BACKGROUND: Human papillomavirus (HPV) vaccination has the potential to enhance prevention of cervical cancer, especially in countries where screening programmes are currently unaffordable or impractical. Rare adverse events and longer-term benefits of HPV vaccination, such as effects on cancer rates, are difficult to examine in randomised controlled trials (RCTs) and require large data from population-level studies to inform decision-making.
OBJECTIVES: We aimed to assess population-level effects of HPV vaccination programmes on HPV-related disease and harms from vaccination.
SEARCH METHODS: We conducted electronic searches on 11 September 2024 in CENTRAL (Cochrane Library), Ovid MEDLINE and Ovid Embase. We also searched vaccine manufacturer websites and checked reference lists from an index of HPV studies and other relevant systematic reviews.
SELECTION CRITERIA: We included studies that assessed the impact of HPV vaccination on the general population. This included population-level studies comparing outcomes before and after the introduction of HPV vaccine. We also included individual-level, non-randomised comparative studies, such as cohort studies, case-control studies, cross-sectional studies and self-controlled case series.
DATA COLLECTION AND ANALYSIS: We used methods recommended by Cochrane. Two review authors carried out data extraction independently using pretested data extraction forms. We assessed the risk of bias of all included effect estimates using different tools according to study design. We carried out quantitative and qualitative data synthesis separately by outcome and study design. We performed meta-analysis on studies that reported effect estimates adjusted for confounding, with a focus on those receiving HPV vaccination at or before the age of 16 years (the target age group for vaccination). We rated the certainty of the evidence with GRADE.
MAIN RESULTS: We included 225 studies from 347 records in this review, evaluating over 132 million people. We included 86 cohort studies, four case-control studies, 46 cross-sectional studies, 69 pre-post vaccine introduction studies, five RCT extensions and two self-controlled case series. Thirteen additional studies reported on more than one type of analysis. Of the included studies, 177 reported only on females, 11 only males and 37 a combination of males and females. Risk of bias ranged from overall moderate risk to critical risk. Clinical outcomes There was moderate-certainty evidence from 20 studies that HPV vaccination reduces the incidence of cervical cancer. Five cohort studies including 4,390,243 females reported adjusted estimates showing a reduced risk of cervical cancer following HPV vaccination in the long term (risk ratio (RR) 0.37, 95% confidence interval (CI) 0.25 to 0.56; I2 = 88%). There was a significant interaction with age at vaccination, with a greater risk reduction in younger people. For those vaccinated at or before 16 years of age, covering 4.54 million person-years, there was an 80% reduced risk of cervical cancer (RR 0.20, 95% CI 0.09 to 0.44; I2 = 69%). One cohort study, one case-control study, one cross-sectional study and three RCT extension studies all reported no cases of cervical cancer in the HPV vaccine groups. Eight pre-post vaccine introduction studies each reported a reduction in cervical cancer incidence following HPV vaccine introduction but did not provide data in a form that allowed for meta-analysis. There was moderate-certainty evidence from 23 studies that HPV vaccination reduces the incidence of cervical intraepithelial neoplasia grade 3 or higher (CIN3+), including 12 cohort studies. For 1.5 million females vaccinated at or before the age of 16 years in two cohort studies, there was a reduction of CIN3+ incidence of 74% in the long term (RR 0.26, 95% CI 0.12 to 0.56; I2 = 80%). Three case-control studies, one RCT extension study and three cross-sectional studies also reported a decreased risk of CIN3+ in vaccinated participants. One cross-sectional study reported no difference in the risk of CIN3+. Three pre-post vaccine introduction studies reported a decrease in CIN3+ incidence following HPV vaccine introduction. There was moderate-certainty evidence from 37 studies that HPV vaccination reduces the incidence of CIN2+. In cohort studies with females vaccinated at or before the age of 16 years, a reduction in risk was seen in the medium term (RR 0.59, 95% CI 0.54 to 0.65; 2 cohort studies, 233,468 females; I2 = 0%) and long term (RR 0.38, 95% CI 0.31 to 0.45; 5 cohort studies, 6,455,176 females; I2 = 64%). There was moderate-certainty evidence from 47 studies that HPV vaccination reduces the incidence of anogenital warts. From the cohort studies with adjusted estimates, the pooled impact of HPV vaccination on rates of anogenital warts indicated a reduction of 47% in the medium term (RR 0.53, 95% CI 0.37 to 0.77; 4 studies, 6,430,295 females and 313 males; I2 = 98%) and 53% in the long term (RR 0.47, 95% CI 0.36 to 0.61; 13 studies, 4.5 million person-years plus 5,802,969 females and males; I2 = 99%). Twenty-three pre-post vaccine introduction studies reported a decrease in anogenital warts incidence following the introduction of HPV vaccine. Six studies reported no difference in anogenital warts incidence. There was only very low-certainty evidence on the effect of HPV vaccination on the incidence of adenocarcinoma in situ (three studies) and vulval cancer (five studies). No studies were identified that reported on community rates of serious adverse events following HPV vaccination. Specific adverse events Across a range of study designs, HPV vaccination was not associated with an increased risk of postural orthostatic tachycardia syndrome, chronic fatigue syndrome/myalgic encephalomyelitis, paralysis, complex regional pain syndrome, premature ovarian failure, infertility or sexual activity (all moderate-certainty evidence). There was evidence that suggests HPV vaccination was not associated with an increased risk of Guillain-Barré syndrome (low-certainty evidence).
AUTHORS' CONCLUSIONS: There are now long-term outcome data from different countries and from different study designs that consistently report a reduction in the development of high-grade CIN and cervical cancer in females vaccinated against HPV in early adolescence. Data show that there is greater benefit to vaccinating younger adolescents prior to becoming sexually active. There is evidence that HPV vaccination does not increase the risk of the most common adverse events reported on social media.
| Discipline Area | Score |
|---|---|
| Physician |  |
Physician rater
Millions of people across 225 studies. Heterogeneity for cervical cancer 88%, CIN3 80%, and anogenital warts 98% signals differences in study design, population, vaccine coverage, follow-ups, and healthcare infrastructure. Generalizability is skewed, as mostly weighted toward high-income country regions. Screening, access, herd immunity, population mobility, and sexual behaviour patterns matter. A wide confidence interval for cervical cancer and vaccination under 16 years implies imprecision for the above reasons. It is reassuring to note that side effects are not alarming.
Physician rater
This review adds the evidence for prevention of cervical cancer, pre-cancerous lesions, and anogenital warts with HPV vaccination. Although many countries have a screening programme, this shows the importance of HPV vaccination in all countries, even when screening isn't available.
Physician rater
This systematic review offers my Public Health motivated primary care group practice the impetus that the HPV vaccines mitigate the risks of anogenital warts by 47% in five cohort studies. The relative risk reported by these researchers was 53%, with a 95% confidence interval of 37% to 77%.
, McMaster University