Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial

Abstract

Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months' follow-up. Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. Trial registrations NCT00092521 and NCT00092534. INTRODUCTIONHuman papillomaviruses (HPVs) are responsible for about 500 000 cases of cervical cancer a year globally 1 and 10 million further cases of high grade cervical intraepithelial neoplasias (grades II or III), 2 immediate precursors to malignancy. It is estimated that 30 million women and men acquire anogenital warts (condyloma acuminata) or low grade cervical intraepithelial neoplasia each year, 2 which may be an underestimation given the inadequacy of reporting in many countries and evidence of a rising incidence over time. Although many low grade lesions of the lower genital tract resolve spontaneously in immunocompetent subjects, this type of lesion contributes greatly to the clinical and economic burden of HPV disease in women. The psychosocial 3 4 and economic 5 6 implications of condyloma are substantial and reflect, in part, the high transmis...

Efficacy of Human Papillomavirus 16 and 18 (HPV-16/18) AS04-Adjuvanted Vaccine against Cervical Infection and Precancer in Young Women: Final Event-Driven Analysis of the Randomized, Double-Blind PATRICIA Trial

“…Efficacy was 96.5% against CIN1ϩ, 98.4% against CIN2ϩ, and 100% against the immediate precursor of invasive cervical cancer, CIN3ϩ. These results are generally in line with published data regarding efficacy due to vaccine types for the licensed quadrivalent HPV-6/11/16/18 vaccine in a similar cohort of women, despite there being differences in methodologies between these studies (24,25).…”

Could the human papillomavirus vaccines drive virulence evolution?

“…A 'leak' that has not been considered, and what we find here to be important, is what happens when the vaccine does not block infection and viral shedding. Given that challenge infections by vaccine-targeted types were detectable in vaccinated women [40] during HPV vaccine trials, we argue that the vaccine does not always fully block viral shedding. Indeed, a humoral response may not always provide perfect protection from viral challenge [53].…”

“…(d) Host heterogeneity: immune status HPV vaccine efficacy in immunocompetent patients is very high, where most vaccinated individuals clear challenge infections within six months [40]. The effect of the HPV vaccine in immunocompromised patients should be diminished, and overall the strength of the immune response will vary among individuals.…”

Broad Cross-Protection Is Induced in Preclinical Models by a Human Papillomavirus Vaccine Composed of L1/L2 Chimeric Virus-Like Particles

“…All three vaccines contain recombinant virus-like particles (VLPs) assembled from the L1 major capsid proteins of different HPVs and have demonstrated protective efficacy against HPVs in the vaccine (14)(15)(16)(17)(18). Moreover, the HPV-16/18 L1 vaccine and HPV-6/11/16/18 vaccine have also demonstrated different degrees of protective efficacy against nonvaccine HPVs (19,20), and even though head-to-head comparisons have not been performed, the HPV-16/18 L1 vaccine appears to elicit broader cross-protection than the HPV-6/11/16/18 vaccine (21).…”