Carolina Porras1, Sabrina H Tsang2, Rolando Herrero3, Diego Guillén4, Teresa M Darragh5, Mark H Stoler6, Allan Hildesheim2, Sarah Wagner7, Joseph Boland7, Douglas R Lowy2, John T Schiller2, Mark Schiffman2, John Schussler8, Mitchell H Gail2, Wim Quint9, Rebeca Ocampo4, Jorge Morales4, Ana C Rodríguez10, Shangying Hu2, Joshua N Sampson2, Aimée R Kreimer2. 1. Agencia Costarricense de Investigaciones Biomédicas, Fundación INCIENSA, San José, Costa Rica. Electronic address: cporras@acibcr.com. 2. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA. 3. Agencia Costarricense de Investigaciones Biomédicas, Fundación INCIENSA, San José, Costa Rica; Early Detection and Prevention Section, International Agency for Research on Cancer, World Health Organization, Lyon, France. 4. Agencia Costarricense de Investigaciones Biomédicas, Fundación INCIENSA, San José, Costa Rica. 5. University of California, San Francisco, San Francisco, CA, USA. 6. Department of Pathology, University of Virginia, Charlottesville, VA, USA. 7. Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD, USA. 8. Information Management Services, Calverton, MD, USA. 9. DDL Diagnostic Laboratory, Rijswijk, Netherlands. 10. San José, Costa Rica.
Abstract
BACKGROUND: Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+). METHODS: Women aged 18-25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464. FINDINGS: 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0-4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7-11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1-11·7), 4·6 years (4·3-5·3) for the original control group, and 6·2 years (5·5-6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2-100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0-99·6). Similar protection was observed against HPV 16/18-associated CIN3-specifically at year 11, vaccine efficacy was 100% (95% CI 78·8-100·0) and cumulative vaccine efficacy was 94·9% (73·7-99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine. INTERPRETATION: The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable. FUNDING: US National Cancer Institute.
BACKGROUND: Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+). METHODS: Women aged 18-25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464. FINDINGS: 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0-4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7-11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1-11·7), 4·6 years (4·3-5·3) for the original control group, and 6·2 years (5·5-6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2-100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0-99·6). Similar protection was observed against HPV 16/18-associated CIN3-specifically at year 11, vaccine efficacy was 100% (95% CI 78·8-100·0) and cumulative vaccine efficacy was 94·9% (73·7-99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine. INTERPRETATION: The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable. FUNDING: US National Cancer Institute.
Authors: Tapio Luostarinen; Dan Apter; Joakim Dillner; Tiina Eriksson; Katja Harjula; Kari Natunen; Jorma Paavonen; Eero Pukkala; Matti Lehtinen Journal: Int J Cancer Date: 2018-01-04 Impact factor: 7.396
Authors: Susanne K Kjaer; Mari Nygård; Joakim Dillner; J Brooke Marshall; David Radley; Meng Li; Christian Munk; Bo T Hansen; Lara G Sigurdardottir; Maria Hortlund; Laufey Tryggvadottir; Amita Joshi; Rituparna Das; Alfred J Saah Journal: Clin Infect Dis Date: 2018-01-18 Impact factor: 9.079
Authors: Carolina Porras; Allan Hildesheim; Paula González; Mark Schiffman; Ana Cecilia Rodríguez; Sholom Wacholder; Silvia Jiménez; Wim Quint; Diego Guillen; Aimée R Kreimer; Rolando Herrero Journal: J Natl Cancer Inst Date: 2014-12-05 Impact factor: 13.506
Authors: Warner K Huh; Elmar A Joura; Anna R Giuliano; Ole-Erik Iversen; Rosires Pereira de Andrade; Kevin A Ault; Deborah Bartholomew; Ramon M Cestero; Edison N Fedrizzi; Angelica L Hirschberg; Marie-Hélène Mayrand; Angela Maria Ruiz-Sternberg; Jack T Stapleton; Dorothy J Wiley; Alex Ferenczy; Robert Kurman; Brigitte M Ronnett; Mark H Stoler; Jack Cuzick; Suzanne M Garland; Susanne K Kjaer; Oliver M Bautista; Richard Haupt; Erin Moeller; Michael Ritter; Christine C Roberts; Christine Shields; Alain Luxembourg Journal: Lancet Date: 2017-09-05 Impact factor: 79.321
Authors: Thomas Iftner; Klaus-Joachim Neis; Alejandra Castanon; Rebecca Landy; Barbara Holz; Astrid Woll-Herrmann; Angelika Iftner; Annette Staebler; Diethelm Wallwiener; Claus Hann von Weyhern; Felix Neis; Juliane Haedicke-Jarboui; Peter Martus; Sara Brucker; Melanie Henes; Peter Sasieni Journal: J Clin Microbiol Date: 2019-01-02 Impact factor: 5.948
Authors: Jaimie Z Shing; Shangying Hu; Rolando Herrero; Allan Hildesheim; Carolina Porras; Joshua N Sampson; John Schussler; John T Schiller; Douglas R Lowy; Mónica S Sierra; Loretto Carvajal; Aimée R Kreimer Journal: Lancet Oncol Date: 2022-06-13 Impact factor: 54.433
Authors: Mir Yousufuddin Ali Khan; Sudeshna Bandyopadhyay; Ahmed Alrajjal; Moumita Saha Roy Choudhury; Rouba Ali-Fehmi; Vinod B Shidham Journal: Cytojournal Date: 2022-04-30 Impact factor: 2.345
Authors: Mónica S Sierra; Sabrina H Tsang; Shangying Hu; Carolina Porras; Rolando Herrero; Aimée R Kreimer; John Schussler; Joseph Boland; Sarah Wagner; Bernal Cortes; Ana C Rodríguez; Wim Quint; Leen-Jan van Doorn; Mark Schiffman; Joshua N Sampson; Allan Hildesheim Journal: J Infect Dis Date: 2021-08-02 Impact factor: 5.226