Clinical Unmasking May Cause Increased Rates of High-Grade Cervical Neoplasia From Non–Vaccine Preventable HPV

Investigators reported that vaccinated patients had a higher rate of grade 2/3 cervical neoplasia due to non–vaccine preventable human papillomavirus compared with unvaccinated patients, an event commonly termed clinical unmasking.

Patients who received the human papillomavirus (HPV) vaccine experienced a higher incidence of grade 2/3 cervical neoplasia (CIN2/3+) due to non–vaccine preventable human vs the unvaccinated population, termed clinical unmasking, according to a phase 3 trial (NCT00128661; NCT00867464) and a follow-up study (NCT00867464) published in The Lancet Oncology.

The median follow-up during years 7 to 11 for patients who had CIN2+ events was 52.8 months for those who received the vaccine and 49.8 months for those who didn’t. Higher rates of CIN2+ during time points 7 to 11 years were observed with non-preventable HPV types in the vaccine group with 61 events at a rate of 22.0 per 1000 patients (95% CI, 17.1-28.0) compared with the control group with 33 events at a rate of 12.9 per 1000 patients (95% CI, 9.0-17.8). Higher rates of CIN3+ due to unpreventable HPV were also observed in the vaccine group with 41 events at a rate of 14.5 per 1000 patients (95% CI, 10.6-19.4) and 16 events at a rate of 6.2 per 1000 patients (95% CI, 3.7-9.8) in the control group.

“Our findings suggest that in populations in which cervical cancer screening is routinely and effectively conducted, the vaccine effect against cervical disease irrespective of HPV type might decline over time due to increases in disease attributed to non-preventable HPV types following vaccination. Yet, we reiterate that the high net benefit to cervical cancer prevention will persist. Specifically, the vaccine has high efficacy against vaccine-targeted types HPV 16 and 18, the most carcinogenic types due to their disproportionally high prevalence and attributable fraction in cancer cases,” investigators of the study wrote.

A total 7466 patients were included in the HPV vaccine group (n = 3727) or the hepatitis A vaccine control group (n = 3739) from June 28, 2004 to December 21, 2005. Moreover , 2836 patients comprised the unvaccinated group and enrolled from March 30, 2009 to July 5, 2012. A total of 3467 patients were included in the HPV vaccine group vs 3492 in the control group after excluding those who received both vaccines, didn’t turn up for follow-up appointments, or who already had a previous end point. The analytical cohort for years 1 through 4, assessing the endpoint of CIN3+, was comprised of 3491 patients from the HPV vaccination cohort and 3512 patients from the hepatitis A cohort. For 7- to 11-year time points for the CIN2+ end point, 2767 patients in the HPV vaccine group were included vs 2563 in the control group, as well as 2826 and 2592 patients for the vaccinated and unvaccinated cohorts, respectively, for the CIN3+ end point.

Investigators set out to determine absolute rate differences by HPV type over 11 years. After merging 2 follow-up periods per 1000 patients, investigators reported observing additional CIN2+ event related to non-preventable HPV types in the vaccinated group vs the control group. Less CIN2+ events associated with HPV 16, 18, 31, 33, or 45 were observed per 1000 vaccinated patients vs unvaccinated patients. The decrease in CIN2+ events related to vaccine target and cross protected types yielded an estimated overall reduction of roughly 36.2 per 1000 patients.

The clinical unmasking effects after 11 years yielded even more CIN3+ events associated with non-preventable HPV types per 1000 vaccinated vs unvaccinated patients. Notably, the absolute rate differences regardless of disease type for CIN3+ events were not statistically significantly associated with HPV 31, 33, or 45.

The post-hoc analysis was conducted for years 7 to 11 with 61 CIN2+ events that were associated with non-preventable HPV in those vaccinated during the long-term follow-up. Of these events, 41% were associated with HPV 52 or 58, 41% with carcinogenic types not prevented by vaccination, 7% could not be attributed to carcinogenic types, and 2% had an unknown casual type. Of the 41 CIN3+ events, 49% were related to HPV 52 or 58, 41% with carcinogenic types, 7% were not associated with carcinogenic types, and 2% had an unknown casual type.


Shing JZ, Hu S, Herrero R, et al. Precancerous cervical lesions caused by non-vaccine-preventable HPV types after vaccination with the bivalent AS04-adjuvanted HPV vaccine: an analysis of the long-term follow-up study from the randomised Costa Rica HPV Vaccine Trial. Lancet Oncol. 2022;23(7):940-949. doi:10.1016/S1470-2045(22)00291-1