Table 9.
Benefits and harms of the HPV vaccines: summary of harms of special interest and post hoc exploratory harm analyses
| Summary of harms of special interest and post hoc exploratory harm analysesa | Serious harms | New onset diseasesd | General harmse | ||||||
|---|---|---|---|---|---|---|---|---|---|
| HPV vaccine (N = 47,075) | Comparator (N = 48,595) | Risk ratiof[95% CI] | HPV vaccine (N = 47,075) | Comparator (N = 48,595) | Risk ratiof [95% CI] | HPV vaccine (N = 47,075) | Comparator (N = 48,595) | Risk ratiof [95% CI] | |
| Harms of special interest (MedDRA-preferred terms, n = participants) | |||||||||
| Anaphylaxis | 2 | 4 | 0.59 [0.13, 2.82] | 11 | 8 | 1.18 [0.48, 2.91] | 0 | 0 | Not applicable |
| Chronic fatigue syndrome (CFS) | 0 | 0 | Not applicable | 0 | 0 | Not applicable | 0 | 0 | Not applicable |
| Chronic regional pain syndrome (CRPS) | 0 | 0 | Not applicable | 0 | 0 | Not applicable | 0 | 0 | Not applicable |
| Guillain-Barré syndrome (GBS) | 0 | 0 | Not applicable | 0 | 0 | Not applicable | 0 | 0 | Not applicable |
| Postural orthostatic tachycardia syndrome (POTS) | 0 | 0 | Not applicable | 0 | 0 | Not applicable | 0 | 0 | Not applicable |
| Premature ovarian failure (POF) | 0 | 0 | Not applicable | 1 | 0 | 3.00 [0.12, 73.48] | 0 | 0 | Not applicable |
| Syncope | 4 | 3 | 0.94 [0.23, 3.81] | 62 | 60 | 1.03 [0.58, 1.84] | 7 | 7 | 0.77 [0.25, 2.34] |
| Post hoc exploratory analyses of VigiBase® harm clustersb | |||||||||
| Expected systemic reactions | 25 | 11 | 1.96 [0.96, 3.98] | 1465 | 1358 | 1.03 [0.93, 1.14] | 10,926 | 9948 | Not applicableg |
| Allergic/hypersensitivity reactions | 2 | 2 | 0.96 [0.14, 6.52] | 284 | 279 | 1.05 [0.82, 1.35] | 1912 | 1469 | 1.30 [1.18, 1.45] |
| Vasovagal reactions | 9 | 5 | 1.31 [0.50, 3.46] | 232 | 212 | 1.06 [0.78, 1.44] | 173 | 123 | 1.20 [0.93, 1.55] |
| Post hoc exploratory analyses of CRPS and POTSc | |||||||||
| Harms judged as ‘definitely associated’ with CRPS | 95 | 57 | 1.54 [1.11, 2.14] | 5079 | 4790 | 1.04 [0.98, 1.10] | 27,899 | 23,223 | Not applicableg |
| Harms judged as ‘definitely associated’ with POTS | 56 | 26 | 1.92 [1.21, 3.07] | 3675 | 3352 | 1.08 [1.01, 1.15] | 18,207 | 16,288 | Not applicableg |
aSee Additional file 4 sections 13 and 14 for meta-analyses of the harms of special interest and post hoc exploratory harm analyses. There was no applicable fatal harm of special interest. It was not feasible to present this summary table for the 16 subgroups (based on age group, gender, type of HPV vaccine and comparator) of the 24 included clinical study reports. As we did not obtain complete case report forms or individual participant data, we could not assign harms to individual participants
bAs the included studies’ harm assessments were at risk of low internal and external validity (see Table 1 and the “Discussion” section), we compared the three largest harm clusters reported from pharmacovigilance up to 1 January 2015 to the World Health Organisation’s (WHO) VigiBase with the clinical study report data. We did this to see if the pharmacovigilance data were similar to the study data. VigiBase’s largest HPV vaccine harm cluster (expected systemic reactions) consists of ‘headache, nausea, pyrexia, dizziness and vomiting’. VigiBase’s second largest HPV vaccine harm cluster (allergic/hypersensitivity reactions) consists of ‘pruritis, urticaria, rash and erythema’. VigiBase’s third largest HPV vaccine harm cluster (vasovagal reactions) consists of ‘syncope, dizziness, loss of consciousness, pallor and seizure’. As we synthesised individual MedDRA-preferred term classified harms, our post hoc exploratory analyses of VigiBase harm clusters may therefore include a participant more than once in each separate analysis
cWe asked a physician with clinical expertise in POTS and CRPS to assess the reported MedDRA terms as ‘definitely’, ‘probably’, ‘probably not’ or ‘definitely not’ associated with the syndromes. The physician was blinded to the allocation groups and outcome data. The data was synthesised for those MedDRA-preferred terms that the physician judged ‘definitely’ associated with POTS or CRPS. As we synthesised individual MedDRA-preferred terms, our post hoc exploratory analyses of CRPS and POTS may include a participant more than once in each separate analysis
dNew onset diseases were compiled of the harm categories ‘medically significant conditions’ (for Cervarix) and ‘new medical history’ (for the HPV 16 vaccine, Gardasil and Gardasil 9)
eGeneral harms were compiled of the harm categories ‘solicited general adverse events’, ‘unsolicited general adverse events’ (for Cervarix) and ‘systemic adverse events’ (for Gardasil, Gardasil 9 and the HPV 16 vaccine)
fRisk ratios were calculated with the random-effects inverse variance method
gSome numerators exceeded the denominators making the result nonsensical. Therefore, we did not perform meta-analyses