FUTURE / Quadrivalent HPV Vaccine Efficacy Trials

Cervical cancer prevention in the early 2000s rested mainly on Pap smear screening, a secondary prevention strategy that required repeated cytological examinations over a woman's lifetime and depended heavily on health system access for its effectiveness. HPV types 16 and 18 together account for approximately 70% of cervical cancers globally, and Harald zur Hausen had found the tumor-causing HPV 16 type in cervical cancer biopsies in 1983 and cloned HPV 16 and 18 from patients in 1984. The logical next step was a prophylactic vaccine targeting those types.

Part of the scientific foundation came from Ian Frazer and Jian Zhou at the University of Queensland, who in the early 1990s developed the technology to produce virus-like particles, proteins that assembled into the structural shell of HPV without containing viral DNA. VLPs could generate a strong immune response without being infectious. Zhou died in 1999, before the vaccine reached licensure. Merck licensed the VLP platform and developed the quadrivalent formulation targeting HPV types 6, 11, 16, and 18, with types 6 and 11 responsible for most genital warts.

The FUTURE I and FUTURE II trials randomized more than 17,000 women aged 15 to 26 to the quadrivalent vaccine or placebo across multiple countries. In women who were seronegative and DNA-negative at baseline for the relevant types, the per-protocol efficacy against HPV 16/18-related CIN 2/3 or adenocarcinoma in situ reached 98% in FUTURE II. FUTURE II alone randomized 12,167 women, and Diane Harper was among the authors of the FUTURE I report. The FDA licensed Gardasil on June 8, 2006, on the basis of these trials.

The FUTURE II paper also showed the vaccine's limits. Among all randomized women, including those already infected, efficacy against HPV 16/18-related high-grade lesions was 44%, and against high-grade lesions of any HPV type 17%, so the benefit depended on vaccinating before exposure. In March 2007 the US Advisory Committee on Immunization Practices recommended a three-dose series for girls at 11 to 12 years, allowed it from age 9, and advised catch-up vaccination from 13 to 26. Vaccinating children before sexual debut, and the cost of the series, drew public debate, and how long protection lasted was not yet known at licensure.

The United States recommended routine vaccination in 2007, and Australia began vaccinating all women aged 12 to 26 with the quadrivalent vaccine between 2007 and 2009. In Victoria, high-grade cervical abnormalities in girls under 18 were already falling by 2009, less than three years after the program began. The vaccine's scope expanded progressively: vaccination programs extended to boys in several countries, and a nine-valent formulation covering seven oncogenic HPV types replaced the quadrivalent version as the standard product. Genital warts, caused mostly by types 6 and 11, were a second target of the quadrivalent vaccine.