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.
Last compiled 2026-09-21 · 5 syndrome groups · 34 cited records · draft for expert review ·
Data: pavs.bundle.json (generated from data/pavs/*.json by build_pavs_dashboard.py)
Terms
- PAVS — Post-acute vaccination syndromes
- 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.
- PACVS / PVS — Post-acute COVID-19 vaccination syndrome / post-vaccination syndrome
- 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. [Semmler et al. 2023, Krumholz et al. 2023]
- GWI / CMI — Gulf War Illness / chronic multisymptom illness
- 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. [Hotopf et al. 2000, James et al. 2024]
- ASIA — Autoimmune/inflammatory syndrome induced by adjuvants
- 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. [Cohen Tervaert et al. 2023, Hawkes et al. 2015]
- MMF — Macrophagic myofasciitis
- A histological finding of aluminium-containing macrophage infiltrates at a prior injection site, proposed by some authors as a marker of adjuvant persistence. [Gherardi et al. 2019]
Comparison across vaccines
| Vaccine | Named syndrome | Key symptom clusters | Estimated onset window | Reported in case series / spontaneous reports | Large registry / population studies | Regulator / committee position | Key studies |
|---|---|---|---|---|---|---|---|
| COVID-19 (mRNA) | Post-acute COVID-19 vaccination syndrome (PACVS) / post-vaccination syndrome (PVS) | Exercise intolerance; Excessive fatigue; Numbness / neuropathy; Brain fog / cognitive; Dysautonomia / POTS-type | 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. [Krumholz et al. 2023] | 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. | 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. | 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. | |
| HPV | Post-HPV vaccination disorder (Japan) / suspected autonomic dysfunction after HPV vaccination | Fatigue; Headache; Widespread pain / CRPS-like; Orthostatic intolerance / dysautonomia; Cognitive dysfunction; Sleep and menstrual disturbance | 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. [Hineno & Ikeda 2021, Ozawa et al. 2017] | 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. | 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. | 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. [EMA PRAC, Nov 2015, WHO GACVS, Dec 2015 statement on HPV vaccine safety, WHO GACVS, Jun 2017 statement on HPV vaccine safety] | |
| Anthrax (AVA) | Gulf War Illness / chronic multisymptom illness (CMI) — anthrax-vaccine hypothesis | Chronic multisymptom illness (CDC-defined in the UK cohort; symptom frequencies not compiled) | Not compiled. GWI is identified in cohorts studied years after deployment; the sources compiled do not report a time from vaccination to onset. | 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. | 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. | 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. [IOM 2002] | |
| Hepatitis B | Chronic fatigue syndrome / fibromyalgia following hepatitis B vaccination (ASIA framing) | Neurological; Musculoskeletal; Fatigue; Psychiatric; Gastrointestinal; Mucocutaneous | 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. [Agmon-Levin et al. 2014, Zafrir et al. 2012] | 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. | 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. | 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. [IOM 2011] | |
| Aluminium-adjuvanted vaccines (overview) | ASIA (autoimmune/inflammatory syndrome induced by adjuvants) and macrophagic myofasciitis (MMF) | Myalgia; Chronic fatigue; Cognitive dysfunction (MMF cohorts); Autonomic and subjective symptoms (per ASIA reviews) | Not standardised across the sources compiled. | 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). | 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. | 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. [WHO GACVS, Jun 2012] |
Vaccine-specific detail
COVID-19 (mRNA) — Post-acute COVID-19 vaccination syndrome (PACVS) / post-vaccination syndrome (PVS)
On this site: COVID-19 vaccine summary · Long COVID treatment
Also called: PACVS; PVS; long-vax syndrome (used in some reviews)
Reported in case series / spontaneous reports
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.
Large registry / population studies
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.
Onset latency
- Median 3 days from index vaccination, IQR 1–8 (n=241; Krumholz et al. 2023)
Reported symptom frequency — Krumholz et al. 2023, n=241 UNVERIFIED CASE-SERIES REPORTS
| Symptom (as reported) | Domain | Frequency in this selected group |
|---|---|---|
| Exercise intolerance * | Exercise intolerance / PEM | |
| Excessive fatigue | Fatigue | |
| Numbness | Other reported | |
| Brain fog | Cognitive | |
| Neuropathy | Other reported |
Source: Abstract (five most common symptoms only). Percentages describe a clinic-referred or self-selected group without a comparison group; they are not injury rates. * = source item approximates the domain. PubMed 37986769 · PMC full text · DOI
Biomarker / autoantibody findings
| Marker | Reported finding | Source |
|---|---|---|
| Angiotensin II type 1 receptor (AT1R) autoantibody | Altered in PACVS vs. healthy vaccinated controls; ROC-AUC 0.824 ± 0.027. | Semmler et al. 2023 |
| Alpha-2B adrenergic receptor autoantibody | Altered in PACVS vs. controls; ROC-AUC 0.828 ± 0.025. | Semmler et al. 2023 |
| Interleukin-6 (IL-6) | Increased in PACVS; ROC-AUC 0.850 ± 0.022. Combined markers reported sensitivity 90% for discriminating PACVS from normal post-vaccination state. | Semmler et al. 2023 |
Official positions
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.
Proposed mechanisms (hypotheses, not established causes)
- Altered functional receptor autoantibody pattern with elevated IL-6 (hypothesis; observational association in one German cohort). [Semmler et al. 2023]
Alternative explanations documented in the literature
- Symptoms overlap with post-infection long COVID and ME/CFS; unrecognised prior infection is a possible confounder unless excluded by testing. [Semmler et al. 2023, Yong et al. 2023]
- Self-selected online recruitment can over-represent severely affected people and cannot estimate incidence. [Krumholz et al. 2023]
Study list
| Study | Evidence type | N | Key finding | Quality note (GRADE-style, editorial) | Primary source |
|---|---|---|---|---|---|
| Krumholz et al. 2023 — Yale LISTEN online cohort, 241 people medRxiv (preprint) | Case series / patient survey Descriptive analysis of self-reported online cohort (preprint) | 241 | 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). Descriptive (no causal test) | Grade: Very low 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. | PubMed 37986769 · PMC full text · DOI |
| Semmler et al. 2023 — PACVS vs. healthy vaccinated controls (autoantibodies, IL-6) Vaccines (Basel) 11(11) | Mechanistic / biomarker Case-control biomarker study | 280 | 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. Reports association | Grade: Very low 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. | PubMed 38005974 · PMC full text · DOI |
| Kwan et al. 2022 — POTS diagnoses after vaccination vs infection (sequence-symmetry) Nat Cardiovasc Res 1 | Registry / SCCS / cohort / case-control Sequence-symmetry analysis, health-system records | 284,592 | 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. Mixed / qualified | Grade: Low Diagnosis-based; sequence-symmetry designs can be affected by increased healthcare contact around vaccination and by diagnostic delay. Authors note probable low incidence. | PubMed 37303827 · PMC full text · DOI |
| Yong et al. 2023 — meta-analysis of POTS after infection vs vaccination Auton Neurosci 250 | Narrative / systematic review Systematic review and meta-analysis | — | 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. Mixed / qualified | Grade: Not graded Vaccination pool rests on only two studies with a very wide interval; heterogeneity high. | PubMed 38000119 · DOI |
Disclaimers specific to this syndrome
- 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.
HPV — Post-HPV vaccination disorder (Japan) / suspected autonomic dysfunction after HPV vaccination
On this site: HPV vaccine summary · Package-insert ingredients
Also called: 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
Reported in case series / spontaneous reports
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.
Large registry / population studies
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.
Onset latency
- Median 199 days from first dose, range 0–1532 (n=87; Hineno & Ikeda 2021)
- Mean 319.7 ± 349.3 days from first dose, range 1–1532 (n=72; Ozawa et al. 2017)
Reported symptom frequency — Hineno & Ikeda 2021, n=87 UNVERIFIED CASE-SERIES REPORTS
| Symptom (as reported) | Domain | Frequency in this selected group |
|---|---|---|
| General fatigue | Fatigue | |
| Severe headache | Other reported | |
| Widespread pain | Pain | |
| Dysautonomic symptoms | Autonomic / POTS | |
| Motor dysfunction | Other reported | |
| Abnormal sensation | Other reported | |
| Learning impairment * | Cognitive | |
| Sleep disturbance | Other reported | |
| Menstrual abnormality | Other reported | |
| Limb shaking | Other reported |
Source: Table: 'Frequency of symptoms and signs in the 87 patients studied' (PMC8402449). Percentages describe a clinic-referred or self-selected group without a comparison group; they are not injury rates. * = source item approximates the domain. PubMed 34451981 · PMC full text · DOI
Reported symptom frequency — Brinth et al. 2015, n=35 UNVERIFIED CASE-SERIES REPORTS
| Symptom (as reported) | Domain | Frequency in this selected group |
|---|---|---|
| Orthostatic intolerance | Autonomic / POTS | |
| Nausea | Gastrointestinal | |
| Chronic headache | Other reported | |
| Fatigue | Fatigue | |
| Cognitive dysfunction | Cognitive | |
| Segmental dystonia | Other reported | |
| Neuropathic pain | Pain |
Source: Abstract. Percentages describe a clinic-referred or self-selected group without a comparison group; they are not injury rates. PubMed 25882168 · DOI
Biomarker / autoantibody findings
| Marker | Reported finding | Source |
|---|---|---|
| Autoantibodies to neuroendocrine receptors (GPCR family) | 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. verify | Mehlsen et al. 2022 |
Official positions
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. [EMA PRAC, Nov 2015, WHO GACVS, Dec 2015 statement on HPV vaccine safety, WHO GACVS, Jun 2017 statement on HPV vaccine safety]
Proposed mechanisms (hypotheses, not established causes)
- Functional autoantibodies against neuroendocrine / autonomic GPCRs (hypothesis; reported in a Danish patient cohort, not established as causal). [Mehlsen et al. 2022, Blitshteyn et al. 2018]
- Aluminium-adjuvant persistence within ASIA framework (hypothesis; see ASIA / aluminium entry for critique). [Cohen Tervaert et al. 2023, Hawkes et al. 2015]
Alternative explanations documented in the literature
- Coincidental temporal association: syndromes of this type occur in the unvaccinated adolescent population. [Hviid et al. 2020, EMA PRAC, Nov 2015]
- Stimulated reporting: a Danish cluster analysis attributed one cluster of serious-AE reports, with a spike in December 2015, to likely media stimulation. [Ward et al. 2019]
Study list
| Study | Evidence type | N | Key finding | Quality note (GRADE-style, editorial) | Primary source |
|---|---|---|---|---|---|
| Hineno & Ikeda 2021 — Japanese clinic series, 87 patients Vaccines (Basel) 9 | Case series / patient survey Single-centre retrospective clinical series | 87 | 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. Descriptive (no causal test) | Grade: Very low 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. | PubMed 34451981 · PMC full text · DOI |
| Ozawa et al. 2017 — Japanese clinic series, 72 patients Drug Saf 40 | Case series / patient survey Single-centre clinical series | 72 | 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. Descriptive (no causal test) | Grade: Very low 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. | PubMed 28744844 · PMC full text · DOI |
| Brinth et al. 2015 — Danish syncope-unit series, 35 women Vaccine 33 | Case series / patient survey Referral-based clinical series | 35 | POTS diagnosed in 21 of 35 (60%; 95% CI 43–77%). The authors call for work to elucidate a potential causal link. Descriptive (no causal test) | Grade: Very low Referred for orthostatic intolerance, so 100% orthostatic intolerance is by selection. No unvaccinated comparison. | PubMed 25882168 · DOI |
| Brinth et al. 2015 — Danish series, 53 patients Dan Med J 62 | Case series / patient survey Referral-based clinical series | 53 | All 53 had symptoms consistent with pronounced autonomic dysfunction. The authors state their findings neither confirm nor dismiss a causal link. Descriptive (no causal test) | Grade: Very low Percent frequencies not available in the abstract; patient overlap with the 35-woman series is possible and not stated in the abstract. | PubMed 25872549 |
| Mehlsen et al. 2022 — autoantibody study, Danish patients verify J Autoimmun 133 | Mechanistic / biomarker Patient vs. comparison autoantibody assay | — | 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. Reports association | Grade: Very low 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). | PubMed 36356549 · DOI |
| Blitshteyn et al. 2018 — review of HPV case series Immunol Res 66 | Narrative / systematic review Narrative review of case series | — | 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. Mixed / qualified | Grade: Not graded Authors include clinicians who authored some reviewed series; hypothesis paper calling for case-control studies. | PubMed 30478703 · DOI |
| Ward et al. 2019 — cluster analysis of Danish serious AE reports Euro Surveill 24(19):1800380 | Spontaneous reports Latent class cluster analysis of spontaneous reports | 963 | 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. Descriptive (no causal test) | Grade: Very low Report counts cannot give incidence; reporting is affected by publicity. The authors are from the Danish national health authority. | PubMed 31088598 · PMC full text · DOI |
| Pellegrino et al. 2015 — VAERS analysis of suspected ASIA after HPV vaccine Immunol Res 61 | Spontaneous reports Analysis of VAERS reports | 2,207 | 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). Descriptive (no causal test) | Grade: Very low Reporting rate, not incidence. Reports are unverified and the ASIA criteria are broad (see Hawkes 2015). | PubMed 25381482 · DOI |
| Hviid et al. 2020 — Danish nationwide SCCS BMJ 370:m2930 | Registry / SCCS / cohort / case-control Self-controlled case series, nationwide registers | 869 | 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. No association found | Grade: Low 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. | PubMed 32878745 · PMC full text · DOI |
| Feiring et al. 2017 — Norwegian register study Vaccine 35 | Registry / SCCS / cohort / case-control Register-based cohort (Cox regression) | 176,453 | 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). No association found | Grade: Low Registry CFS/ME diagnosis; ascertainment depends on diagnosis coding. Also showed that pre-existing health status shapes both risk and vaccine uptake. | PubMed 28648542 · DOI |
| Hviid et al. 2018 — Danish/Swedish adult women cohort J Intern Med 283 | Registry / SCCS / cohort / case-control Cohort and SCCS, nationwide registers | 3,126,790 | 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. No association found | Grade: Low 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. | PubMed 29044769 · DOI |
| EMA PRAC, Nov 2015 — HPV vaccines Article 20 review EMA referral / news release, 5–6 Nov 2015 | Regulator / expert-committee review EU Article 20 referral; PRAC benefit-risk review | — | 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. No association found | Grade: Not graded Review reflects evidence up to Nov 2015; predates the 2021 Japanese long-term series and the 2022 autoantibody paper. | Official document · EMA news release |
| WHO GACVS, Dec 2015 statement on HPV vaccine safety WHO GACVS | Regulator / expert-committee review Expert committee statement | — | "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. No association found | Grade: Not graded Quoted from WHO GACVS topic page summary; verify against the full statement. | Official document · WHO GACVS HPV safety topic page |
| WHO GACVS, Jun 2017 statement on HPV vaccine safety WHO GACVS | Regulator / expert-committee review Expert committee statement | — | "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." No association found | Grade: Not graded Quoted from WHO GACVS topic page summary; predates the 2021 and 2022 patient-series and biomarker papers. | Official document |
Disclaimers specific to this syndrome
- 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.
Anthrax (AVA) — Gulf War Illness / chronic multisymptom illness (CMI) — anthrax-vaccine hypothesis
Also called: GWI; CMI; Gulf War syndrome
Reported in case series / spontaneous reports
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.
Large registry / population studies
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.
Onset latency
Not compiled. GWI is identified in cohorts studied years after deployment; the sources compiled do not report a time from vaccination to onset.
Biomarker / autoantibody findings
| Marker | Reported finding | Source |
|---|---|---|
| HLA class II alleles | 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. | James et al. 2024 |
| Predicted PA–HLA-II binding affinity (in silico) | Negatively correlated with GWI symptom severity across 458 veterans (r = −0.356, p < 0.001). | James & Georgopoulos 2025 |
Official positions
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. [IOM 2002]
Proposed mechanisms (hypotheses, not established causes)
- 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). [James et al. 2024, James & Georgopoulos 2025]
Alternative explanations documented in the literature
- GWI has multiple candidate exposures and stressors in deployment; UK data suggest vaccination combined with deployment stress, not vaccination alone. [Hotopf et al. 2000]
- Vaccination status in the veteran samples was recorded retrospectively; recall and selection bias are possible. [James et al. 2024]
Study list
| Study | Evidence type | N | Key finding | Quality note (GRADE-style, editorial) | Primary source |
|---|---|---|---|---|---|
| James et al. 2024 — anthrax vaccination, GWI and HLA (111 veterans) Vaccines (Basel) 12(6) | Case series / patient survey Cross-sectional veteran sample with HLA typing and in-silico binding analysis | 111 | 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. Reports association | Grade: Very low 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. | PubMed 38932342 · PMC full text · DOI |
| James & Georgopoulos 2025 — HLA-II binding affinity and GWI severity (458 veterans) Vaccines (Basel) 13(1) | Mechanistic / biomarker In-silico HLA binding vs symptom severity correlation | 458 | 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). Reports association | Grade: Very low 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. | PubMed 39852867 · PMC full text · DOI |
| Hotopf et al. 2000 — UK Gulf War veterans, vaccines and ill health BMJ 320 | Registry / SCCS / cohort / case-control Cross-sectional study of UK veterans with vaccine records | 923 | 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. Mixed / qualified | Grade: Low Concerns multiple vaccines (not anthrax specifically); only 28% had records; cross-sectional and self-reported outcomes. | PubMed 10818024 · PMC full text · DOI |
| IOM 2002 — The Anthrax Vaccine: Is It Safe? Does It Work? National Academies Press; doi:10.17226/10310 | Regulator / expert-committee review Congressionally mandated expert-committee review for DoD | — | "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. No association found | Grade: Not graded Predates the 2024–2025 HLA-based papers; the committee explicitly described the data as limited. | DOI · Official document · Findings and recommendations (NAP reader) |
| Sulsky et al. 2004 — US Army disability cohort, 716,833 soldiers J Occup Environ Med 46 | Registry / SCCS / cohort / case-control Historical cohort (Cox proportional hazards) | 716,833 | 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. No association found | Grade: Low 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. | PubMed 15602181 · DOI |
Disclaimers specific to this syndrome
- 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.
Hepatitis B — Chronic fatigue syndrome / fibromyalgia following hepatitis B vaccination (ASIA framing)
On this site: Hepatitis B vaccine summary
Also called: post-HBV-vaccine CFS/FM; ASIA after hepatitis B vaccine
Reported in case series / spontaneous reports
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.
Large registry / population studies
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.
Onset latency
- Mean 38.6 ± 79.4 days from last dose (n=19; Agmon-Levin et al. 2014)
- Mean 43.2 days from last dose (n=93; Zafrir et al. 2012)
Reported symptom frequency — Agmon-Levin et al. 2014, n=19 UNVERIFIED CASE-SERIES REPORTS
| Symptom (as reported) | Domain | Frequency in this selected group |
|---|---|---|
| Neurological manifestations | Other reported | |
| Musculoskeletal | Other reported | |
| Psychiatric | Other reported | |
| Fatigue | Fatigue | |
| Gastrointestinal complaints | Gastrointestinal | |
| Mucocutaneous | Other reported |
Source: Abstract. Percentages describe a clinic-referred or self-selected group without a comparison group; they are not injury rates. PubMed 25427994 · DOI
Reported symptom frequency — Zafrir et al. 2012, n=93 UNVERIFIED CASE-SERIES REPORTS
| Symptom (as reported) | Domain | Frequency in this selected group |
|---|---|---|
| Neuro-psychiatric | Other reported | |
| Musculoskeletal | Other reported | |
| Gastrointestinal | Gastrointestinal | |
| Fatigue | Fatigue | |
| Mucocutaneous | Other reported |
Source: Abstract. Percentages describe a clinic-referred or self-selected group without a comparison group; they are not injury rates. PubMed 22235045 · DOI
Biomarker / autoantibody findings
| Marker | Reported finding | Source |
|---|---|---|
| Autoantibodies (various) | 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. | Agmon-Levin et al. 2014 |
Official positions
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. [IOM 2011]
Proposed mechanisms (hypotheses, not established causes)
- Adjuvant-triggered autoimmunity within the ASIA framework, with autoimmune susceptibility and vaccine-associated adverse events proposed as risk factors (hypothesis). [Agmon-Levin et al. 2014, Hawkes et al. 2015]
Alternative explanations documented in the literature
- 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. [Agmon-Levin et al. 2014, Zafrir et al. 2012]
- ASIA criteria are broad enough that few autoimmune presentations could be excluded. [Hawkes et al. 2015]
Study list
| Study | Evidence type | N | Key finding | Quality note (GRADE-style, editorial) | Primary source |
|---|---|---|---|---|---|
| Agmon-Levin et al. 2014 — CFS / fibromyalgia after hepatitis B vaccine, 19 patients Immunol Res 60 | Case series / patient survey Medical-records case series applying ASIA criteria | 19 | 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. Descriptive (no causal test) | Grade: Very low 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. | PubMed 25427994 · DOI |
| Ascherio et al. 2001 — hepatitis B vaccine and MS, US nurse cohorts N Engl J Med 344 | Registry / SCCS / cohort / case-control Nested case-control in the Nurses' Health Studies | 837 | 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. No association found | Grade: Low Outcome is MS, not CFS/fibromyalgia; wide confidence intervals; women only; vaccination confirmed by certificates. | PubMed 11172163 · DOI |
| Hernán et al. 2004 — hepatitis B vaccine and MS, UK GPRD Neurology 63 | Registry / SCCS / cohort / case-control Nested case-control, UK General Practice Research Database | 1,767 | 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. Reports association | Grade: Low Outcome is MS, not CFS/fibromyalgia; relatively few cases; the authors themselves called for confirmation. | PubMed 15365133 · DOI |
| IOM 2011 — Adverse Effects of Vaccines: Evidence and Causality (hepatitis B chapter) National Academies Press (report released 2011; NAP edition 2012); doi:10.17226/13164 | Regulator / expert-committee review Expert-committee causality review | — | "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." Mixed / qualified | Grade: Not graded Predates the 2014 Agmon-Levin series; CFS and fibromyalgia were not found in the hepatitis B conclusions extracted for this compile. | DOI · Official document |
| Zafrir et al. 2012 — immune-mediated disease after hepatitis B vaccine, 93 patients Lupus 21 | Case series / patient survey Retrospective medical-records series applying ASIA criteria | 93 | 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). Descriptive (no causal test) | Grade: Very low 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. | PubMed 22235045 · DOI |
Disclaimers specific to this syndrome
- 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.
Aluminium-adjuvanted vaccines (overview) — ASIA (autoimmune/inflammatory syndrome induced by adjuvants) and macrophagic myofasciitis (MMF)
Also called: Shoenfeld's syndrome; ASIA; MMF-associated chronic fatigue
Reported in case series / spontaneous reports
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).
Large registry / population studies
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.
Onset latency
Not standardised across the sources compiled.
Biomarker / autoantibody findings
| Marker | Reported finding | Source |
|---|---|---|
| Macrophagic myofasciitis (deltoid biopsy) | 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. | Gherardi et al. 2001, Gherardi et al. 2019 |
Official positions
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. [WHO GACVS, Jun 2012]
Proposed mechanisms (hypotheses, not established causes)
- Poorly degradable particulate aluminium adjuvant is captured by immune cells, persists (MMF) and disseminates, provoking inflammation (hypothesis; animal work and MMF cohorts). [Gherardi et al. 2001, Gherardi et al. 2019]
- Adjuvant-triggered autoimmunity in genetically susceptible individuals; dysregulated autonomic GPCR autoantibodies and small-fibre neuropathy proposed as additional ASIA features. [Cohen Tervaert et al. 2023]
Alternative explanations documented in the literature
- ASIA criteria are broad; few autoimmune conditions can be excluded, which weakens specificity. [Hawkes et al. 2015]
Study list
| Study | Evidence type | N | Key finding | Quality note (GRADE-style, editorial) | Primary source |
|---|---|---|---|---|---|
| Gherardi et al. 2019 — MMF, ME/CFS and aluminium adjuvant persistence (review) Autoimmun Rev 18 | Narrative / systematic review Narrative review by proponents of the aluminium hypothesis | — | 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. Reports association | Grade: Not graded 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. | PubMed 31059838 · DOI |
| Cohen Tervaert et al. 2023 — ASIA in 2023 (review) Autoimmun Rev 22 | Narrative / systematic review Narrative review by ASIA proponents | — | Summarises accumulated evidence; proposes adding dysregulated non-classical GPCR autoantibodies and small-fibre neuropathy to ASIA criteria as possible explanations for dysautonomia. Reports association | Grade: Not graded Written by authors associated with the ASIA concept; not a systematic search. | PubMed 36738954 · DOI |
| Hawkes et al. 2015 — critical appraisal of ASIA (systematic review) J Autoimmun 59 | Narrative / systematic review Systematic review of 27 animal, epidemiological and case studies | 27 | 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. No association found | Grade: Not graded Pre-dates 2019–2024 MMF and dysautonomia literature; number of studies reviewed is small (27). | PubMed 25794485 · DOI |
| WHO GACVS, Jun 2012 — aluminium adjuvants WHO GACVS | Regulator / expert-committee review Expert committee statement | — | "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. No association found | Grade: Not graded 2012 statement; predates Gherardi 2019 and Cohen Tervaert 2023; addresses toxicological safety thresholds, not ASIA or MMF specifically. | Official document |
| Gherardi et al. 2001 — macrophagic myofasciitis and aluminium hydroxide persistence Brain 124 | Case series / patient survey Biopsy series with electron microscopy, chemical analysis and a rat experiment | 50 | 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. Reports association | Grade: Very low 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. | PubMed 11522584 · DOI |
| Andersson et al. 2025 — Danish nationwide cohort, aluminium-adsorbed vaccines Ann Intern Med 178 | Registry / SCCS / cohort / case-control Nationwide register cohort using time-varying aluminium content of vaccines | 1,224,176 | 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. No association found | Grade: Low 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. | PubMed 40658954 · DOI |
Disclaimers specific to this syndrome
- 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.
Cross-vaccine comparison
All charts are generated from the same cited data files as the tables. Each marker or cell links to its study record.
Symptom overlap
| Study | Fatigue | Exercise intolerance / PEM | Autonomic / POTS | Pain | Cognitive | Gastrointestinal |
|---|---|---|---|---|---|---|
| COVID-19 (mRNA) Krumholz et al. 2023 n=241 | 69% | 71%* | not reported— | not reported— | 63% | not reported— |
| HPV Hineno & Ikeda 2021 n=87 | 83.9% | not reported— | 81.6% | 81.6% | 59.8%* | not reported— |
| HPV Brinth et al. 2015 n=35 | 82% | not reported— | 100% | 68% | 77% | 94% |
| Hepatitis B Agmon-Levin et al. 2014 n=19 | 63.1% | not reported— | not reported— | not reported— | not reported— | 58% |
| Hepatitis B Zafrir et al. 2012 n=93 | 42% | not reported— | not reported— | not reported— | not reported— | 50% |
Scale: 0% → 100% of the group. Source tables and links are in each vaccine section below.
Onset latency
Only summary statistics are published for these groups, so this shows reported medians, means and ranges, not the underlying distributions. Studies use different reference events (first dose, last dose, index vaccination) and different populations; do not read the horizontal ordering as a comparison of vaccines.
Data table for this chart
| Study | Vaccine | Statistic (days) | Range | Reference event |
|---|---|---|---|---|
| Krumholz et al. 2023 | COVID-19 (mRNA) | median 3 | IQR 1–8 | index vaccination |
| Hineno & Ikeda 2021 | HPV | median 199 | 0–1532 | first dose |
| Ozawa et al. 2017 | HPV | mean 319.7 ± 349.3 | 1–1532 | first dose |
| Agmon-Levin et al. 2014 | Hepatitis B | mean 38.6 ± 79.4 | not reported | last dose |
| Zafrir et al. 2012 | Hepatitis B | mean 43.2 | not reported | last dose |
Timeline of studies and regulator reviews
Filter by evidence type using the controls under “Study explorer”; the timeline and explorer share them.
Study explorer
| Vaccine | Author / year | Design | N | Key finding | Quality note (GRADE-style) | Primary source |
|---|
Methodology and evidence grading
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.
- 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.
Evidence types
| Type | What it can and cannot show |
|---|---|
| Case series / patient survey | Clinic-referred or self-selected patients; no unexposed comparison. |
| Spontaneous reports | Passive surveillance (e.g., VAERS, national AE registers); unverified, subject to stimulated reporting. |
| Registry / SCCS / cohort / case-control | Compares vaccinated with unvaccinated persons or risk vs. control windows. |
| Mechanistic / biomarker | Biomarker, in-silico or animal work; hypothesis-generating. |
| Narrative / systematic review | Secondary synthesis; check whether authors advocate a position. |
| Regulator / expert-committee review | EMA, WHO GACVS, IOM/NASEM and similar. |
Default GRADE-style rating by design
| Design | Starting rating | Why |
|---|---|---|
| Case series, patient survey, spontaneous reports | Very low | No comparison group; selection and recall bias; cannot estimate risk. |
| Registry / SCCS / cohort / case-control | Low | Comparison group present, but outcome coding, healthy-vaccinee effects, diagnostic delay and confounding remain. |
| Mechanistic / biomarker / in-silico | Very low | Hypothesis-generating; does not test whether the vaccine causes illness. |
| Narrative review | Not graded | Depends on the sources reviewed and the authors' stated position. |
| Regulator / expert-committee review | Not graded | Not a study; reflects the committee's reading of evidence available at the time. |
Ratings are editorial and provisional. They are not a formal GRADE assessment and do not judge whether any individual’s illness was caused by a vaccine.
Research gaps across vaccines
- 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.