A Cochrane review [Abstract] 1 included 26 trials with a total of 73 428 participants. Persistent infection with high-risk human papillomaviruses (hrHPV) types is causally linked with the development of cervical intraepithelial neoplasia grade 2 and above (CIN2+), CIN grade 3 and above (CIN3+), and cervical cancer. HPV types 16 and 18 cause approximately 70% of cervical cancers worldwide. Studies were not of sufficient duration to evaluate cervical cancer outcomes. In adolescent girls and women (aged 15 to 26) negative for hrHPV DNA at baseline, HPV vaccines reduce CIN2+, CIN3+, adenocarcinoma-in-situ (AIS) associated with HPV16/18 compared with placebo in adolescent girls and women (table T1). In those HPV16/18 negative(aged 15 to 26 years), vaccines reduce CIN2+ associated with HPV16/18 from 113 to 6 /10 000 (RR 0.05, 95% CI 0.03 to 0.10). In women 24 years or older the absolute and relative reduction in the risk of these lesions is smaller (from 45 to 14/10,000; RR 0.30, 95% CI 0.11 to 0.81). HPV vaccines reduce the risk of CIN3+ and AIS associated with HPV16/18 in younger women (RR 0.05, 95% CI 0.02 to 0.14), and (RR 0.09, 95% CI 0.01 to 0.72), respectively. The risk of serious adverse events was similar between control and HPV vaccines in women of all ages (669 versus 656/10 000, RR 0.98, 95% CI 0.92 to 1.05; high certainty).
| Outcome | Relative effect(95% CI)RR | Risk with placebo | Risk with HPV vaccination (95% CI) | №of participants(studies)Certainty of evidence |
|---|---|---|---|---|
| CIN2+ associated with HPV16/18.Follow-up: 3 to 5 years | 0.01(0.00 to 0.05) | 164 per 10 000 | 2 per 10 000(0 to 8) | 23 676(3) High |
| CIN3+ associated with HPV16/18.Follow-up: 3 to 5 years | 0.01(0.00 to 0.10) | 70 per 10 000 | 0 per 10 000(0 to 7) | 20 214(2) High |
| Adenoca in situ associated with HPV16/18.Follow-up: 3 to 5 years | 0.10(0.01 to 0.82) | 9 per 10 000 | 0 per 10 000(0 to 7) | 20 214(2) Moderate |
| Any CIN2+ irrespective of HPV type, bivalent or quadrivalent vaccineFollow-up: 2 to 6 years | 0.37(0.25 to 0.55) | 287 per 10 000 | 106 per 10 000(72 to 158) | 25 180 (5) High |
| Any CIN3+ irrespective of HPV typeFollow-up (bivalent): 4 years | 0.08(0.03 to 0.23) | 81 per 10 000 | 6 per 10 000(3 to 19) | 11 423(2) High |
| Any CIN3+ irrespective of HPV type Follow-up (quadrivalent): 3.5 years | R0.54(0.36 to 0.82) | 143 per 10 000 | 77 per 10 000(51 to 117 ) | 9296(1) Moderate |
A meta-analysis 2 included 65 articles in 14 high-income countries (60 million individuals): 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+. After 5-8 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0.17, 95% CI 0.11 to 0.25) among girls aged 13-19 years, and decreased significantly by 66% (RR 0.34, 95% CI 0.23 to 0.49) among women aged 20-24 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0.46, 95% CI 0.33 to 0.66) among girls aged 13-19 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0.33, 95% CI 0.24 to 0.46) among girls aged 15-19 years, decreased significantly by 54% (RR 0.46, 95% CI 0.36-0.60) among women aged 20-24 years, and decreased significantly by 31% (RR 0.69, 95% CI 0.53 to 0.89) among women aged 25-29 years. Among boys aged 15-19 years anogenital wart diagnoses decreased significantly by 48% (RR 0.52, 95% CI 0.37 to 0.75) and among men aged 20-24 years they decreased significantly by 32% (RR 0.68, 95% CI 0.47 to 0.98). After 5-9 years of vaccination, CIN2+ decreased significantly by 51% (RR 0.49, 95% CI 0.42 to 0.58) among screened girls aged 15-19 years and decreased significantly by 31% (RR 0.69, 95% CI 0.57 to 0.84) among women aged 20-24 years.
A retrospective population study 3 in Scotland included 138 692 women born between 1 January 1988 and 5 June 1996 and who had a smear test result recorded at age 20. Compared with unvaccinated women born in 1988, vaccinated women born in 1995 and 1996 showed an 89% reduction (95% CI 81% to 94%) in prevalent cervical intraepithelial neoplasia (CIN) grade 3 or worse (from 0.59% (0.48% to 0.71%) to 0.06% (0.04% to 0.11%)), an 88% reduction (83% to 92%) in CIN grade 2 or worse (from 1.44% (1.28% to 1.63%) to 0.17% (0.12% to 0.24%)), and a 79% reduction (69% to 86%) in CIN grade 1 (from 0.69% (0.58% to 0.63%) to 0.15% (0.10% to 0.21%)). Younger age at immunisation was associated with increasing vaccine effectiveness: 86% (75% to 92%) for CIN grade 3 or worse for women vaccinated at age 12-13 compared with 51% (28% to 66%) for women vaccinated at age 17. Evidence of herd protection against high grade cervical disease was found in unvaccinated girls in the 1995 and 1996 cohorts.
Another Cochrane review [Abstract] 4 included 20 trials with a total of 31 940 participants. For females aged 9-15 years, the antibody responses after 2 doses vs 3 doses schedules were similar after up to 5 years of follow-up (bivalent, quadrivalent, and nonavalent vaccines, 4 RCTs). Evidence about serious adverse events in studies comparing dose schedules was of very low-certainty owing to imprecision and indirectness (3 doses 35/1159; 2 doses 36/1158; 4 RCTs). For females and males aged 9-14 years, the antibody responses were stronger with a longer interval (6 or 12 months) between the first two doses of HPV vaccine than a shorter interval (2 or 6 months) at up to 3 years of follow-up (4 RCTs).
A study 5 using nationwide Swedish registers assessed the relationship between quadrivalent HPV vaccination and risk of invasive cervical cancer in a population of 1 672 983 girls and women who were 10 to 30 years of age from 2006 through 2017. After adjustment for age at follow-up, the incidence rate ratio for the comparison of the vaccinated population with the unvaccinated population was 0.51 (95% CI 0.32 to 0.82). After adjustment for all covariates, the incidence rate ratio was 0.12 (95% CI 0.00 to 0.34) among women who had been vaccinated before the age of 17 years and 0.47 (95% CI 0.27 to 0.75) among women who had been vaccinated at the age of 17 to 30 years.
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