ATLANTA — The efficacy of GlaxoSmithKline's human papillomavirus vaccine against cervical intraepithelial neoplasia grade 2 or higher has been confirmed in a final analysis of phase III data from more than 18,000 women in 14 countries.
And in a separate head-to-head comparison involving a total of more than 1,100 women, immune responses to the oncogenic HPV strains 16 and 18 were significantly better with GSK's Cervarix than with Merck & Co.'s HPV vaccine Gardasil, Dr. Gary Dubin said at the June meeting of the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices.
GSK's phase III data on Cervarix were submitted to the Food and Drug Administration in March 2009 and are still under review. The vaccine is currently licensed in more than 95 countries including 27 in the European Union, according to Dr. Dubin, vice president, North American clinical development, GSK.
The final analysis enrolled 18,644 women aged 15–25 years in a double-blind, randomized, controlled trial using the hepatitis A vaccine as the control. Mean follow-up was 39 months after the first of three doses.
The primary objective was to assess efficacy against the development of cervical intraepithelial neoplasia-2 (CIN2+) associated with HPV-16 and HPV-18 in women who were DNA negative and seronegative at baseline and DNA negative at 6 months for the HPV type considered in the analysis. The final analysis was conducted when at least 36 cases of the primary end point were observed in the according-to-protocol cohort.
Among the 14,656 seronegative women who had received all three doses of study vaccine, the overall efficacy of Cervarix against HPV-16/18 CIN2+ lesions was 93%. In total, 4/7,344 Cervarix recipients and 56/7,312 controls were found to have HPV-16/18 DNA in lesions during follow-up. Irrespective of baseline serostatus, vaccine efficacy was 91% for HPV-16/18.
In the subset of 11,641 totally vaccinated naive women, defined as those who at baseline had normal cytology, had no HPV DNA for 14 oncogenic types, and were seronegative for HPV-16 and HPV-18, Cervarix efficacy was 98% against HPV-16/18 CIN2+ lesions. For the total vaccinated cohort of 18,644 women, vaccine efficacy against HPV-16/18 CIN2+ lesions was 53%, reflecting the fact that many women in this cohort had preexisting lesions, he said.
Irrespective of HPV lesion type, the efficacy of Cervarix in the naive women was 70% against CIN2+ lesions and 87% against CIN3+ lesions. For the total vaccinated cohort, irrespective of HPV lesion type, Cervarix efficacy was 30% for CIN2+ lesions and 33% for CIN3+ lesions.
Examination by the cumulative incidence over time showed that lesion development occurred at the same rates in the vaccine and control groups until about month 18, when the curve separation became apparent.
This is because most of the lesions detected during the first 18 months of the trial were derived from preexisting infections. Only after there was a “washout” of these lesions did the prophylactic effect of the vaccine become apparent, Dr. Dubin pointed out.
Cervarix also had a significant impact on colposcopy referrals, with reductions of 26% in the naive group and 10% in the total vaccinated cohort. Cervical excision procedures were also affected, with reductions of 10% in the naive and 25% in the total vaccinated group compared with the placebo group.
Cervarix also showed efficacy against CIN2+ lesions caused by nonvaccine types that are genetically related to vaccine types, particularly HPV-31 (related to HPV-16) and HPV-45 (related to HPV-18), Dr. Dubin said.
A safety analysis showed identical rates of serious adverse events (7.5% with both Cervarix and hepatitis A vaccine) and of new-onset autoimmune disease (0.8% for both). There were similar rates of medically significant conditions (32% with Cervarix vs. 32% with placebo), congenital anomalies (0.7% vs. 0.5%), and spontaneous abortions (9.1% and 8.7%).
The head-to-head comparison was the first for the two licensed vaccines using the same methodology for immunogenicity and safety.
The primary objective was to compare the geometric mean titers of HPV-16 and HPV-18 serum neutralizing antibodies at month 7 following vaccination in women aged 18–26 years. A secondary end point was serum neutralizing geometric mean titers at month 7 in women aged 27–35 and 36–45 years.
The observer-blinded study was conducted at 40 U.S. centers in a total of 1,106 women randomized to receive Cervarix or Gardasil according to the recommended administration schedules: 0, 1, and 6 months for Cervarix and 0, 2, and 6 months for Gardasil. Placebo injections were given to the Gardasil group at 1 month and the Cervarix group at 2 months.
Cervarix induced significantly higher serum neutralizing antibody titers than did Gardasil. In women aged 18–26, antibody titers for Cervarix were 3.7-fold higher against HPV-16 and 7.3-fold higher against HPV-18 compared with results for Gardasil. In women aged 27–35 years, those differences were 4.8-fold and 9.1-fold, and for 36- to 45-year-olds, 2.3-fold and 6.8-fold.