Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data

The findings in table 3 are not unexpected. As reported previously by Brown et al.[1] and as stated in our manuscript,[2] we have also previously shown in the FUTURE I and II clinical trials that vaccination reduced the incidence of cervical intraepithelial neoplasia grade 3 or worse associated with 10 non-vaccine HPV types by 32.5% (6.0% to 51.9%), and the analyses in Table 3 suggest some of the subsequent disease that is prevented is due to protection against HPV types that are phylogenetically related to HPV6/11/16/18.

Also, as stated in our manuscript,[2] another study has shown the HPV6/11/16/18 vaccine generates an anamnestic response in women aged 15-26 who are seropositive pre-vaccination,[3, 4] and that the HPV6/11/16/18 vaccine prevents reinfection or reactivation of disease that is related to vaccine HPV types.[5]

The data presented in our manuscript also showed that only 2 women in the vaccine arm developed HPV6/11/16/18-related cervical disease post-surgery, compared with 9 in the placebo arm, corresponding to a vaccine efficacy of 79%. Six of the 9 women in the placebo arm who developed HPV6/11/16/18-related cervical disease post-surgery had a vaccine HPV type that was not detected in the original surgical specimen, suggesting the lesion that was diagnosed post-surgery was from a new infection and not due to residual disease. Four of the 6 women in the placebo group that developed HPV6/11/16/18-related cervical intraepithelial neoplasia post-surgery with an HPV type not in the original surgical specimen also reported at least one new partner during the interval between the first surgical surgery and the subsequent disease diagnosis.

For these reasons, the authors conclude the observed efficacy is related to vaccination. Although the exact underlying mechanism is not fully known, these observed reductions are felt to be clinically significant.

References

1. Brown DR, Kjaer SK, Sigurdsson K et al. The impact of quadrivalent HPV (type 6/11/16/18) L1 VLP vaccine on infection and disease due to oncogenic non-vaccine HPV types in generally HPV naive women aged 16-26. J Infect Dis 2009;199(7):926-935.

2. Joura EA, Garland SM, Paavonen J et al. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data. BMJ 2012;344:e1401.

3. Villa LL, Ault K, Giuliano AR et al. Immunologic responses following administration of a vaccine targeting human papillomavirus types 6, 11, 16 and 18. Vaccine 2006;24(27-28):5571-5583.

4. Olsson S-E, Villa LL, Costa R et al. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like-particle vaccine. Vaccine 2007;25(26):4931-4939.

5. Olsson S-E, Kjaer SK, Sigurdsson K et al. Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection. Human Vaccines 2009;5(10):696-704.

Human papillomavirus (HPV) quadrivalent vaccine cannot prevent progression of HPV infection to cervical lesion in women with ongoing HPV infection at the time of vaccination. The retrospective pooled analysis has demonstrated that HPV vaccine can significantly decrease the incidence of vaccine HPV 16/18 related-, non vaccine HPV 31 related- any subsequent cervical lesion in patients after cervical surgery. Vaccine was also associated with non-significant decrease of cervical intraepithelial neoplasia grade 1 or worse for seven other high-risk type of HPV, recurrent vulvar or vaginal low grade disease (genital warts, vulvar intraepithelial neoplasia grade I, or vaginal intraepithelial neoplasia grade I).

These conclusions are based on the two clinical trials of four years follow-up. However, authors have mentioned that prophylactic HPV vaccine can be efficacious for atleast 10 years quoting Rowhani-Rahbar A et al in their reference. Rowhani-Rahbar A et al have followed their monovalent HPV 16 vaccine recipient for period ranging from 7.2 to 9.5 years[1]. Bivalent HPV (type 16/18) and quadrivalent HPV (type 6/11/16/18) vaccine has shown their clinical efficacy against infection and cervical lesion for maximum period of 8.4 years and 5 years respectively[2,3]. Although the immune response of quadrivalent vaccine against HPV type 16 is maintained at five years, it wanes considerably against HPV type 18. Efficacy of quadrivalent vaccine is maintained against HPV 18 associated clinical endpoints despite the waning antibody level. There is no correlation between antibody level against HPV and the protection it offers against subsequent infection, cervical and other genital lesions[3,4]. Long-term surveillance of vaccinated subjects should include not only clinical follow-up of subjects to ascertain the efficacy of HPV vaccines but also correlation of titres of vaccine-induced antibody level with clinical efficacy.

References

1. Rowhani-Rahbar A, Mao C, Hughes JP, Alvarez FB, Bryan JT, Hawes SE, et al. Long-term efficacy of a prophylactic human papillomavirus type 16 vaccine. Vaccine 2009;27:5612-9.

2. Roteli-Martins CM, Naud P, Borba P, Teixeira J, De Carvalho N, Zahaf T, et al. Sustained immunogenicity and efficacy of the HPV-16/18 AS04-adjuvanted vaccine: follow-up to 8.4 years. Abstract presented at the 28th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), Nice, France,May 4–8, 2010.

3. Harper DM, Franco EL, Wheeler CM, Ferris DG, Jenkins A, Schiund A, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection
with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004;364:1757-65.

4. Joura EA, Kjaer SK, Wheeler CM, Sigurdsson K, Iversen OE, Hernandez-Avila M, et al. HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine. Vaccine 2008;26:6844-51.