospective clinical series", "n": 87, "population": "Female patients examined June 2013–March 2021: 200 examined, 148 analysed, 87 diagnosed with HPV-vaccination-related symptoms by the authors' own criteria (32 'definite', 55 'probable'). Age at first dose 11–19 (mean 13.5).", "key_finding": "Symptom cluster of orthostatic intolerance, chronic regional pain and cognitive dysfunction; median 199 days from first dose to onset. The authors write that a causal link has not been demonstrated.", "direction": "descriptive", "grade": "very_low", "quality_note": "No comparison group; 87 of 200 examined patients selected using criteria proposed by the authors (32 definite, 55 probable); single referral centre; percentages describe the selected group only.", "symptoms": [ { "label": "General fatigue", "domain": "fatigue", "pct": 83.9, "n": 73 }, { "label": "Severe headache", "domain": "other", "pct": 82.8, "n": 72 }, { "label": "Widespread pain", "domain": "pain", "pct": 81.6, "n": 71 }, { "label": "Dysautonomic symptoms", "domain": "autonomic", "pct": 81.6, "n": 71 }, { "label": "Motor dysfunction", "domain": "other", "pct": 64.4, "n": 56 }, { "label": "Abnormal sensation", "domain": "other", "pct": 59.8, "n": 52 }, { "label": "Learning impairment", "domain": "cognitive", "pct": 59.8, "n": 52, "proxy": true }, { "label": "Sleep disturbance", "domain": "other", "pct": 50.6, "n": 44 }, { "label": "Menstrual abnormality", "domain": "other", "pct": 50.6, "n": 44 }, { "label": "Limb shaking", "domain": "other", "pct": 47.1, "n": 41 } ], "symptom_source": "Table: 'Frequency of symptoms and signs in the 87 patients studied' (PMC8402449)", "onset": { "statistic": "median", "days": 199, "min": 0, "max": 1532, "anchor": "first dose" } }, { "id": "ozawa-2017", "citation": "Ozawa et al. 2017 — Japanese clinic series, 72 patients", "authors": "Ozawa K, Hineno A, Kinoshita T, Ishihara S", "year": 2017, "title": "Suspected Adverse Effects After Human Papillomavirus Vaccination: A Temporal Relationship Between Vaccine Administration and the Appearance of Symptoms in Japan.", "journal": "Drug Saf 40", "pmid": "28744844", "pmc": "PMC5688202", "doi": "10.1007/s40264-017-0574-6", "type": "case_series", "design": "Single-centre clinical series", "n": 72, "population": "163 patients examined June 2013–Dec 2016; 120 after exclusions; 30 'definite' + 42 'probable' by study-specific criteria.", "key_finding": "Mean 319.7 ± 349.3 days (range 1–1,532) from first dose to onset. Period of vaccination overlapped with the period of symptom development. The authors state a causal link has not been established and that their diagnostic criteria are not validated.", "direction": "descriptive", "grade": "very_low", "quality_note": "Criteria created for the study and not validated (authors' own statement); no comparison group; likely overlaps with the 2021 series (same authors, same Japanese centre and period), though the abstracts do not state this.", "symptoms": [], "onset": { "statistic": "mean", "days": 319.7, "sd": 349.3, "min": 1, "max": 1532, "anchor": "first dose" } }, { "id": "brinth-2015-vaccine", "citation": "Brinth et al. 2015 — Danish syncope-unit series, 35 women", "authors": "Brinth LS, Pors K, Theibel AC, Mehlsen J", "year": 2015, "title": "Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus.", "journal": "Vaccine 33", "pmid": "25882168", "doi": "10.1016/j.vaccine.2015.03.098", "type": "case_series", "design": "Referral-based clinical series", "n": 35, "population": "Women aged 23.3 ± 7.1 years referred for orthostatic intolerance after quadrivalent HPV vaccination.", "key_finding": "POTS diagnosed in 21 of 35 (60%; 95% CI 43–77%). The authors call for work to elucidate a potential causal link.", "direction": "descriptive", "grade": "very_low", "quality_note": "Referred for orthostatic intolerance, so 100% orthostatic intolerance is by selection. No unvaccinated comparison.", "symptoms": [ { "label": "Orthostatic intolerance", "domain": "autonomic", "pct": 100 }, { "label": "Nausea", "domain": "gi", "pct": 94 }, { "label": "Chronic headache", "domain": "other", "pct": 82 }, { "label": "Fatigue", "domain": "fatigue", "pct": 82 }, { "label": "Cognitive dysfunction", "domain": "cognitive", "pct": 77 }, { "label": "Segmental dystonia", "domain": "other", "pct": 72 }, { "label": "Neuropathic pain", "domain": "pain", "pct": 68 } ], "symptom_source": "Abstract" }, { "id": "brinth-2015-dmj", "citation": "Brinth et al. 2015 — Danish series, 53 patients", "authors": "Brinth L, Theibel AC, Pors K, Mehlsen J", "year": 2015, "title": "Suspected side effects to the quadrivalent human papilloma vaccine.", "journal": "Dan Med J 62", "pmid": "25872549", "type": "case_series", "design": "Referral-based clinical series", "n": 53, "population": "Patients referred to a Syncope Unit for tilt-table testing after quadrivalent HPV vaccination.", "key_finding": "All 53 had symptoms consistent with pronounced autonomic dysfunction. The authors state their findings neither confirm nor dismiss a causal link.", "direction": "descriptive", "grade": "very_low", "quality_note": "Percent frequencies not available in the abstract; patient overlap with the 35-woman series is possible and not stated in the abstract.", "symptoms": [] }, { "id": "mehlsen-2022", "citation": "Mehlsen et al. 2022 — autoantibody study, Danish patients", "authors": "Mehlsen J, Brinth L, Pors K, Varming K", "year": 2022, "title": "Autoimmunity in patients reporting long-term complications after exposure to human papilloma virus vaccination.", "journal": "J Autoimmun 133", "pmid": "36356549", "doi": "10.1016/j.jaut.2022.102921", "type": "mechanistic", "design": "Patient vs. comparison autoantibody assay", "n": null, "population": "Danish patients reporting long-term complications after HPV vaccination.", "key_finding": "Authors report changed autoantibodies directed against neuroendocrine receptors. Full abstract could not be retrieved in this compile; verify numbers against the paper before citing effect sizes.", "direction": "reports_association", "grade": "very_low", "quality_note": "Biomarker association in a selected patient group; cannot show that vaccination caused the change. Compare against long-COVID and ME/CFS cohorts (see research gaps).", "symptoms": [], "verify": true }, { "id": "blitshteyn-2018", "citation": "Blitshteyn et al. 2018 — review of HPV case series", "authors": "Blitshteyn S, Brinth L, Hendrickson JE, Martinez-Lavin M", "year": 2018, "title": "Autonomic dysfunction and HPV immunization: an overview.", "journal": "Immunol Res 66", "pmid": "30478703", "doi": "10.1007/s12026-018-9036-1", "type": "review", "design": "Narrative review of case series", "n": null, "population": "Case series from several countries.", "key_finding": "Symptom clusters across case series are described as similar. Authors propose vaccine-triggered, immune-mediated autonomic dysfunction in genetically susceptible individuals and state that temporal relationship does not equate to causality.", "direction": "mixed", "grade": "n/a", "quality_note": "Authors include clinicians who authored some reviewed series; hypothesis paper calling for case-control studies.", "symptoms": [] }, { "id": "ward-2019", "citation": "Ward et al. 2019 — cluster analysis of Danish serious AE reports", "authors": "Ward D, Thorsen NM, Frisch M, Valentiner-Branth P", "year": 2019, "title": "A cluster analysis of serious adverse event reports after human papillomavirus (HPV) vaccination in Danish girls and young women, September 2009 to August 2017.", "journal": "Euro Surveill 24(19):1800380", "pmid": "31088598", "pmc": "PMC6518966", "doi": "10.2807/1560-7917.ES.2019.24.19.1800380", "type": "spontaneous_reports", "design": "Latent class cluster analysis of spontaneous reports", "n": 963, "population": "All serious AE reports from females in Denmark, Sep 2009–Aug 2017.", "key_finding": "Four clusters; fatigue, dizziness and headache most common. One cluster, largely submitted during a period of heightened media activity including a spike in December 2015, was characterised as likely media stimulated and focused on CFS/POTS-type symptoms.", "direction": "descriptive", "grade": "very_low", "quality_note": "Report counts cannot give incidence; reporting is affected by publicity. The authors are from the Danish national health authority.", "symptoms": [] }, { "id": "pellegrino-2015", "citation": "Pellegrino et al. 2015 — VAERS analysis of suspected ASIA after HPV vaccine", "authors": "Pellegrino P, Perrone V, Pozzi M, Carnovale C", "year": 2015, "title": "The epidemiological profile of ASIA syndrome after HPV vaccination: an evaluation based on the Vaccine Adverse Event Reporting Systems.", "journal": "Immunol Res 61", "pmid": "25381482", "doi": "10.1007/s12026-014-8567-3", "type": "spontaneous_reports", "design": "Analysis of VAERS reports", "n": 2207, "population": "VAERS reports meeting ASIA guideline criteria after causality assessment.", "key_finding": "2,207 cases probably or possibly related; most common manifestations pyrexia (58%), myalgia (27%), arthralgia/arthritis (19%). Estimated reporting rate 3.6 per 100,000 doses distributed (95% CI 3.4–3.7).", "direction": "descriptive", "grade": "very_low", "quality_note": "Reporting rate, not incidence. Reports are unverified and the ASIA criteria are broad (see Hawkes 2015).", "symptoms": [] }, { "id": "hviid-2020", "citation": "Hviid et al. 2020 — Danish nationwide SCCS", "authors": "Hviid A, Thorsen NM, Valentiner-Branth P, Frisch M", "year": 2020, "title": "Association between quadrivalent human papillomavirus vaccination and selected syndromes with autonomic dysfunction in Danish females: population based, self-controlled, case series analysis.", "journal": "BMJ 370:m2930", "pmid": "32878745", "pmc": "PMC7463169", "doi": "10.1136/bmj.m2930", "type": "registry_sccs", "design": "Self-controlled case series, nationwide registers", "n": 869, "population": "869 cases (136 CFS, 535 CRPS, 198 POTS) from 1,375,737 Danish-born females aged 10–44, 2007–16; 10,581,902 person-years.", "key_finding": "Composite rate ratio 0.99 (95% CI 0.74–1.32) in the 365 days after vaccination. Individual: CFS 0.38 (0.13–1.09); CRPS 1.31 (0.91–1.90); POTS 0.86 (0.48–1.54). An increase of up to 32% cannot be formally excluded.", "direction": "no_association", "grade": "low", "quality_note": "Large and nationwide; outcome is ICD-10-coded diagnoses, which may not capture every symptomatic patient in case series. Confidence limits leave room for a modest increase, particularly for CRPS.", "symptoms": [] }, { "id": "feiring-2017", "citation": "Feiring et al. 2017 — Norwegian register study", "authors": "Feiring B, Laake I, Bakken IJ, Greve-Isdahl M", "year": 2017, "title": "HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway.", "journal": "Vaccine 35", "pmid": "28648542", "doi": "10.1016/j.vaccine.2017.06.031", "type": "registry_sccs", "design": "Register-based cohort (Cox regression)", "n": 176453, "population": "176,453 girls born 1997–2002 eligible for HPV vaccination; incidence data on 824,133 boys and girls aged 10–17.", "key_finding": "HR 0.86 (95% CI 0.69–1.08) over follow-up; 0.96 (0.64–1.43) in the first two years after vaccination. Prior hospital contacts strongly predicted CFS/ME (HR 5.23 for ≥7 contacts).", "direction": "no_association", "grade": "low", "quality_note": "Registry CFS/ME diagnosis; ascertainment depends on diagnosis coding. Also showed that pre-existing health status shapes both risk and vaccine uptake.", "symptoms": [] }, { "id": "hviid-2018", "citation": "Hviid et al. 2018 — Danish/Swedish adult women cohort", "authors": "Hviid A, Svanström H, Scheller NM, Grönlund O", "year": 2018, "title": "Human papillomavirus vaccination of adult women and risk of autoimmune and neurological diseases.", "journal": "J Intern Med 283", "pmid": "29044769", "doi": "10.1111/joim.12694", "type": "registry_sccs", "design": "Cohort and SCCS, nationwide registers", "n": 3126790, "population": "3,126,790 women aged 18–44 (Denmark and Sweden); 45 pre-selected autoimmune / neurological outcomes.", "key_finding": "After multiple-testing correction and SCCS, only coeliac disease (RR 1.56, 95% CI 1.29–1.89) remained; authors interpret it as likely unmasking of under-diagnosed disease.", "direction": "no_association", "grade": "low", "quality_note": "Adult women; not the adolescent population of the Japanese series. Outcome list is pre-specified (45 conditions); the abstract does not state that it tests the syndrome cluster in the Japanese and Danish case series.", "symptoms": [] }, { "id": "ema-2015", "citation": "EMA PRAC, Nov 2015 — HPV vaccines Article 20 review", "authors": "European Medicines Agency, Pharmacovigilance Risk Assessment Committee", "year": 2015, "title": "Review concludes evidence does not support that HPV vaccines cause CRPS or POTS.", "journal": "EMA referral / news release, 5–6 Nov 2015", "url": "https://www.ema.europa.eu/en/medicines/human/referrals/human-papillomavirus-vaccines-cervarix-gardasil-gardasil-9-silgard", "extra_links": [ { "label": "EMA news release", "url": "https://www.ema.europa.eu/en/news/review-concludes-evidence-does-not-support-hpv-vaccines-cause-crps-or-pots" } ], "type": "regulator_review", "design": "EU Article 20 referral; PRAC benefit-risk review", "n": null, "population": "Cervarix, Gardasil/Silgard, Gardasil 9; more than 80 million recipients worldwide at the time of review.", "key_finding": "PRAC concluded the evidence does not support a causal link between the vaccines and CRPS or POTS. It cited general-population rates of about 150 per million (CRPS) and at least 150 per million (POTS) among girls and women aged 10–19 per year.", "direction": "no_association", "grade": "n/a", "quality_note": "Review reflects evidence up to Nov 2015; predates the 2021 Japanese long-term series and the 2022 autoantibody paper.", "symptoms": [] }, { "id": "gacvs-2015", "citation": "WHO GACVS, Dec 2015 statement on HPV vaccine safety", "authors": "WHO Global Advisory Committee on Vaccine Safety", "year": 2015, "title": "GACVS statement on safety of HPV vaccines, 17 Dec 2015.", "journal": "WHO GACVS", "url": "https://cdn.who.int/media/docs/default-source/pvg/vaccine-safety/gacvs/gacvs_hpv_statement_17dec2015.pdf?sfvrsn=6bd04fd6_1", "extra_links": [ { "label": "WHO GACVS HPV safety topic page", "url": "https://www.who.int/groups/global-advisory-committee-on-vaccine-safety/topics/human-papillomavirus-vaccines/safety" } ], "type": "regulator_review", "design": "Expert committee statement", "n": null, "population": "Pre- and post-licensure data reviewed by GACVS.", "key_finding": "\"Reviews of pre- and post-licensure data provide no evidence that these syndromes are associated with HPV vaccination.\" The committee noted difficulty diagnosing CRPS and POTS in adolescents.", "direction": "no_association", "grade": "n/a", "quality_note": "Quoted from WHO GACVS topic page summary; verify against the full statement.", "symptoms": [] }, { "id": "gacvs-2017", "citation": "WHO GACVS, Jun 2017 statement on HPV vaccine safety", "authors": "WHO Global Advisory Committee on Vaccine Safety", "year": 2017, "title": "GACVS meeting 7–8 June 2017: HPV vaccine safety.", "journal": "WHO GACVS", "url": "https://www.who.int/groups/global-advisory-committee-on-vaccine-safety/topics/human-papillomavirus-vaccines/safety", "type": "regulator_review", "design": "Expert committee statement", "n": null, "population": "Included new epidemiological survey data from Japan.", "key_finding": "\"There is still no evidence to suggest a causal association between HPV vaccine and CRPS, POTS or the diverse symptoms that include pain and motor dysfunction.\"", "direction": "no_association", "grade": "n/a", "quality_note": "Quoted from WHO GACVS topic page summary; predates the 2021 and 2022 patient-series and biomarker papers.", "symptoms": [] } ], "disclaimers": [ "Population studies show rate ratios close to 1 for CFS, CRPS and POTS after HPV vaccination; case-series frequencies describe selected patients only.", "Japanese series use author-proposed diagnostic criteria that have not been independently validated." ], "research_gaps": [ "Unified biomarker panel across HPV-symptomatic, PACVS, long-COVID and healthy-vaccinated cohorts.", "Independent replication of the autoantibody findings with blinded assays and matched controls.", "Registry studies using the case definition of the clinic series rather than only ICD codes for CFS, CRPS and POTS.", "Updated regulator reviews that address the 2021–2022 patient-series and autoantibody literature." ] }, { "id": "anthrax", "vaccine": "Anthrax (AVA)", "site_pages": [], "site_pages_note": "No anthrax vaccine summary page exists in the local site mirror; link once one is added.", "syndrome_name": "Gulf War Illness / chronic multisymptom illness (CMI) — anthrax-vaccine hypothesis", "aliases": [ "GWI", "CMI", "Gulf War syndrome" ], "key_symptom_clusters": [ "Chronic multisymptom illness (CDC-defined in the UK cohort; symptom frequencies not compiled)" ], "onset_window": { "text": "Not compiled. GWI is identified in cohorts studied years after deployment; the sources compiled do not report a time from vaccination to onset.", "source_ids": [] }, "case_series_summary": "Small US veteran samples report an association between anthrax vaccination and GWI diagnosis (47.1% vs 17.2%, n=111), and between predicted HLA class II binding of the vaccine's protective antigen and symptom severity (r = −0.356, n=458). UK cross-sectional data link multiple vaccines given during deployment to multisymptom illness, without isolating anthrax vaccine.", "registry_summary": "The IOM 2002 committee found no convincing evidence at that time of elevated later-onset health risk among AVA recipients, while noting data were limited. A US Army cohort of 716,833 soldiers (154,456 vaccinated, 1998–2002) found an adjusted hazard ratio of 0.96 (95% CI 0.92–0.99) for disability evaluation, but did not measure GWI/CMI and did not study the 1990–91 Gulf War population.", "regulator_position": "IOM (2002): \"The available data are limited but show no convincing evidence at this time that personnel who have received AVA have elevated risks of later-onset health events.\" Not an FDA or DoD statement; no current regulator statement on the HLA-based hypothesis was located.", "regulator_position_ids": [ "iom-2002" ], "proposed_mechanisms": [ { "text": "Persistence of anthrax protective antigen (PA) in people whose HLA class II alleles bind PA peptides poorly, limiting antibody response (hypothesis; in-silico plus small association samples).", "evidence_level": "hypothesis", "source_ids": [ "james-2024", "james-2025" ] } ], "alternative_explanations": [ { "text": "GWI has multiple candidate exposures and stressors in deployment; UK data suggest vaccination combined with deployment stress, not vaccination alone.", "source_ids": [ "hotopf-2000" ] }, { "text": "Vaccination status in the veteran samples was recorded retrospectively; recall and selection bias are possible.", "source_ids": [ "james-2024" ] } ], "biomarkers": [ { "marker": "HLA class II alleles", "finding": "Of 58 HLA class II alleles found in the sample, 18 (31%) were present in vaccinated veterans without GWI and absent from vaccinated veterans with GWI; in-silico binding to anthrax PA peptides was high for those 18.", "source_ids": [ "james-2024" ] }, { "marker": "Predicted PA–HLA-II binding affinity (in silico)", "finding": "Negatively correlated with GWI symptom severity across 458 veterans (r = −0.356, p < 0.001).", "source_ids": [ "james-2025" ] } ], "key_studies": [ { "id": "james-2024", "citation": "James et al. 2024 — anthrax vaccination, GWI and HLA (111 veterans)", "authors": "James LM, Carpenter AF, Engdahl BE, Johnson RA, Georgopoulos AP et al.", "year": 2024, "title": "Anthrax Vaccination, Gulf War Illness, and Human Leukocyte Antigen (HLA).", "journal": "Vaccines (Basel) 12(6)", "pmid": "38932342", "pmc": "PMC11209475", "doi": "10.3390/vaccines12060613", "type": "case_series", "design": "Cross-sectional veteran sample with HLA typing and in-silico binding analysis", "n": 111, "population": "111 Gulf War veterans (42 with GWI, 69 controls).", "key_finding": "GWI diagnosed in 47.1% of vaccinated vs 17.2% of non-vaccinated veterans (χ² 7.08, p = 0.008; OR 3.947; RR 2.617); symptom severity 1.6× higher in vaccinated. 18 of 58 HLA class II alleles were present only in the vaccinated-without-GWI group.", "direction": "reports_association", "grade": "very_low", "quality_note": "Small non-random sample; vaccination status by recall; HLA claim rests on in-silico predicted binding, not measured antibody response; no multiple-testing detail in the abstract.", "symptoms": [] }, { "id": "james-2025", "citation": "James & Georgopoulos 2025 — HLA-II binding affinity and GWI severity (458 veterans)", "authors": "James LM, Georgopoulos AP", "year": 2025, "title": "Negative Association of Gulf War Illness Symptomatology with Predicted Binding Affinity of Anthrax Vaccine Antigen to Human Leukocyte (HLA) Class II Molecules.", "journal": "Vaccines (Basel) 13(1)", "pmid": "39852867", "pmc": "PMC11768865", "doi": "10.3390/vaccines13010088", "type": "mechanistic", "design": "In-silico HLA binding vs symptom severity correlation", "n": 458, "population": "458 Gulf War veterans with HLA-II typing (DPB1, DQB1, DRB1).", "key_finding": "Stronger overall predicted PA-peptide binding to the veteran's HLA-II alleles correlated with lower GWI symptom severity (r = −0.356, p < 0.001).", "direction": "reports_association", "grade": "very_low", "quality_note": "Predicted binding, not measured immunity; the abstract does not describe how vaccination status was handled; same research group as the 2024 paper; needs independent replication.", "symptoms": [] }, { "id": "hotopf-2000", "citation": "Hotopf et al. 2000 — UK Gulf War veterans, vaccines and ill health", "authors": "Hotopf M, David A, Hull L, Ismail K et al.", "year": 2000, "title": "Role of vaccinations as risk factors for ill health in veterans of the Gulf war: cross sectional study.", "journal": "BMJ 320", "pmid": "10818024", "pmc": "PMC27378", "doi": "10.1136/bmj.320.7246.1363", "type": "registry_sccs", "design": "Cross-sectional study of UK veterans with vaccine records", "n": 923, "population": "923 veterans with vaccine records (28% of 3,284 responders).", "key_finding": "Multiple vaccines received during deployment were associated with five of six health outcomes; the strongest was CDC-defined multisymptom illness (OR 5.0, 95% CI 2.5–9.8). Multiple vaccines before deployment were associated with only one outcome (post-traumatic stress reaction). Authors suggest vaccination combined with deployment stress, not vaccines alone.", "direction": "mixed", "grade": "low", "quality_note": "Concerns multiple vaccines (not anthrax specifically); only 28% had records; cross-sectional and self-reported outcomes.", "symptoms": [] }, { "id": "iom-2002", "citation": "IOM 2002 — The Anthrax Vaccine: Is It Safe? Does It Work?", "authors": "Institute of Medicine, Committee to Assess the Safety and Efficacy of the Anthrax Vaccine", "year": 2002, "title": "The Anthrax Vaccine: Is It Safe? Does It Work?", "journal": "National Academies Press; doi:10.17226/10310", "url": "https://nap.nationalacademies.org/catalog/10310", "extra_links": [ { "label": "Findings and recommendations (NAP reader)", "url": "https://www.nationalacademies.org/read/10310/chapter/2" } ], "doi": "10.17226/10310", "type": "regulator_review", "design": "Congressionally mandated expert-committee review for DoD", "n": null, "population": "Committee convened Oct 2000.", "key_finding": "\"The available data are limited but show no convincing evidence at this time that personnel who have received AVA have elevated risks of later-onset health events.\" Also: no evidence that life-threatening or permanently disabling immediate-onset events occur at higher rates than in the general population. Local injection-site and systemic reactions were fairly common and less common, respectively.", "direction": "no_association", "grade": "n/a", "quality_note": "Predates the 2024–2025 HLA-based papers; the committee explicitly described the data as limited.", "symptoms": [] }, { "id": "sulsky-2004", "citation": "Sulsky et al. 2004 — US Army disability cohort, 716,833 soldiers", "authors": "Sulsky SI, Grabenstein JD, Delbos RG", "year": 2004, "title": "Disability among U.S. Army personnel vaccinated against anthrax.", "journal": "J Occup Environ Med 46", "pmid": "15602181", "doi": "10.1097/01.jom.0000141664.90587.47", "type": "registry_sccs", "design": "Historical cohort (Cox proportional hazards)", "n": 716833, "population": "716,833 active-duty US Army soldiers (154,456 vaccinated with ≥1 AVA dose, Mar 1998–Feb 2002), followed 4.25 years.", "key_finding": "Adjusted HR for evaluation for disability discharge 0.96 (95% CI 0.92–0.99); sub-analyses (men, women, permanent, temporary, musculoskeletal, neurologic) ranged 0.90–1.04. Authors conclude anthrax vaccination does not increase risk of disability.", "direction": "no_association", "grade": "low", "quality_note": "Outcome is administrative disability evaluation, not GWI or CMI; cohort is post-1998 US Army personnel, not the 1990–91 Gulf War population; authors note selection for vaccination or vaccine tolerance may partly explain the result.", "symptoms": [] } ], "disclaimers": [ "Anthrax vaccine exposure in the Gulf War was one of multiple exposures; these sources do not isolate it from other factors.", "The HLA hypothesis has been advanced primarily by one research group and relies on in-silico binding predictions." ], "research_gaps": [ "Independent replication of the HLA-II protective-allele finding with measured anti-PA antibody titres.", "Prospective cohorts of AVA recipients with baseline symptom screening and HLA typing (military and civilian).", "Comparison of GWI biomarkers with PACVS, HPV-symptomatic and long-COVID biomarkers on a common panel.", "Updated committee review addressing the 2024–2025 HLA literature." ] }, { "id": "hepatitis-b", "vaccine": "Hepatitis B", "site_pages": [ { "label": "Hepatitis B vaccine summary", "href": "/hepatitis-b-vaccine.html" } ], "syndrome_name": "Chronic fatigue syndrome / fibromyalgia following hepatitis B vaccination (ASIA framing)", "aliases": [ "post-HBV-vaccine CFS/FM", "ASIA after hepatitis B vaccine" ], "key_symptom_clusters": [ "Neurological", "Musculoskeletal", "Fatigue", "Psychiatric", "Gastrointestinal", "Mucocutaneous" ], "onset_window": { "text": "Mean 38.6 ± 79.4 days from the last dose to symptom onset (range days to one year) in a 19-patient series; mean 43.2 days from the last dose in a 93-patient series. The anchor is the last dose, unlike the HPV series, which use the first.", "source_ids": [ "agmon-levin-2014", "zafrir-2012" ] }, "case_series_summary": "A 19-patient US medical-records series reports neurological (84.2%), musculoskeletal (78.9%), psychiatric (63.1%), fatigue (63.1%), GI (58%) and mucocutaneous (36.8%) manifestations; autoantibodies in 71% of those tested; all 19 fulfilled ASIA criteria as applied by the authors. A second series of 93 patients with immune-mediated disease, all of whom had sought legal consultation, reported a similar latency (43.2 days) and 86% fulfilling ASIA criteria.", "registry_summary": "For the hepatitis B – multiple sclerosis question (the most-studied chronic outcome), a nested case-control in two US nurse cohorts found no association (RR 0.9, 95% CI 0.5–1.6), while a UK primary-care database study reported OR 3.1 (95% CI 1.5–6.3) for vaccination within 3 years. The IOM 2011 committee judged the evidence inadequate to accept or reject a causal relationship. No registry study of CFS or fibromyalgia after hepatitis B vaccine was compiled.", "regulator_position": "IOM (2011): evidence inadequate to accept or reject a causal relationship between hepatitis B vaccine and MS (adults and children), Guillain-Barré syndrome, optic neuritis, encephalitis or seizures; evidence convincingly supports anaphylaxis in yeast-sensitive individuals. CFS and fibromyalgia were not among the hepatitis B conclusions extracted for this compile.", "regulator_position_ids": [ "iom-2011-hepb" ], "proposed_mechanisms": [ { "text": "Adjuvant-triggered autoimmunity within the ASIA framework, with autoimmune susceptibility and vaccine-associated adverse events proposed as risk factors (hypothesis).", "evidence_level": "hypothesis", "source_ids": [ "agmon-levin-2014", "hawkes-2015" ] } ], "alternative_explanations": [ { "text": "Case selection: the 93-patient series consisted solely of people who sought legal consultation. Patients were identified because they had both a syndrome and a prior hepatitis B vaccination; background rates of CFS and fibromyalgia in the vaccinated population would produce coincident cases.", "source_ids": [ "agmon-levin-2014", "zafrir-2012" ] }, { "text": "ASIA criteria are broad enough that few autoimmune presentations could be excluded.", "source_ids": [ "hawkes-2015" ] } ], "biomarkers": [ { "marker": "Autoantibodies (various)", "finding": "Detected in 71% of patients tested (denominator of those tested not given in the abstract); higher titres proposed by the authors as a possible risk factor.", "source_ids": [ "agmon-levin-2014" ] } ], "key_studies": [ { "id": "agmon-levin-2014", "citation": "Agmon-Levin et al. 2014 — CFS / fibromyalgia after hepatitis B vaccine, 19 patients", "authors": "Agmon-Levin N, Zafrir Y, Kivity S, Balofsky A et al.", "year": 2014, "title": "Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA).", "journal": "Immunol Res 60", "pmid": "25427994", "doi": "10.1007/s12026-014-8604-2", "type": "case_series", "design": "Medical-records case series applying ASIA criteria", "n": 19, "population": "19 patients with CFS and/or fibromyalgia after hepatitis B vaccination (1990–2008, several US centres); mean age 28.6 ± 11; 68.4% female; 21.05% with personal or family autoimmune history; 8 (42.1%) continued vaccination despite adverse events.", "key_finding": "Manifestations: neurological 84.2%, musculoskeletal 78.9%, psychiatric 63.1%, fatigue 63.1%, GI 58%, mucocutaneous 36.8%. Autoantibodies in 71% of tested patients. All patients fulfilled ASIA criteria. Mean latency from last dose 38.6 ± 79.4 days.", "direction": "descriptive", "grade": "very_low", "quality_note": "n=19 selected retrospectively from medical records; ASIA criteria applied by the proposing group; no comparison group; the abstract does not state how patients were identified or the denominator.", "symptoms": [ { "label": "Neurological manifestations", "domain": "other", "pct": 84.2 }, { "label": "Musculoskeletal", "domain": "other", "pct": 78.9 }, { "label": "Psychiatric", "domain": "other", "pct": 63.1 }, { "label": "Fatigue", "domain": "fatigue", "pct": 63.1 }, { "label": "Gastrointestinal complaints", "domain": "gi", "pct": 58 }, { "label": "Mucocutaneous", "domain": "other", "pct": 36.8 } ], "symptom_source": "Abstract", "onset": { "statistic": "mean", "days": 38.6, "sd": 79.4, "anchor": "last dose" } }, { "id": "ascherio-2001", "citation": "Ascherio et al. 2001 — hepatitis B vaccine and MS, US nurse cohorts", "authors": "Ascherio A, Zhang SM, Hernán MA, Olek MJ et al.", "year": 2001, "title": "Hepatitis B vaccination and the risk of multiple sclerosis.", "journal": "N Engl J Med 344", "pmid": "11172163", "doi": "10.1056/NEJM200102013440502", "type": "registry_sccs", "design": "Nested case-control in the Nurses' Health Studies", "n": 837, "population": "192 women with MS and 645 matched controls.", "key_finding": "Multivariate RR of MS after hepatitis B vaccination at any time 0.9 (95% CI 0.5–1.6); within 2 years before onset 0.7 (0.3–1.8). No dose–response relation.", "direction": "no_association", "grade": "low", "quality_note": "Outcome is MS, not CFS/fibromyalgia; wide confidence intervals; women only; vaccination confirmed by certificates.", "symptoms": [] }, { "id": "hernan-2004", "citation": "Hernán et al. 2004 — hepatitis B vaccine and MS, UK GPRD", "authors": "Hernán MA, Jick SS, Olek MJ, Jick H", "year": 2004, "title": "Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study.", "journal": "Neurology 63", "pmid": "15365133", "doi": "10.1212/01.wnl.0000138433.61870.82", "type": "registry_sccs", "design": "Nested case-control, UK General Practice Research Database", "n": 1767, "population": "163 MS cases and 1,604 matched controls.", "key_finding": "OR of MS for hepatitis B vaccination within 3 years before index date was 3.1 (95% CI 1.5–6.3); no increase for tetanus or influenza vaccines. Authors state results are consistent with an association and challenge the idea that the relation is well understood.", "direction": "reports_association", "grade": "low", "quality_note": "Outcome is MS, not CFS/fibromyalgia; relatively few cases; the authors themselves called for confirmation.", "symptoms": [] }, { "id": "iom-2011-hepb", "citation": "IOM 2011 — Adverse Effects of Vaccines: Evidence and Causality (hepatitis B chapter)", "authors": "Institute of Medicine, Committee to Review Adverse Effects of Vaccines", "year": 2011, "title": "Adverse Effects of Vaccines: Evidence and Causality — Hepatitis B Vaccine.", "journal": "National Academies Press (report released 2011; NAP edition 2012); doi:10.17226/13164", "url": "https://www.nationalacademies.org/read/13164/chapter/10", "doi": "10.17226/13164", "type": "regulator_review", "design": "Expert-committee causality review", "n": null, "population": "Published literature to the review date.", "key_finding": "\"The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and onset of MS in adults\" (same wording for MS in children, GBS, optic neuritis, encephalitis, seizures). \"The evidence convincingly supports a causal relationship between hepatitis B vaccine and anaphylaxis in yeast-sensitive individuals.\"", "direction": "mixed", "grade": "n/a", "quality_note": "Predates the 2014 Agmon-Levin series; CFS and fibromyalgia were not found in the hepatitis B conclusions extracted for this compile.", "symptoms": [] }, { "id": "zafrir-2012", "citation": "Zafrir et al. 2012 — immune-mediated disease after hepatitis B vaccine, 93 patients", "authors": "Zafrir Y, Agmon-Levin N, Paz Z, Shilton T et al.", "year": 2012, "title": "Autoimmunity following hepatitis B vaccine as part of the spectrum of 'Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants' (ASIA): analysis of 93 cases.", "journal": "Lupus 21", "pmid": "22235045", "doi": "10.1177/0961203311429318", "type": "case_series", "design": "Retrospective medical-records series applying ASIA criteria", "n": 93, "population": "93 of 114 US patients with immune-mediated disease after hepatitis B vaccination who were diagnosed before seeking legal consultation. Mean age 26.5 ± 15; 69.2% female.", "key_finding": "Mean latency 43.2 days from last dose. Manifestations: neuro-psychiatric 70%, musculoskeletal 59%, GI 50%, fatigue 42%, mucocutaneous 30%. Elevated autoantibody titres in 80% of sera tested. 80/93 (86%) fulfilled ASIA criteria (57/59 adults, 23/34 children).", "direction": "descriptive", "grade": "very_low", "quality_note": "All patients sought legal consultation (selection bias); mixed immune-mediated diagnoses, not specifically CFS or fibromyalgia; ASIA criteria applied by the group that proposed them; no comparison group.", "symptoms": [ { "label": "Neuro-psychiatric", "domain": "other", "pct": 70 }, { "label": "Musculoskeletal", "domain": "other", "pct": 59 }, { "label": "Gastrointestinal", "domain": "gi", "pct": 50 }, { "label": "Fatigue", "domain": "fatigue", "pct": 42 }, { "label": "Mucocutaneous", "domain": "other", "pct": 30 } ], "symptom_source": "Abstract", "onset": { "statistic": "mean", "days": 43.2, "anchor": "last dose" } } ], "disclaimers": [ "Registry studies compiled address multiple sclerosis, not the CFS/fibromyalgia phenotype in the case series.", "The 19-patient series describes retrospectively identified cases; it cannot estimate how often this occurs." ], "research_gaps": [ "Registry or SCCS study of CFS/ME and fibromyalgia after hepatitis B vaccination using standard diagnostic definitions.", "Controlled autoantibody comparison in vaccinated-symptomatic vs. vaccinated-well adults, including the number tested.", "Comparison of the case-series phenotype with HPV-symptomatic and PACVS cohorts." ] }, { "id": "asia-aluminum", "vaccine": "Aluminium-adjuvanted vaccines (overview)", "site_pages": [], "syndrome_name": "ASIA (autoimmune/inflammatory syndrome induced by adjuvants) and macrophagic myofasciitis (MMF)", "aliases": [ "Shoenfeld's syndrome", "ASIA", "MMF-associated chronic fatigue" ], "key_symptom_clusters": [ "Myalgia", "Chronic fatigue", "Cognitive dysfunction (MMF cohorts)", "Autonomic and subjective symptoms (per ASIA reviews)" ], "onset_window": { "text": "Not standardised across the sources compiled.", "source_ids": [] }, "case_series_summary": "Proponent reviews describe post-immunisation ME/CFS, myalgia and cognitive dysfunction linked to aluminium adjuvant persistence (MMF biopsy finding) and propose adding GPCR autoantibodies and small-fibre neuropathy to ASIA criteria. A VAERS analysis identified 2,207 suspected-ASIA reports after HPV vaccine (see HPV entry).", "registry_summary": "A 2025 Danish cohort of 1.22 million children found no association between cumulative early-life aluminium from vaccines and 50 chronic disorders (adjusted HR for any autoimmune disorder 0.98, 95% CI 0.94–1.02); it did not examine fatigue or dysautonomia-type illness. A 2015 systematic review of 27 animal, epidemiological and case studies found no robust animal model at biologically relevant doses, criteria too broad to exclude much autoimmune disease, and a lack of reproducible evidence for a consistent adjuvant–disease relationship.", "regulator_position": "WHO GACVS (2012): risk assessment 'further supports the clinical trial and epidemiological evidence of the safety of aluminium in vaccines'; body burden after aluminium-containing vaccines did not exceed safe US regulatory thresholds. The GACVS page reviewed did not address ASIA or MMF.", "regulator_position_ids": [ "gacvs-aluminium-2012" ], "proposed_mechanisms": [ { "text": "Poorly degradable particulate aluminium adjuvant is captured by immune cells, persists (MMF) and disseminates, provoking inflammation (hypothesis; animal work and MMF cohorts).", "evidence_level": "hypothesis", "source_ids": [ "gherardi-2001", "gherardi-2019" ] }, { "text": "Adjuvant-triggered autoimmunity in genetically susceptible individuals; dysregulated autonomic GPCR autoantibodies and small-fibre neuropathy proposed as additional ASIA features.", "evidence_level": "hypothesis", "source_ids": [ "cohen-tervaert-2023" ] } ], "alternative_explanations": [ { "text": "ASIA criteria are broad; few autoimmune conditions can be excluded, which weakens specificity.", "source_ids": [ "hawkes-2015" ] } ], "biomarkers": [ { "marker": "Macrophagic myofasciitis (deltoid biopsy)", "finding": "Proposed by Gherardi et al. as a histological biomarker of long-lasting aluminium persistence in patients with myalgia; frequency in unvaccinated or vaccinated-well people is not given in the abstract. In a 50-patient series, all had received aluminium-containing vaccines a median 36 months before biopsy.", "source_ids": [ "gherardi-2001", "gherardi-2019" ] } ], "key_studies": [ { "id": "gherardi-2019", "citation": "Gherardi et al. 2019 — MMF, ME/CFS and aluminium adjuvant persistence (review)", "authors": "Gherardi RK, Crépeaux G, Authier FJ", "year": 2019, "title": "Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system.", "journal": "Autoimmun Rev 18", "pmid": "31059838", "doi": "10.1016/j.autrev.2019.05.006", "type": "review", "design": "Narrative review by proponents of the aluminium hypothesis", "n": null, "population": "Epidemiological, clinical and animal evidence (sheep, mice).", "key_finding": "Authors argue ME/CFS is a major adverse effect of vaccines containing poorly degradable particulate aluminium adjuvants and describe MMF, brain perfusion/metabolism changes and animal neurotoxicity. Authors state post-immunisation ME/CFS is the core manifestation of ASIA.", "direction": "reports_association", "grade": "n/a", "quality_note": "Advocacy-leaning narrative review; contains several primary observations that need independent confirmation; the abstract cites an epidemiological comparison of vaccinated and unvaccinated militaries without giving figures.", "symptoms": [] }, { "id": "cohen-tervaert-2023", "citation": "Cohen Tervaert et al. 2023 — ASIA in 2023 (review)", "authors": "Cohen Tervaert JW, Martinez-Lavin M, Jara LJ, Halpert G et al.", "year": 2023, "title": "Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in 2023.", "journal": "Autoimmun Rev 22", "pmid": "36738954", "doi": "10.1016/j.autrev.2023.103287", "type": "review", "design": "Narrative review by ASIA proponents", "n": null, "population": "Literature on adjuvant-associated conditions including silicone implants, meshes, HPV and COVID-19 vaccines.", "key_finding": "Summarises accumulated evidence; proposes adding dysregulated non-classical GPCR autoantibodies and small-fibre neuropathy to ASIA criteria as possible explanations for dysautonomia.", "direction": "reports_association", "grade": "n/a", "quality_note": "Written by authors associated with the ASIA concept; not a systematic search.", "symptoms": [] }, { "id": "hawkes-2015", "citation": "Hawkes et al. 2015 — critical appraisal of ASIA (systematic review)", "authors": "Hawkes D, Benhamu J, Sidwell T, Miles R et al.", "year": 2015, "title": "Revisiting adverse reactions to vaccines: A critical appraisal of Autoimmune Syndrome Induced by Adjuvants (ASIA).", "journal": "J Autoimmun 59", "pmid": "25794485", "doi": "10.1016/j.jaut.2015.02.005", "type": "review", "design": "Systematic review of 27 animal, epidemiological and case studies", "n": 27, "population": "Studies published after the 2011 ASIA proposal (over 80 publications discussed ASIA).", "key_finding": "Found no robust animal model at biologically relevant adjuvant doses; ASIA criteria lack stringency, so very few autoimmune cases could be excluded; human studies too diverse to show a consistent adjuvant–disease relationship. Suggests mandatory temporal-association and dose criteria.", "direction": "no_association", "grade": "n/a", "quality_note": "Pre-dates 2019–2024 MMF and dysautonomia literature; number of studies reviewed is small (27).", "symptoms": [] }, { "id": "gacvs-aluminium-2012", "citation": "WHO GACVS, Jun 2012 — aluminium adjuvants", "authors": "WHO Global Advisory Committee on Vaccine Safety", "year": 2012, "title": "GACVS review of aluminium adjuvants (meeting 6–7 June 2012).", "journal": "WHO GACVS", "url": "https://www.who.int/groups/global-advisory-committee-on-vaccine-safety/topics/adjuvants", "type": "regulator_review", "design": "Expert committee statement", "n": null, "population": "Risk assessment including FDA body-burden calculations.", "key_finding": "\"The comprehensive risk assessment further supports the clinical trial and epidemiological evidence of the safety of aluminium in vaccines.\" Body burden after aluminium-containing vaccines never exceeds safe US regulatory thresholds. The page reviewed did not address ASIA or MMF.", "direction": "no_association", "grade": "n/a", "quality_note": "2012 statement; predates Gherardi 2019 and Cohen Tervaert 2023; addresses toxicological safety thresholds, not ASIA or MMF specifically.", "symptoms": [] }, { "id": "gherardi-2001", "citation": "Gherardi et al. 2001 — macrophagic myofasciitis and aluminium hydroxide persistence", "authors": "Gherardi RK, Coquet M, Cherin P, Belec L et al.", "year": 2001, "title": "Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle.", "journal": "Brain 124", "pmid": "11522584", "doi": "10.1093/brain/124.9.1821", "type": "case_series", "design": "Biopsy series with electron microscopy, chemical analysis and a rat experiment", "n": 50, "population": "Patients with diffuse arthromyalgias and fatigue who had deltoid biopsy; electron microscopy in 40 consecutive cases; vaccine history in 50 patients.", "key_finding": "Inclusions in macrophages corresponded to aluminium hydroxide. 50/50 patients had received hepatitis B (86%), hepatitis A (19%) or tetanus (58%) vaccines a median 36 months (range 3–96) before biopsy. Myalgia followed vaccination (median 11 months) in 94%. The lesion was reproduced in rats. Authors conclude the MMF lesion follows intramuscular aluminium-hydroxide vaccines and marks long-term local persistence.", "direction": "reports_association", "grade": "very_low", "quality_note": "Patients were selected because they had myalgia and biopsy; the abstract describes no biopsy series of vaccinated-well people, so it shows persistence at the injection site, not that persistence causes systemic illness.", "symptoms": [] }, { "id": "andersson-2025", "citation": "Andersson et al. 2025 — Danish nationwide cohort, aluminium-adsorbed vaccines", "authors": "Andersson NW, Bech Svalgaard I, Hoffmann SS, Hviid A", "year": 2025, "title": "Aluminum-Adsorbed Vaccines and Chronic Diseases in Childhood: A Nationwide Cohort Study.", "journal": "Ann Intern Med 178", "pmid": "40658954", "doi": "10.7326/ANNALS-25-00997", "type": "registry_sccs", "design": "Nationwide register cohort using time-varying aluminium content of vaccines", "n": 1224176, "population": "1,224,176 children born in Denmark 1997–2018, followed to 2020; cumulative aluminium from vaccines in the first 2 years of life.", "key_finding": "No association with any of 50 chronic disorders. Adjusted HR per 1 mg of aluminium: any autoimmune disorder 0.98 (95% CI 0.94–1.02); any atopic/allergic 0.99 (0.98–1.01); any neurodevelopmental 0.93 (0.90–0.97). Small effects for rarer disorders could not be excluded.", "direction": "no_association", "grade": "low", "quality_note": "Outcomes are childhood autoimmune, atopic and neurodevelopmental diagnoses; it does not test the fatigue / dysautonomia / MMF phenotype. Individual records not reviewed. Authors are at a national public-health institute; post-publication commentary questioning exposure misclassification and conflicts of interest exists but is not compiled here.", "symptoms": [] } ], "disclaimers": [ "ASIA is a proposed concept, not an accepted regulatory diagnosis. Its criteria are contested.", "Reviews in this group differ sharply in position; both a proponent and a critical systematic review are included." ], "research_gaps": [ "Controlled studies of MMF biopsy prevalence in vaccinated-symptomatic vs. vaccinated-well people.", "Animal models at biologically relevant adjuvant doses with pre-registered endpoints.", "Validation study of ASIA criteria (sensitivity and specificity against non-adjuvant-exposed autoimmune disease).", "Regulator review addressing MMF and the aluminium-persistence hypothesis directly." ] } ] }