Comparison of different human papillomavirus (HPV) vaccine types and dose schedules for prevention of HPV‐related disease in females and males

22 Nov 2019

Human papillomaviruses (HPV) are a group of viruses that infect the skin and mucous membranes. Some types of HPV are sexually transmitted and are common in young people. Most infections will be cleared by the immune system, but some people will experience persistent infection with certain HPV types that go on to cause abnormalities in infected cells. These changes are called 'precancerous' because they can develop into cancers of the cervix, vagina, vulva, anal canal, penis, and head and neck. Infection with other HPV types causes warts in the genital area or around the anus.

Vaccination aims to prevent future HPV infections. Three HPV vaccines are in use – a bivalent one (protects against two HPV types), a quadrivalent one (protects against four HPV types), and a nonavalent one (protects against nine HPV types). In women, three doses of the bivalent or the quadrivalent HPV vaccines protect against precancer of the cervix caused by the HPV types contained in the vaccine. Evidence about the nonavalent vaccine, about the effects of the quadrivalent vaccine in males, and about the effects of HPV vaccines in people with HIV infection, has not yet been reviewed thoroughly. Uptake of HPV vaccines remains low in many countries. Simpler vaccine schedules, or giving the vaccine to both girls and boys, could increase the number of people being vaccinated.

Trials of HPV vaccines are not always designed to collect data about precancer and cancer, for several reasons. Firstly, HPV vaccine is routinely given before girls become sexually active, and it is not ethical to take specimens from the cervix of girls who have not had sex. Secondly, HPV‐related precancer and cancer are rare and do not develop until years after HPV infection has occurred. Thirdly, participants in a trial will be offered treatment if precancer develops, so progression to cervical cancer would be even rarer, even without vaccination. An international committee of experts states that, in some circumstances, antibody levels (i.e. showing a strong immune system response), can be used to demonstrate protection against cervical and anal cancer. The antibody levels following vaccination in a trial should not be lower than those found in other studies on adults in whom the vaccine has been shown to protect against severe HPV‐related cervical or anal disease.

Review question(s)

How effective or harmful are different HPV vaccine schedules (i.e. number and timing of doses) and different HPV vaccines in females and males?

Main results

These results are based on research evidence to 27 September 2018. We analysed 20 studies involving 31,940 people.

Studies comparing two doses of HPV vaccine to three doses, or comparing the time interval between doses, focus on immune system responses rather than infection or disease outcomes. Two doses of HPV vaccine result in similar immune system responses to three doses, and a longer interval (up to 12 months) between doses gives a stronger immune system response than a shorter interval. There is insufficient evidence to determine whether there was a difference between the vaccine schedules for serious adverse events and death.

In 16‐ to 26‐year‐old men, one study showed evidence of moderate certainty that a quadrivalent HPV vaccine provides better protection against external genital lesions and genital warts than a dummy treatment (control). In 16‐ to 26‐year‐old women, one study showed that the nonavalent and quadrivalent vaccines provide the same levels of protection against cervical, vaginal, and vulval precancer lesions and cancer (high‐certainty evidence).

There was evidence that the quadrivalent vaccine resulted in more local adverse events (such as pain, swelling, and redness at the injection site) than a control treatment in males, and that the nonavalent vaccine resulted in more local adverse events than the quadrivalent vaccine in males and females. Evidence about serious adverse events and deaths from studies comparing different HPV vaccine types or dose schedules was of low or very low‐certainty.

In people living with HIV, HPV vaccines result in reasonable levels of immune system response, but evidence about their effects on persistent HPV infection or HPV‐related disease outcomes and harms is limited.

Certainty of the evidence

No major issues were identified with the methodological quality of the studies for the measurements of infection and disease outcomes, or for immune system responses. Our certainty in the evidence about serious harms and deaths across all the studies comparing different HPV vaccines and vaccine schedules is low, either because of their low frequency, or because the evidence is indirect, or both. Evidence graded as high certainty means that we were confident that further research is unlikely to change our findings. Moderate‐certainty evidence means that there is a possibility that further research may have an important effect on our findings, whilst low‐certainty evidence means that our confidence was limited and further research may have an important impact on our findings. Very low‐certainty evidence means that we were uncertain about the result.


A two‐dose schedule of HPV vaccines in young females results in immune system responses that are comparable with a three‐dose schedule. In males, the quadrivalent HPV vaccine appears to be effective in the prevention of external genital lesions and genital warts. Quadrivalent and nonavalent HPV vaccines in young women result in similar levels of protection against cervical, vaginal, and vulval precancer lesions and cancer. Evidence about the efficacy and harms in people living with HIV is limited. Further long‐term population‐level studies are needed to continue monitoring safety of these vaccines, to determine for how long two doses of vaccine can provide protection against HPV‐related disease, the effect against HPV‐related cancer, and whether a two‐dose immunisation schedule will increase vaccine coverage.