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Showing content from https://pubmed.ncbi.nlm.nih.gov/35709811/ below:

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

Randomized Controlled Trial

. 2022 Jul;23(7):940-949. doi: 10.1016/S1470-2045(22)00291-1. Epub 2022 Jun 13. 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 Shangying Hu², Rolando Herrero³, Allan Hildesheim⁴, Carolina Porras⁵, Joshua N Sampson⁴, John Schussler⁶, John T Schiller⁷, Douglas R Lowy⁷, Mónica S Sierra⁴, Loretto Carvajal⁸, Aimée R Kreimer⁴; Costa Rica HPV Vaccine Trial Group

Collaborators, Affiliations

Collaborators

Costa Rica HPV Vaccine Trial Group: Bernal Cortés, Paula González, Rolando Herrero, Silvia E Jiménez, Carolina Porras, Ana Cecilia Rodríguez, Allan Hildesheim, Aimée R Kreimer, Douglas R Lowy, Mark Schiffman, John T Schiller, Mark Sherman, Sholom Wacholder, Ligia A Pinto, Troy J Kemp, Mary K Sidawy, Wim Quint, Leen-Jan van Doorn, Linda Struijk, Joel M Palefsky, Teresa M Darragh, Mark H Stoler

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: jaimie.shing@nih.gov.
² Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ Agencia Costarricense de Investigaciones Biomédicas (ACIB), Fundación INCIENSA, San José, Costa Rica; Early Detection and Prevention Section, International Agency for Research on Cancer, WHO, Lyon, France.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Agencia Costarricense de Investigaciones Biomédicas (ACIB), Fundación INCIENSA, San José, Costa Rica.
⁶ Information Management Services, Silver Spring, MD, USA.
⁷ Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Agencia Costarricense de Investigaciones Biomédicas (ACIB), Fundación INCIENSA, San José, Costa Rica.

PMID: 35709811
PMCID: PMC9255557
DOI: 10.1016/S1470-2045(22)00291-1

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Randomized Controlled Trial

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

Jaimie Z Shing et al. Lancet Oncol. 2022 Jul.

. 2022 Jul;23(7):940-949. doi: 10.1016/S1470-2045(22)00291-1. Epub 2022 Jun 13. Authors Jaimie Z Shing¹, Shangying Hu², Rolando Herrero³, Allan Hildesheim⁴, Carolina Porras⁵, Joshua N Sampson⁴, John Schussler⁶, John T Schiller⁷, Douglas R Lowy⁷, Mónica S Sierra⁴, Loretto Carvajal⁸, Aimée R Kreimer⁴; Costa Rica HPV Vaccine Trial Group Collaborators

Costa Rica HPV Vaccine Trial Group: Bernal Cortés, Paula González, Rolando Herrero, Silvia E Jiménez, Carolina Porras, Ana Cecilia Rodríguez, Allan Hildesheim, Aimée R Kreimer, Douglas R Lowy, Mark Schiffman, John T Schiller, Mark Sherman, Sholom Wacholder, Ligia A Pinto, Troy J Kemp, Mary K Sidawy, Wim Quint, Leen-Jan van Doorn, Linda Struijk, Joel M Palefsky, Teresa M Darragh, Mark H Stoler

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: jaimie.shing@nih.gov.
² Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ Agencia Costarricense de Investigaciones Biomédicas (ACIB), Fundación INCIENSA, San José, Costa Rica; Early Detection and Prevention Section, International Agency for Research on Cancer, WHO, Lyon, France.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Agencia Costarricense de Investigaciones Biomédicas (ACIB), Fundación INCIENSA, San José, Costa Rica.
⁶ Information Management Services, Silver Spring, MD, USA.
⁷ Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Agencia Costarricense de Investigaciones Biomédicas (ACIB), Fundación INCIENSA, San José, Costa Rica.

PMID: 35709811
PMCID: PMC9255557
DOI: 10.1016/S1470-2045(22)00291-1

Item in Clipboard

Abstract

Background: In women vaccinated against human papillomavirus (HPV), reductions in cervical disease and related procedures results in more women having intact transformation zones, potentially increasing the risk of cervical lesions caused by non-vaccine-preventable HPV types, a phenomenon termed clinical unmasking. We aimed to evaluate HPV vaccine efficacy against cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) attributed to non-preventable HPV types in the long-term follow-up phase of the Costa Rica HPV Vaccine Trial (CVT).

Methods: CVT was a randomised, double-blind, community-based trial done in Costa Rica. Eligible participants were women aged 18-25 years who were in general good health. Participants were randomly assigned (1:1) to receive an HPV 16 and 18 AS04-adjuvanted vaccine or control hepatitis A vaccine, using a blocked randomisation method (permuted block sizes of 14, 16, and 18). Vaccines in both groups were administered intramuscularly with 0·5 mL doses at 0, 1, and 6 months. Masking of vaccine allocation was maintained throughout the 4-year randomised trial phase, after which participants in the hepatitis A virus vaccine control group were provided the HPV vaccine and exited the study; a screening-only, unvaccinated control group was enrolled. The unvaccinated control group and HPV vaccine group were followed up for 7 years, during which treatment allocation was not masked. One of the prespecified primary endpoints for the long-term follow-up phase was precancers associated with HPV types not prevented by the vaccine, defined as histologically confirmed incident CIN2+ events or CIN3+ events attributed to any HPV type except HPV 16, 18, 31, 33, and 45. Our primary analytical period was years 7-11. Primary analyses were in all participants with at least one follow-up visit and excluded participants with a previous endpoint (ie, modified intention-to-treat cohort). Safety endpoints have been reported elsewhere. This trial is registered with ClinicalTrials.gov, NCT00128661 and NCT00867464. The randomised, masked trial phase is completed; an unmasked subset of women in the HPV-vaccinated group is under active investigation.

Findings: Between June 28, 2004, and Dec 21, 2005, 7466 participants were enrolled (HPV vaccine group n=3727 and hepatitis A virus vaccine control group n=3739). Between March 30, 2009, and July 5, 2012, 2836 women enrolled in the new unvaccinated control group. The primary analytical cohort (years 7 to 11) included 2767 participants in the HPV vaccine group and 2563 in the unvaccinated group for the CIN2+ events endpoint assessment and 2826 participants in the HPV vaccine group and 2592 in the unvaccinated control group for the CIN3+ events endpoint assessment. Median follow-up during years 7 to 11 for women included for the CIN2+ events analysis was 52·8 months (IQR 44·0 to 60·7) for the HPV vaccine group and 49·8 months (42·0 to 56·9) for the unvaccinated control group. During years 7 to 11, clinical unmasking was observed with a negative vaccine efficacy against CIN2+ events attributed to non-preventable HPV types (-71·2% [95% CI -164·0 to -12·5]), with 9·2 (95% CI 2·1 to 15·6) additional CIN2+ events attributed to non-preventable HPV types per 1000 HPV-vaccinated participants versus HPV-unvaccinated participants. 27·0 (95% CI 14·2 to 39·9) fewer CIN2+ events irrespective of HPV type per 1000 vaccinated participants were observed during 11 years of follow-up. Vaccine efficacy against CIN3+ events attributed to non-preventable HPV types during years 7 to 11 was -135·0% (95% CI -329·8 to -33·5), with 8·3 (3·0 to 12·8) additional CIN3+ events attributed to non-preventable HPV types per 1000 vaccinated participants versus unvaccinated participants.

Interpretation: Higher rates of CIN2+ events and CIN3+ events due to non-preventable HPV types in vaccinated versus unvaccinated participants suggests clinical unmasking could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programmes in screened populations. Importantly, the net benefit of vaccination remains considerable; therefore, HPV vaccination should still be prioritised as primary prevention for cervical cancer.

Funding: National Cancer Institute and National Institutes of Health Office of Research on Women's Health.

Translation: For the Spanish translation of the abstract see Supplementary Materials section.

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Conflict of interest statement

Declaration of interests JTS and DRL report that they are named inventors on US Government-owned HPV vaccine patents with expired licenses to GlaxoSmithKline and Merck. All other authors declare no competing interests.

Figures
Figure 1.. Study profile.

CIN = cervical…

Figure 1.. Study profile.

CIN = cervical intraepithelial neoplasia.

Figure 1.. Study profile.

CIN = cervical intraepithelial neoplasia.

Figure 2.. Distribution of HPV types in…

Figure 2.. Distribution of HPV types in “unmasked” CIN2+ and CIN3+ events caused by non-vaccine-preventable…
Figure 2.. Distribution of HPV types in “unmasked” CIN2+ and CIN3+ events caused by non-vaccine-preventable types in the HPV vaccine group in years 7-11.

CIN = cervical intraepithelial neoplasia.