Key messages
- In women and girls aged 15 to 25 years receiving human papillomavirus (HPV) vaccination with Cervarix, Gardasil or Gardasil-9, compared with no HPV vaccination, there was a slight reduction in high-grade cervical pre-cancer (abnormal-looking cells that may become cancer if left untreated) after four to six years. In those vaccinated with Gardasil or Gardasil-9 compared with no vaccination, there was a small reduction in pre-cancer of the vulva and vagina after four years. HPV vaccination reduced the risk of anogenital warts and the need for treatment for HPV-related disease. No study lasted long enough to report on the development of cancers.
- Some pain and swelling at the injection site were common after HPV vaccination, but we found no serious unwanted effects.
- Most studies included people aged 15 years and over, who are more likely to have been exposed to the infection and therefore less likely to benefit from vaccination. The trials were too short to measure long-term outcomes like the development of cancer.
What is human papillomavirus (HPV)?
HPV is a common infection. It is transmitted between people through close contact, including vaginal, anal or oral sex. There are many types of HPV. Some types can cause cancer. Cervical cancer is the most common type, but it can also cause vaginal, vulval, penile, anal, and head and neck cancer, and anogenital warts, so HPV can affect both men and women. Cervical cancer usually takes more than 10 years to develop after initial infection. Other HPV-related cancers develop more slowly.
How can HPV vaccines help?
HPV vaccines aim to prevent the types of HPV infections that sometimes cause cancers and anogenital warts. The HPV vaccines do not work as well in people that have already been exposed to HPV, so most vaccination programmes are for young people before they become sexually active.
What did we want to find out?
We wanted to find out if HPV vaccines:
- prevent cancers and pre-cancers (abnormal-looking cells that may become cancer if left untreated);
- reduce the need for treatment of HPV-related disease;
- prevent anogenital warts; and
- cause any unwanted effects.
What did we do?
We searched for studies that compared:
- an HPV vaccine with either a placebo (a dummy vaccine), a non-HPV vaccine or no vaccine; or
- different HPV vaccines or number of doses of HPV vaccines.
We compared and summarised the results, and rated our confidence in the evidence, based on factors such as study methods and sizes. We were supported by an Independent Advisory Group, including consumers.
What did we find?
We found 60 studies with 157,414 people. The biggest study involved 34,412 people and the smallest 11 people. They were followed from 4 days to 11 years. Studies took place around the world. Most lasted for 12 months. Pharmaceutical companies funded 44 of the studies.
Main results
- The studies were not long enough to tell us directly about prevention of cancers and focussed on shorter-term outcomes.
- In women and girls aged 15 to 25 years, Cervarix and Gardasil reduced all high-grade cervical pre-cancer (CIN2+) in the short term. In women over 25 years, there was little to no difference.
- In people aged 15 to 25 years, there was little to no difference in high-grade anal or penile pre-cancer in the short term. Gardasil and Gardasil-9 vaccines reduced high-grade vaginal or vulval pre-cancer in this group of people.
- HPV vaccination reduced the risk of anogenital warts and the number of people aged 15 to 25 years needing treatment for possible early-stage HPV-related cancer.
- Some pain and swelling were common after all HPV vaccines, but there were no serious unwanted effects. We do not know whether there are differences in risks between different vaccines.
What are the limitations of the evidence?
We had some concerns about the way some studies were done, which might affect some results. We are moderately confident in the evidence for serious unwanted effects, treatment of HPV-related disease, cervical, vaginal and vulval pre-cancer, and anogenital warts. We are less confident in the evidence on cancer and penile and anal pre-cancer because there were few cases, studies were too short to measure cancer and people in the studies were older than people who receive the vaccines.
Many studies were industry-funded, but we found no differences compared with independently funded studies.
How up-to-date is this evidence?
The evidence is current to 18 September 2024.
Read the full abstract
Cervical cancer is the fourth most common cause of cancer-related death amongst females worldwide. Persistent infection with high-risk human papillomavirus (HPV) is the key factor in cervical cancer development. HPV vaccines aim to prevent cancer by generating antibodies against HPV infection.
Objectives
To evaluate the safety and efficacy of HPV vaccines, in females and males, to prevent cervical cancer and other HPV-related diseases, in standard (pairwise) and network meta-analysis (NMA) of randomised controlled trials.
Search strategy
On 10 January 2022, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase. We searched Epistemonikos, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, the Health Technology Assessment database and vaccine manufacturer websites, and we checked reference lists from other relevant systematic reviews. We applied for Clinical Study Reports (CSRs) from the European Medicines Agency. An update search of electronic databases was done on 18 September 2024.
Selection criteria
We included randomised controlled trials (RCTs) regardless of language or publication status, assessing HPV vaccines pre-qualified by the World Health Organization (WHO) (Cervarix, Gardasil, Gardasil-9 and Cecolin).
Data collection and analysis
We used methods recommended by Cochrane. We primarily used CSRs to collect data, and we included outcome data irrespective of participants' baseline HPV infection or serostatus. We assessed risk of bias using the Cochrane tool (RoB 2). All outcomes were dichotomous, and we estimated risk ratios (RR) with 95% confidence intervals (CI). We used pairwise analysis for all outcomes. Where data were available, we carried out NMA for critical outcomes for networks in females and males in three age groups, ranking the vaccines using surface under the cumulative ranking curve (SUCRA) and mean ranks. We assessed the certainty of evidence using the GRADE approach.
Main results
We included 60 individual studies with 157,414 participants ranging in follow-up from seven months to 11 years. Few participants were under 15. There were no studies for males under 15 years and males over 25 years. We obtained CSRs for 33 of the included studies. We assessed the risk of bias as low to 'some concerns' for the critical outcomes.
Cancer and pre-cancer outcomes
The studies were not of sufficient duration for cancers to develop. Four studies reported on cancer. No cancers were detected.
Critical pre-cancer outcomes were reported in 15- to 25-year-old populations by 11 studies and in > 25-year-old females by three studies with up to seven years follow-up. None were reported in the under 15 years age group.
In 15- to 25-year-old females, there was a reduction in CIN2+ irrespective of HPV type after six years (RR 0.70, 95% CI 0.56 to 0.88) (moderate-certainty) and a larger reduction in CIN2+ from vaccine-matched HPV types after six years (RR 0.40, 95% CI 0.30 to 0.54) (moderate-certainty). In females over 25 years old, there was little to no difference between Cervarix and Gardasil compared with control (moderate-certainty). There was no evidence on CIN2+ irrespective of HPV type from studies assessing Cecolin, or from studies assessing different dose schedules.
In 15- to 25-year-old females, there was a slight reduction in vaccine-matched HPV-type high-grade vulval (VIN) or vaginal (VaIN) intraepithelial neoplasia following vaccination with Gardasil or Gardasil-9 (moderate-certainty). The NMA found a slight reduction of 1 case per 1000 following Gardasil (RR 0.21, 95% CI 0.1 to 0.45) and 0 cases per 1000 following Gardasil-9 (RR 0.16, 95% CI 0.05 to 0.51). Little to no difference was found in the NMA for Cervarix compared with control (RR 0.28, 95% CI 0.06 to 1.37), or for Cervarix, Gardasil and Gardasil-9 compared to each other.
There was a reduction in high-grade anal intraepithelial neoplasia (AIN) irrespective of HPV type in the Gardasil group in one study in men who have sex with men (RR 0.75, 95% CI 0.53 to 1.07) (low-certainty).
For both high-grade penile intraepithelial neoplasia (PeIN) irrespective of HPV type and vaccine-matched HPV-type high-grade PeIN, little to no difference per 1000 participants was reported in the Gardasil group in one study with 3880 participants at 36 months follow-up (RR 1.00, 95% CI 0.20 to 4.93) (low-certainty).
Serious adverse events
In a pairwise analysis of serious adverse events in 39 studies across all vaccine types with 97,272 participants, there was little to no difference in the HPV vaccine groups compared with the control group at up to 72 months follow-up (RR 0.99, 95% CI 0.94 to 1.04) (high-certainty).
Treatment rates for HPV-related pre-invasive disease
In pairwise analysis of five studies with 38,606 participants, there were 12 fewer people that needed to seek treatment per 1000 participants (95% CI 5 to 17 fewer per 1000) in the HPV vaccine groups compared with the control group rate at up to 84 months follow-up (RR 0.76, 95% CI 0.65 to 0.89) (moderate-certainty).
Anogenital warts
In pairwise analysis of three studies with 21,271 participants, there were 25 fewer cases of anogenital warts irrespective of HPV type per 1000 participants (95% CI 22 to 28 fewer per 1000) in the HPV vaccine groups compared with the control group rate at up to 48 months follow-up (RR 0.38, 95% CI 0.32 to 0.46) (high-certainty). In the NMA for females 15 to 25 years old, Gardasil-9 was most likely to reduce the risk of developing anogenital warts.
Authors' conclusions
The evidence in this network meta-analysis of HPV vaccines is based on extensive searches and analyses. There is evidence from randomised controlled trials that HPV vaccination reduces the risk of pre-cancerous outcomes such as CIN2+ and anogenital warts. No data were available for cervical cancer or other cancer outcomes, and no data on pre-cancer outcomes were available for vaccination under age 15 years. There were no safety concerns noted in the studies.
