Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica

Rolando Herrero, Wim Quint, Allan Hildesheim, Paula Gonzalez, Linda Struijk, Hormuzd A Katki, Carolina Porras, Mark Schiffman, Ana Cecilia Rodriguez, Diane Solomon, Silvia Jimenez, John T Schiller, Douglas R Lowy, Leen-Jan van Doorn, Sholom Wacholder, Aimée R Kreimer, CVT Vaccine Group, Rolando Herrero, Mario Alfaro, M Concepción Bratti, Bernal Cortés, Albert Espinoza, Yenory Estrada, Paula González, Diego Guillén, Silvia E Jiménez, Jorge Morales, Luis Villegas, Lidia Ana Morera, Carolina Porras, Ana Cecilia Rodríguez, Allan Hildesheim, Aimée R Kreimer, Douglas R Lowy, Nora Macklin, Mark Schiffman, John T Schiller, Mark Sherman, Diane Solomon, Sholom Wacholder, Enrique Freer, José Bonilla, Alfonso García-Piñeres, Sandra Silva, Ivannia Atmella, Margarita Ramı, Ligia Pinto, Troy Kemp, Martha Hutchinson, Mary Sidawy, Wim Quint, Leen-Jan van Doorn, Linda Struijk, Rolando Herrero, Wim Quint, Allan Hildesheim, Paula Gonzalez, Linda Struijk, Hormuzd A Katki, Carolina Porras, Mark Schiffman, Ana Cecilia Rodriguez, Diane Solomon, Silvia Jimenez, John T Schiller, Douglas R Lowy, Leen-Jan van Doorn, Sholom Wacholder, Aimée R Kreimer, CVT Vaccine Group, Rolando Herrero, Mario Alfaro, M Concepción Bratti, Bernal Cortés, Albert Espinoza, Yenory Estrada, Paula González, Diego Guillén, Silvia E Jiménez, Jorge Morales, Luis Villegas, Lidia Ana Morera, Carolina Porras, Ana Cecilia Rodríguez, Allan Hildesheim, Aimée R Kreimer, Douglas R Lowy, Nora Macklin, Mark Schiffman, John T Schiller, Mark Sherman, Diane Solomon, Sholom Wacholder, Enrique Freer, José Bonilla, Alfonso García-Piñeres, Sandra Silva, Ivannia Atmella, Margarita Ramı, Ligia Pinto, Troy Kemp, Martha Hutchinson, Mary Sidawy, Wim Quint, Leen-Jan van Doorn, Linda Struijk

Abstract

Background: Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination.

Methods and findings: A total of 7,466 women 18-25 years old were randomized (1∶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CI = 63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CI = 63% to 79%) (p versus oral VE = 0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses.

Conclusions: HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer. ClinicalTrials.gov, Registry number NCT00128661.

Conflict of interest statement

Competing Interests: JTS and DRL report that they are named inventors on US Government-owned HPV vaccine patents (US 5,437,951; US 5,709,996; US 5,716,620; US 5,744,142; US 5,756,284; US 5,871,998; US 5,985,610; US 7,220,419; and US 7,361,356: “Self-assembling recombinant papillomavirus capsid proteins”) that are licensed to GlaxoSmithKline and Merck and for which the National Cancer Institute receives licensing fees. They are entitled to limited royalties as specified by federal law. The following authors: Wim Quint, Leen-Jan van Doorn and Linda Struijk are employed by the commercial company DDL Diagnostic Laboratory, Rijswijk, The Netherlands. Vaccine was provided for our trial by GlaxoSmithKline Biologicals (GSK), under a Clinical Trials Agreement with the National Cancer Institute. GSK also provided support for aspects of the trial associated with regulatory submission needs of the company under FDA BB-IND 7920. The other authors declare that they have no conflicts of interest. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Consort diagram.
Figure 1. Consort diagram.

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