Benefits and harms of the human papillomavirus (HPV) vaccines: systematic review with meta-analyses of trial data from clinical study reports

Jørgensen, Lars; Gøtzsche, Peter C.; Jefferson, Tom

doi:10.1186/s13643-019-0983-y

Systematic Reviews

Table 9 Benefits and harms of the HPV vaccines: summary of harms of special interest and post hoc exploratory harm analyses

From: Benefits and harms of the human papillomavirus (HPV) vaccines: systematic review with meta-analyses of trial data from clinical study reports

Summary of harms of special interest and post hoc exploratory harm analyses^a	Serious harms			New onset diseases^d			General harms^e
	HPV vaccine (N = 47,075)	Comparator (N = 48,595)	Risk ratio^f[95% CI]	HPV vaccine (N = 47,075)	Comparator (N = 48,595)	Risk ratio^f [95% CI]	HPV vaccine (N = 47,075)	Comparator (N = 48,595)	Risk ratio^f [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 clusters^b
Expected systemic reactions	25	11	1.96 [0.96, 3.98]	1465	1358	1.03 [0.93, 1.14]	10,926	9948	Not applicable^g
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 POTS^c
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 applicable^g
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 applicable^g

^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

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ISSN: 2046-4053

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