M. Alexander Otto, MSS, PA
October 01, 2020
M. Alexander Otto is a physician assistant and award-winning medical journalist who has worked for several major news outlets before joining Medscape, including McClatchy and Bloomberg.

Quadrivalent human papillomavirus (HPV) vaccination was associated with a substantial reduction in the incidence of cervical cancer in a Swedish review of more than 1 million girls and women vaccinated from 2006–2017.

It’s been shown that the vaccine (Gardasil) helps prevent genital warts and high-grade cervical lesions, but until now, data on the ability of the vaccine to prevent cervical cancer, although widely assumed, had been lacking.

“Our results extend [the] knowledge base by showing that quadrivalent HPV vaccination is also associated with a substantially reduced risk of invasive cervical cancer, which is the ultimate intent of HPV vaccination program,” said investigators led by Jiayao Lei, PhD, a researcher in the Department of Medical Epidemiology and Biostatistics at the Karolinska Institute, Stockholm, Sweden.

“This work provides evidence of actual cancer prevention,” commented Diane Harper, MD, an HPV expert and professor in the Departments of Family Medicine and Obstetrics & Gynecology at the University of Michigan, Ann Arbor, Michigan. She was the principal investigator on the original Gardasil trial.

This study “shows that the quadrivalent HPV vaccine provides prevention from the sexually transmitted HPV infection that actually reduces the incidence of cervical cancer in young women up to 30 years of age,” she said when approached for comment.

However, she also added a note of caution. These new results show “that vaccinated women still develop cervical cancer, but at a slower rate. This makes the connection between early-age vaccination and continued adult life screening incredibly important,” Harper told Medscape Medical News

Cervical cancer was diagnosed in 19 of the 527,871 women (0.004%) who had received at least one dose of the vaccine, vs 538 among the 1,145,112 women (0.05%) who had not.

The cumulative incidence was 47 cases per 100,000 vaccinated women and 94 cases per 100,000 unvaccinated women. The cervical cancer incidence rate ratio for the comparison of vaccinated vs unvaccinated women was 0.37 (95% CI, 0.21 – 0.57).

The risk reduction was even greater among women who had been vaccinated before the age of 17, with a cumulative incidence of four vs 54 cases per 100,000 for women vaccinated after age 17. The incidence rate ratio was 0.12 (95% CI, 0.00 – 0.34) for women who had been vaccinated before age 17, vs 0.47 (95% CI, 0.27 – 0.75) among those vaccinated from age of 17 to 30 years.

Overall, “the risk of cervical cancer among participants who had initiated vaccination before the age of 17 years was 88% lower than among those who had never been vaccinated,” the investigators noted.

These results “support the recommendation to administer quadrivalent HPV vaccine before exposure to HPV infection to achieve the most substantial benefit,” the investigators said.

Details of the Swedish Review

For their review, Lei and colleagues used several Swedish demographic and health registries to connect vaccination status to incident cervical cancers, using the personal identification numbers Sweden issues to residents.

Participants were followed starting either on their 10th birthday or on January 1, 2006, whichever came later. They were followed until, among other things, diagnosis of invasive cervical cancer; their 31st birthday; or until December 31, 2017, whichever came first.

The quadrivalent HPV vaccine, approved in Sweden 2006, was used almost exclusively during the study period. Participants were considered vaccinated if they had received only one shot, but the investigators set out to analyze a relationship between the incidence of invasive cervical cancer and the number of shots given.

Among other things, the team controlled for age at follow-up, calendar year, county of residence, maternal disease history, and parental characteristics, including education and household income.

The investigators comment that it’s possible that HPV-vaccinated women could have been generally healthier than unvaccinated women and so would have been at lower risk for cervical cancer.

“Confounding by lifestyle and health factors in the women (such as smoking status, sexual activity, oral contraceptive use, and obesity) cannot be excluded; these factors are known to be associated with a risk of cervical cancer,” they say.

HPV is also associated with other types of cancer, including anal and oropharyngeal cancers. But these cancers develop over a longer period than cervical cancer.

Harper noted that the “probability of HPV 16 cancer by time since infection peaks at 40 years after infection for anal cancers and nearly 50 years after infection for oropharyngeal cancers. This means that registries, such as in Sweden, for the next 40 years will record the evidence to say whether HPV vaccination lasts long enough to prevent [these] other HPV 16–associated cancers occurring at a much later time in life.”

The work was funded by the Swedish Foundation for Strategic Research, the Swedish Cancer Society, and the Swedish Research Council and by the China Scholarship Council. Lei and two other investigators report HPV vaccine research funding from Merck, the maker of Gardasil. Harper has disclosed no relevant financial relationships.

N Engl J Med. Published online October 1, 2020.
Jiayao Lei, Ph.D., Alexander Ploner, Ph.D., K. Miriam Elfstrom, Ph.D.,
Jiangrong Wang, Ph.D., Adam Roth, M.D., Ph.D., Fang Fang, M.D., Ph.D.,
Karin Sundstrom, M.D., Ph.D., Joakim Dillner, M.D., Ph.D.,and Par Sparen, Ph.D. HPV Vaccination and the Risk of Invasive Cervical Cancer; 2020. n engl j med 383;14