THE LANCET, Volume 364: Pages 1731-2,
November 13, 2004.




Vaccination against human papillomaviruses shows great promise

It took almost 10 years from the discovery of an association between human papillomavirus (HPV)and cervical cancer1 to the finding of HPV type 16 in cervical cancer tissue.2 It took another 10 years to show that past infection with HPV16 increases the risk for subsequent development of invasive cervical cancer,3 and yet another decade to show that the seven most prevalent HPV types cause 87% of all cervical cancers.4 By comparison,the creation of HPV virus-like-particle (VLP) vaccines has been a rapid breakthrough. VLPs mimic the true structure of the virion and induce a striking antibody response after vaccination.5 2 years ago, Koutsky et al6 showed that vaccination with HPV16 VLPs protected 768 vaccinated women from persistent HPV16 infection.

In today's Lancet, Diane Harper and colleagues now expand this rapid development in a phase 2 trial in just over 1100 participants, a study that lasted 2·5 years. VLPs of the two most important oncogenic HPV types, HPV16 and HPV18, were combined in a preventive vaccine. According- to-protocol and intention-to-treat analyses showed high efficacy for this bivalent vaccine against both the incident and persistent HPV16 and HPV18 infections. This efficacy turned out to be excellent even though the most sensitive method, vaginal self-sampling, was used to define the endpoints.

The efficacy of the bivalent vaccine against HPV18 infection is particularly important. HPV18 is more closely associated with cervical adenocarcinoma, which is more difficult to detect by Pap-smear screening. The target cells of this HPV type (and others such as HPV45) might be endocervical cells. This suggestion is seen in the disease associations—ie, HPV16 is more closely associated with cervical squamous-cell carcinoma, and HPV18 is more closely associated with cervical adenocarcinoma. From the public-health point of view, an intervention effective against cervical adenocarcinoma is indeed needed.

It is also important to emphasise that these oncogenic HPV types are associated with chronic infections,chronic diseases, and neoplasms in many other sites,such as the vulva, vagina, anus, penis, and oropharynx.7,8 The effectiveness of preventive vaccination against the oncogenic HPV types against the non-cervical HPV-associated neoplasms may be as good as against cervical neoplasia.

The cytological endpoints used by Harper and colleagues represent the clinical manifestations of infections with the oncogenic HPVs. It is encouraging that the bivalent vaccine protects against these cytological abnormalities and cervical intraepithelial neoplasia. However, long-term passive follow-up of cohorts of vaccinees and non-vaccinees by population-based cancer registries is needed to prove that HPV vaccination ultimately protects against invasive cervical cancer.9

Licensure of the HPV vaccine is not far away. It will probably be the first licensed vaccine against a common sexually transmitted infection. However, the implementation should be accomplished in a controlled way with community randomised trials. Several questions on the effectiveness and the public-health impact of vaccine implementation remain unanswered.9-11 How to implement HPV vaccination in national vaccination programmes to guarantee high coverage in adolescents before they become sexually active? Should both girls and boys be vaccinated? How many oncogenic HPV types should the vaccine contain? Is resurgence of oncogenic HPV types not included in the vaccine a real threat? When is booster vaccination required? Harper and colleagues show, for instance, that the vaccine induces a robust B-cell response, but it is not known whether it induces a significant T-cell response. While we trust that the remaining questions can be answered, a straightforward message of Harper and colleagues' work is that preventive vaccination against the oncogenic HPV types will soon be available.

*Matti Lehtinen,Jorma Paavonen
National Public Health Institute, Department of Infectious Disease Epidemiology, 00300 Helsinki, Finland (ML); and Department of Obstetrics and Gynaecology, University of Helsinki, Helsinki, Finland (JP)

We are both principal investigators in phase 3 trials of HPV vaccines for Merck and Co and GSK Biologicals.

  1. zur Hausen H. Human papillomaviruses and cancer. Bibl Haemotol 1975;43:569-71.
  2. Durst M, Gissmann,L, Ikenberg H, zur Hausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci USA 1983;80:3812-15.
  3. Lehtinen M, Dillner J, Knekt P, et al. Serological diagnosis of human papillomavirus type 16 infection and the risk for subsequent development of cervical carcinoma. BMJ 1996;312:537-39.
  4. Munoz N, Bosch X, de Sanjose S, et al. Epidemiological classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27.
  5. Harro CD, Susana Pang Y-Y, Roden R, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like-particle vaccine. J Natl Cancer Inst 2001;93:284-92.
  6. Koutsky LA, Ault KA, Wheeler CM, for the Proof of Principle Study Investigators. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:1645-51.
  7. Bjorge T, Engeland A, Luostarinen T, et al. A prospective study implicates human papillomavirus infection as a risk factor for anal and perianal cancer. Br J Cancer 2002;187:61-64.
  8. Mork J, Lie A-K, Glattre E, et al. A prospective study on human papillomavirus as a risk factor for head and neck cancer cancer. N Engl J Med 2001;344:1125-31.
  9. Lehtinen M, Paavonen J. Effectiveness of preventive human papillomavirus vaccination. Int J STD AIDS 2003;14:787-92.
  10. Garnett G, Waddel H. Public health paradoxes and the epidemiology of human papillomavirus vaccination. J Clin Virol 2000;19:101-12.
  11. Pinto L, Edwards J, Castle P, et al. Cellular immune responses to HPV16 L1 in healthy volunteers immunized with recombinant HPV16 L1 virus-like particles. J Infect Dis 2003;188:327-38.

(File created 3 January 2005)