HPV vaccine: what 18 years of follow-up show, and how 9 types differ from 4

The HPV vaccine question usually comes up for parents when a child is 9 to 14: that is the age national programmes target, and the age at which you may have to choose between products, if there is a choice at all. Below is what the large studies measured, in whom, and what they do not yet tell us.

Why does age matter most?

Human papillomavirus is a common infection, and most infections clear on their own. When an infection with a cancer-causing type persists for years, it can lead to precancerous changes and cancer: of the cervix, anal canal, vulva, vagina, penis, and some cancers of the oropharynx.

The vaccines are made of empty protein shells of the virus with no viral DNA, so they cannot cause infection [1]. They do not treat an existing infection, dysplasia or cancer [2]. Hence the main practical point: in the studies, the largest effect is seen in people vaccinated before they meet the virus. Someone already infected with one type can still gain protection against types they have not yet acquired [2].

What have studies shown about cancer?

The longest follow-up on invasive cervical cancer comes from Sweden, published in the BMJ in 2026 [3]. Researchers followed 926,362 girls and women through national registers for up to 18 years. Vaccination with the quadrivalent vaccine happened through routine programmes; there was no randomisation.

Among those who started vaccination before 17, the rate of invasive cervical cancer, adjusted for age, calendar period, social factors and medical history, was 79% lower than among the unvaccinated (incidence rate ratio 0.21; 95% confidence interval 0.13–0.32). Among those who started at 17 or later it was 37% lower (0.63; 0.49–0.81). In absolute terms, cumulative incidence by age 34 was about 30 per 100,000 in those vaccinated before 17, about 100 in those vaccinated later, and about 180 in the unvaccinated. The authors saw no sign of the effect fading: 13–15 years after vaccination the rate ratio was 0.23.

What the study does not say. It is an observational study, not a trial: vaccinated and unvaccinated women may differ in ways the adjustments did not capture, such as screening behaviour. In years 16–18 after vaccination there were no cases among those vaccinated early, but there was also little follow-up time, so the conclusion for the longest interval is weaker. And the figures describe Swedish women up to their mid to late 30s, not any individual's lifetime risk.

England, where schoolgirls aged 12–13 received the bivalent vaccine, shows a similar picture [4]. Comparing cohorts before and after the programme, cervical cancer among those vaccinated at that age was 87% less frequent (95% CI 72–94) and severe dysplasia (CIN3) 97% less frequent. This is also an observational study.

For the 9-valent vaccine, cancer outcomes are not yet available: the vaccine is younger. An extended follow-up of 1,628 Scandinavian women vaccinated at 16–26 in a trial found no cases of high-grade cervical dysplasia linked to vaccine types over 12 years; the result is statistically significant for at least 10 years [5]. The study was funded by the manufacturer. High-grade dysplasia is an important outcome, but not every case would have become cancer.

How do 2, 4 and 9 valences differ?

Valence is the number of virus types in the vaccine [1].

• The bivalent vaccine contains types 16 and 18, which account for about two thirds of cervical cancers worldwide [2].

• The quadrivalent adds 6 and 11, which rarely cause cancer but cause most genital warts.

• The 9-valent adds five cancer-causing types: 31, 33, 45, 52 and 58, which account for roughly another 15% of cervical cancers [2].

Going from two to four types widens coverage of warts; going from four to nine widens coverage of cancer. But nine types does not mean "twice as good": most cancers are linked to 16 and 18, which all three vaccines contain. This is why the WHO considers all licensed vaccines comparable, from a public health perspective, for cervical precancer and cancer, and leaves the choice to local considerations [1].

The 9-valent and quadrivalent vaccines were compared head to head in a randomised trial of 14,215 women aged 16–26 [6, 7]. Among those who completed the course and were not infected with the relevant types at the start, high-grade cervical, vulvar and vaginal lesions linked to the five added types occurred at 0.5 per 10,000 person-years with the 9-valent vaccine and 19 with the quadrivalent; efficacy 97.4% (95% CI 85.0–99.9) [7]. An important caveat from the same trial: counting all participants, including those already infected, and all virus types, the rate of high-grade lesions did not differ between the groups — 14.0 per 1,000 person-years in both [6]. The advantage of the 9-valent vaccine concerns the added types and is greatest in people vaccinated before exposure. The trial was funded by the manufacturer.

What is known about boys?

In males, HPV is linked to cancers of the anal canal and penis and to some oropharyngeal cancers. There are no trials in males with cancer as the outcome — trials measured infection and genital lesions.

A randomised trial of the quadrivalent vaccine enrolled 4,065 males aged 16–26 from 18 countries [8]. Among those who received all three doses and were not infected with vaccine types at the start, external genital lesions from those types were 90.4% less frequent than with placebo. Counting all participants, including those already infected, they were 65.5% less frequent.

In a Japanese trial published in 2026, 1,059 males aged 16–26 received three doses of the 9-valent vaccine or placebo [9]. In the final analysis, persistent (at least 6 months) anogenital infection with types 6, 11, 16 and 18 was 91.6% less frequent, and with types 31, 33, 45, 52 and 58 72.9% less frequent. This is infection, not cancer. The trial was funded by the manufacturer.

Observational estimates of lower cancer rates in young men have appeared, but researchers from the US National Cancer Institute have set out why those figures are hard to interpret [10]: HPV-related cancers in males are rare and take decades to develop. Cervical cancer percentages should not be transferred to boys. In addition, according to the CDC, the five types added in the 9-valent vaccine cause only a small share of HPV-related cancers in males; most of their benefit is in females [12].

One, two or three doses?

Since 2022 the WHO has recommended two doses at least 6 months apart, and as an off-label alternative allows a single dose for girls and boys aged 9–20. People who are immunocompromised or living with HIV should receive at least two doses, and three where possible [1]. National schedules and product labels may differ from these recommendations.

The key new trial here is ESCUDDO in Costa Rica, with 20,330 girls aged 12–16 [11]. They were randomly assigned to one or two doses of the bivalent or 9-valent vaccine. One dose was non-inferior to two for new persistent HPV16/18 infection between months 12 and 60. Effectiveness of each schedule versus no vaccination was at least 97%, but that estimate came from comparison with a separate, non-randomised group of unvaccinated girls and women. The trial did not measure cancer and does not answer the question of lifelong protection; data on single doses in boys are more limited [1].

What if a course was started with the quadrivalent vaccine?

Under CDC guidance, a course started with the bivalent or quadrivalent vaccine can be continued and completed with the 9-valent vaccine; correctly given doses are not repeated [12]. If a course with another vaccine has already been completed, the CDC does not recommend additional 9-valent doses [2], while Canada's advisory committee NACI allows one additional dose as an individual decision with a doctor for people at ongoing risk of exposure [14].

The data on such additional vaccination are mostly about antibodies. In a trial of 618 girls and women aged 12–26 who had previously received three doses of the quadrivalent vaccine, three doses of the 9-valent vaccine produced antibodies to the five new types in more than 98%, but at lower levels than in previously unvaccinated people; the clinical significance of this difference is unknown [13]. Cancer and dysplasia were not measured.

How safe is the vaccine?

The most common reactions are pain, redness and swelling at the injection site, less often headache or fever [2]. Local reactions are more common with the 9-valent than with the quadrivalent vaccine [6]. Adolescents may faint in response to the injection itself, so they are vaccinated seated and observation for about 15 minutes is recommended [2].

Severe allergic reactions are rare: about 1.7 cases per million doses, according to the WHO vaccine safety committee [15]. Anaphylaxis after a previous dose or to a vaccine component is a contraindication to further doses [2].

The US Vaccine Safety Datalink followed more than 1.8 million doses of the 9-valent vaccine in people aged 9–26 and compared them with other vaccines given at that age: it found no statistically significant increase in the risk of Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy or stroke [16]. No study can fully rule out a very rare risk, but a single case of illness after vaccination does not by itself prove a causal link.

What should you ask a doctor?

• Age, and how many doses your national schedule provides.

• Which products were given and on what dates, if a course has started.

• Immune status and contraindications.

• For girls and women: the vaccine does not cover all cancer-causing types and does not replace cervical cancer screening, which follows the same schedule as for unvaccinated women [2].

This article is for information only and does not replace a consultation with a doctor.

Sources

1. World Health Organization. Human papillomavirus vaccines: WHO position paper (2022 update). Weekly Epidemiological Record. 2022;97(50):645–672. who.int

2. CDC. Epidemiology and Prevention of Vaccine-Preventable Diseases (Pink Book), chapter 11: Human Papillomavirus. cdc.gov

3. Wu S et al. Extended follow-up of invasive cervical cancer risk after quadrivalent HPV vaccination: nationwide, register based study. BMJ. 2026. PMID 41740992

4. Falcaro M et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence. Lancet. 2021. PMID 34741816

5. Kjaer SK et al. Long-term effectiveness of the nine-valent human papillomavirus vaccine: interim results after 12 years of follow-up in Scandinavian women. Hum Vaccin Immunother. 2024. PMID 39373579

6. Joura EA et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015. PMID 25693011

7. Huh WK et al. Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 years. Lancet. 2017. PMID 28886907

8. Giuliano AR et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med. 2011. PMID 21288094

9. Hisamoto K et al. Efficacy, immunogenicity, and safety of the 9-valent human papillomavirus vaccine in males aged 16–26 years in Japan. Lancet Infect Dis. 2026. PMID 42546724

10. Chaturvedi AK, Castle PE. Appropriately interpreting evidence of human papillomavirus vaccination and cancer in males. JAMA Oncol. 2026. PMID 42560700

11. Kreimer AR et al. Noninferiority of one HPV vaccine dose to two doses (ESCUDDO). N Engl J Med. 2025. PMID 41337735

12. CDC. Supplemental information and guidance for vaccination providers regarding use of 9-valent HPV vaccine. cdc.gov (PDF)

13. Garland SM et al. Safety and immunogenicity of a 9-valent HPV vaccine in females 12–26 years of age who previously received the quadrivalent HPV vaccine. Vaccine. 2015. PMID 26411885

14. NACI. Updated recommendations on human papillomavirus (HPV) vaccines. Public Health Agency of Canada, 2024. publications.gc.ca (PDF)

15. WHO, Global Advisory Committee on Vaccine Safety. Safety of HPV vaccines. who.int

16. Sundaram ME et al. Extended surveillance to assess safety of 9-valent human papillomavirus vaccine. Hum Vaccin Immunother. 2022. PMID 36577134