Table 7.
Benefits and harms of the HPV vaccines: summary of general harms
| Summary of general harmsa | HPV vaccine total (N = 47,075) | Comparator total (N = 48,595) | Risk ratiof total [95% CI] | Risk ratiof SGAE [95% CI] | Risk ratiof UGAE [95% CI] | Risk ratiof SYAE [95% CI] |
|---|---|---|---|---|---|---|
| Total | ||||||
| Participants with general harmsb | 13,248 | 12,394 | 1.07 [1.03, 1.11] | 1.11 [1.06, 1.16]g | 1.11 [1.06, 1.16]g | 1.01 [0.98, 1.03] |
| Number of MedDRA-classified general harmsb | 37,999 | 31,916 | Not applicable | Not applicable | Not applicable | Not applicable |
| Solicited general adverse events (SGAE)c | 30,408 (80%) | 25,300 (79%) | Not applicable | Not applicable | Not applicable | Not applicable |
| Unsolicited general adverse events (UGAE)d | 3197 (8%) | 3136 (10%) | Not applicable | Not applicable | Not applicable | Not applicable |
| Systemic adverse events (SYAE)e | 4394 (12%) | 3480 (11%) | Not applicable | Not applicable | Not applicable | Not applicable |
| Most common general harms (MedDRA-preferred terms, n = participants) | ||||||
| SGAE and UGAE | ||||||
| Fatigue | 4933 | 4489 | 1.13 [1.08, 1.18] | 1.14 [1.09, 1.19] | 1.00 [0.15, 6.53] | 0.92 [0.70, 1.20] |
| Headache | 5561 | 5246 | 1.06 [1.02, 1.11] | 1.08 [1.03, 1.14] | 1.76 [1.26, 2.47] | 0.98 [0.90, 1.07] |
| Myalgia | 3989 | 3047 | 1.41 [1.24, 1.60] | 1.42 [1.24, 1.63] | 1.15 [0.24, 5.57] | 1.33 [0.95, 1.85] |
| SYAE | ||||||
| Headache | 5561 | 5246 | 1.06 [1.02, 1.11] | 1.08 [1.03, 1.14] | 1.76 [1.26, 2.47] | 0.98 [0.90, 1.07] |
| Pyrexia | 1599 | 1386 | 1.12 [1.02, 1.22] | 1.15 [1.06, 1.25] | 1.47 [0.93, 2.34] | 1.05 [0.80, 1.36] |
| Nasopharyngitis | 339 | 277 | 1.17 [0.91, 1.50] | Not applicable | 1.40 [0.94, 2.09] | 0.95 [0.78, 1.16] |
| General harms most increased by the HPV vaccines (MedDRA-preferred terms, n = participants) | ||||||
| SGAE and UGAE | ||||||
| Fatigue | 4933 | 4489 | 1.13 [1.08, 1.18] | 1.14 [1.09, 1.19] | 1.00 [0.15, 6.53] | 0.92 [0.70, 1.20] |
| Headache | 5561 | 5246 | 1.06 [1.02, 1.11] | 1.08 [1.03, 1.14] | 1.76 [1.26, 2.47] | 0.98 [0.90, 1.07] |
| Myalgia | 3989 | 3047 | 1.41 [1.24, 1.60] | 1.42 [1.24, 1.63] | 1.15 [0.24, 5.57] | 1.33 [0.95, 1.85] |
| SYAE | ||||||
| Myalgia | 3989 | 3047 | 1.41 [1.24, 1.60] | 1.42 [1.24, 1.63] | 1.15 [0.24, 5.57] | 1.33 [0.95, 1.85] |
| Nausea | 213 | 148 | 1.21 [0.89, 1.65] | Not applicable | 1.32 [0.35, 4.98] | 1.25 [0.84, 1.86] |
| Pyrexia | 1599 | 1386 | 1.12 [1.02, 1.22] | 1.15 [1.06, 1.25] | 1.47 [0.93, 2.34] | 1.05 [0.80, 1.36] |
| General harms most decreased by the HPV vaccines (MedDRA-preferred terms, n = participants) | ||||||
| SGAE and UGAE | ||||||
| Influenza | 119 | 120 | 0.91 [0.61, 1.36] | Not applicable | 0.88 [0.39, 1.97] | 0.94 [0.56, 1.58] |
| Cough | 86 | 87 | 0.89 [0.65, 1.21] | Not applicable | 0.83 [0.46, 1.49] | 0.90 [0.60, 1.37] |
| Oropharyngeal pain | 111 | 97 | 1.10 [0.80, 1.50] | Not applicable | 0.91 [0.58, 1.43] | 1.29 [0.75, 2.22] |
| SYAE | ||||||
| Fungal infection | 4 | 11 | 0.78 [0.09, 6.43] | Not applicable | 3.01 [0.31, 28.83] | 0.18 [0.04, 0.82] |
| Sinus headache | 9 | 15 | 0.49 [0.21, 1.14] | Not applicable | Not applicable | 0.49 [0.21, 1.14] |
| Joint injury | 2 | 5 | 0.47 [0.11, 2.01] | Not applicable | 3.01 [0.31, 28.83] | 0.15 [0.03, 0.88] |
aSee Additional file 4 section 12 for meta-analyses of general harms for the 16 subgroups (based on age group, type of HPV vaccine and comparator) of the 24 included clinical study reports. The applied harm categories are MedDRA-preferred terms. The table contains general harms of ‘solicited general adverse events’ (SGAE), ‘unsolicited general adverse events’ (UGAE) and ‘systemic adverse events’ (SYAE). Numbers for ‘HPV vaccine’ and ‘comparator’ are the total of SGAE, UGAE and SYAE, but to avoid double counting of participants, UGAE (that accounted for less than 10% of the general harms) were dismissed from the total risk ratio for studies that reported SGAE and UGAE separately (SGAE and UGAE were not reported as pooled estimates for individual general harms classified with MedDRA-preferred terms; see Additional file 4). It was not feasible to present this summary table for the 16 subgroups (based on age group, type of HPV vaccine and comparator) of the 24 included clinical study reports
bThe clinical study reports reported 69,915 individual MedDRA-classified general harms for 25,642 participants, i.e. 2.7 general harms per participant. General harms were reported as the number of participants with a MedDRA-classified general harm over the total number of participants
cGlaxoSmithKline defined ‘solicited general adverse events’ (SGAE) as “Adverse events to be recorded [from day 0 to day 6 after each vaccination] as endpoints [arthralgia, fatigue, headache, myalgia, pyrexia, rash and urticaria] in the clinical study”
dGlaxoSmithKline defined ‘unsolicited general adverse events’ (UGAE) as “Any AE [adverse event] reported in addition to those solicited during the clinical study. Also, any “solicited” symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited AE”
eMerck Sharp and Dohme defined ‘systemic adverse events’ (SYAE) as “any systemic clinical adverse event that developed on the day of vaccination or during the 14 days after vaccination was recorded on the VRC [vaccination report card]”
fRisk ratios were calculated with the random-effects inverse variance method
gThe total numbers of participants with general harms in Cervarix studies were reported as ‘solicited [SGAE] and unsolicited [UGAE]’, i.e. the risk ratio is similar for SGAE and UGAE