Twenty years on since the approval of the first human papillomavirus (HPV) vaccine, a raft of studies involving millions of people have reached the same conclusion: HPV vaccination is safe and dramatically lowers women’s risk for cervical cancer.

Those are the topline findings of two updated Cochrane reviews on the impact of HPV vaccination — one looking at population levels of cervical and other HPV-related cancers, and the other a network meta-analysis of clinical trial data.

The population studies, involving over 132 million people in all, show that the benefits of vaccination for cervical cancer prevention are unequivocal, according to senior author Jo Morrison, BM, of the University of Exeter in Exeter, England.

“The evidence of safety and efficacy of HPV vaccination is not, and should not be, controversial,” Morrison told Medscape Medical News.

Based on data covering 4.5 million person-years, vaccination by age 16 is associated with an 80% reduction in the risk for cervical cancer (relative risk [RR], 0.20; 95% CI, 0.09-0.44).

Meanwhile, long-term studies of girls vaccinated at ages 12–13 show “even more dramatic” effects, Morrison said — with no cervical cancers detected in those cohorts.

Currently, groups such as the American Cancer Society and American Academy of Pediatrics recommend routine HPV vaccination for all children starting between the ages of 9 and 12. Guidance from the CDC is similar.

The Cochrane update supports such early vaccination. Overall, studies found that cervical cancer protection was less when the HPV vaccine was given after the age of 16.

“It is important to vaccinate before [first] exposure to HPV infection,” Morrison said.

As for safety, the Cochrane team specifically looked for population data supporting any potential link between HPV vaccination and a list of adverse events commonly cited as risks on social media — including postural orthostatic tachycardia syndrome, chronic fatigue syndrome, infertility, and paralysis. They found no such evidence.

Nor was there any evidence that HPV vaccination encouraged earlier sexual activity, another concern often raised on social media.

“It’s great to now have a large body of evidence that shows that HPV vaccines do not cause long-term harms,” Morrison said. She contrasted that against the “very real” harms of cervical cancer, which causes roughly 350,000 deaths per year worldwide.

An HPV expert who was not involved in the reviews called the data “compelling.”

“This is one of the most efficacious vaccines ever invented,” Linda Eckert, MD, a professor of obstetrics and gynecology at the University of Washington in Seattle, told Medscape Medical News.

She agreed that early adolescence is the best time for the HPV shot but also stressed that the benefits are not lost among older teens and young adults or simply because a young person is already sexually active.

“I don’t want doctors to stop [giving the vaccine] at 16,” Eckert said. Even young people who’ve had “two or three” sexual partners, she noted, have not been exposed to all of the HPV strains that vaccination protects against.

The population data Morrison’s team reviewed come from 225 studies conducted worldwide. Most (177) reported on women only, while 11 focused only on men, and 37 involved both sexes.

The companion meta-analysis focused on 60 randomized controlled trials involving over 157,000 participants, as well as various HPV vaccines and different vaccination schedules. Pharmaceutical companies funded 44 of the studies.

Most trials had a follow-up of 12 months, though the range was up to 11 years. In contrast to the population studies, the trials could not provide sufficient data on cancer outcomes.

But in trials with relatively longer follow-up, HPV vaccination did prevent many high-grade precancers of the cervix. Among 15- to 25-year-olds, there was a 60% reduction in grade 2 or worse cervical intraepithelial neoplasia from vaccine-matched HPV types over 6 years (RR, 0.40; 95% CI, 0.30 to 0.54).

In addition, vaccination reduced rates of rare vulvar and vaginal precancers among 15- to 25-year-olds — from three cases per 1000 among control individuals to one per 1000 following Gardasil vaccination (RR, 0.21; 95% CI, 0.1 to 0.45) and 0 per 1000 with Gardasil-9. (RR, 0.16; 95% CI, 0.05 to 0.51).

There was also evidence, from three trials of over 21,000 participants, that vaccination cut the incidence of anogenital warts for up to 4 years of follow-up.

Those short-term endpoints, Morrison said, help in drawing conclusions about the likely long-term efficacy of HPV vaccination “without waiting a generation for the clinically relevant outcomes to develop.”

Eckert agreed. She noted that other than cervical cancer, HPV-linked cancers — including head and neck, penile, and anal cancers — typically develop in older adults.

Proof of the vaccines’ ability to prevent those cancers could take another decade or two to emerge, Eckert said, but there’s no reason to believe outcomes will be much different than what’s been seen with cervical cancer.

In terms of discussing the HPV vaccine with parents and young people, Eckert had advice to clinicians: Keep the focus on future cancer prevention, not sex.

“We made a mistake when we rolled out this vaccine,” she said. “We should have called it the anti-cancer vaccine, not the HPV vaccine.”

Morrison is a senior editor for Cochrane but was not involved in the editorial process for this review. Eckert had no relevant financial disclosures.

Ernie Mundell is a freelance medical journalist based in Los Angeles. He has more than 30 years of experience, including editorial positions at Reuters Health and HealthDay.