Key messages
HPV vaccination:
- reduces the incidence of cervical cancer by around 80% in people vaccinated at or before the age of 16 years;
- reduces the incidence of high-grade cervical pre-cancer lesions, as well as anogenital warts;
- is not associated with an increased risk of long-term side effects or infertility;
- is more effective when given at or before the age of 16 years, before onset of sexual activity.
What is HPV?
Human papillomavirus (HPV) is transmitted between people through sexual contact, including vaginal, anal or oral sex. There are many types of HPV. Some types are harmless, but other types can cause cancer. Cervical cancer is the most common type of cancer that HPV can cause, but it can also cause vaginal, vulval, penile, anal, and head and neck cancer, as well as anogenital warts (a sexually transmitted infection caused by certain types of human papillomavirus). From the time of HPV infection, cervical cancer usually takes more than 10 years to develop, and other cancers take longer.
How can HPV vaccines be beneficial?
In girls and boys, HPV vaccines aim to prevent HPV infection, which can sometimes cause cancer and anogenital warts. The HPV vaccines do not work well in people that have already been exposed to HPV. For this reason, most vaccination programmes aim to offer the vaccine to young people before they become sexually active.
What did we want to find out?
We wanted more information on questions about long-term and rare outcomes that cannot be answered by randomised controlled trials (studies where people are assigned randomly to two or more treatment groups):
- What are the effects of introducing HPV vaccination on community rates of cervical, vaginal, vulval, anal and penile cancer, and the pre-cancerous stages of disease during the development of cancer?
- What are the effects of introducing HPV vaccination on the number of people who develop anogenital warts and the number of people who undergo treatment for HPV-related disease?
We also wanted to know if HPV vaccines were associated with any harmful effects, especially those discussed most frequently on social media.
What did we do?
We searched for studies that evaluated the impact of HPV vaccination on population levels of cervical and other cancers, high-grade pre-cancer lesions (abnormal cell changes that occur after a persistent high-risk HPV infection and can develop into cancer if untreated), anogenital warts, treatment rates, HPV infections and unwanted or harmful (adverse) events. These included studies following groups of people after receiving HPV vaccination and studies observing the change in these diseases after national-level introduction of HPV vaccination.
We also searched social media sites (WebMD and X (formerly Twitter)) for commonly mentioned adverse events related to HPV vaccination. We searched for and included studies evaluating the impact of HPV vaccination on these events.
What did we find?
We found 225 suitable studies from around the world that reported on the benefits and harms of HPV vaccination, including over 132 million people.
HPV vaccination probably reduces the incidence of cervical cancer by around 80% in people vaccinated at or before the age of 16 years. The reduction is lower for people vaccinated later.
HPV vaccination probably reduces the incidence of high-grade cervical pre-cancer lesions (CIN3+, CIN3, CIN2+ and CIN2), as well as anogenital warts. Again, reductions are greater in people who received the HPV vaccine at or before the age of 16 years.
There was lower-certainty evidence for the effect of HPV vaccination on rare diseases that take much longer to develop, such as adenocarcinoma in situ, other pre-cancer lesions and other cancers related to HPV (e.g. vaginal, vulval, anal and penile cancer). We identified fewer studies on these outcomes.
For most of the specific adverse events we looked at, including postural orthostatic tachycardia syndrome, chronic fatigue syndrome/myalgic encephalomyelitis, paralysis, complex regional pain syndrome, Guillain-Barré syndrome and infertility, there was moderate-certainty evidence that HPV vaccination likely does not increase the risk of developing them. HPV vaccination also did not increase sexual activity.
HPV vaccination also appears to reduce treatment rates associated with HPV disease, increases attendance at cervical screening programmes and reduces HPV infections.
What are the limitations of the evidence?
We are moderately confident in our results for cervical cancer, high-grade cervical disease, anogenital warts and specific harms. However, better and larger studies could show more reliable and precise results about the amount of protection.
How up-to-date is this evidence?
The evidence is up-to-date to September 2024.
阅读完整摘要
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.
研究目的
We aimed to assess population-level effects of HPV vaccination programmes on HPV-related disease and harms from vaccination.
检索策略
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.
纳入排除标准
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.
资料收集与分析
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.
主要结果
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).
作者结论
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.
