[NATAP] HPV Vaccine: end of HPV?

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The end for genital human papillomavirus infections?

(2 Editorials follow)

Lancet Oncology 2005; 6:256-257

Margaret Stanley

Department of Pathology, Cambridge University, Tennis Court Road, Cambridge CB1 2HF, UK

Nearly all cervical cancer and its precursor lesions are thought to arise from infection with one of the human papillomavirus (HPV) types.1 These viruses infect skin and mucosae, inducing epithelial proliferation and resulting in warts. About 30-40 types infect the genital tract. Types 6 and 11 and minor types cause anogenital warts, and are rarely detected in malignant anogenital disease. By contrast, HPV 16, 18, 31, 33, 35, 45, and 58, and about eight to ten other minor types, are oncogenic and are found in almost all cervical-cancer biopsy samples and in 90% of high-grade intraepithelial precursor lesions. HPV types 16 and 18 are the most commonly detected HPV in biopsy samples.2

Vaccines have been a cost-effective way to prevent viral diseases. Candidate vaccines for HPV consist of virus-like particles generated by recombinant expression of the major capsid protein, L1, in eukaryotic yeast or baculovirus expression vectors.3 The L1 virus-like particle is an empty capsid (ie, contains no DNA), that has correct conformation and seems to have identical morphology to, and contains the major neutralising epitopes of, the native virion. Proof-of-principle trials of adjuvant HPV 16 L14 or HPV 16 and 18 L15 virus-like particles have shown that 100% of vaccinees in the per-protocol cohort were protected against persistent infection with the homologous HPV type, whereas the placebo group had persistent infections with both HPV and cervical intraepithelial neoplasia (CIN).

Virus-like particles seem to work by eliciting high titres of neutralising serum antibody, but whether this is the actual mechanism by which the vaccine protects against infection is unknown. Nevertheless, concentrations of serum antibody to L1 and the persistence of the antibody response might be crucial for measuring the amount of protection. However, L1 virus-like particle vaccines give type-specific protection, and the number of types in the vaccine will thus be need to be increased to prevent 80-90% of cancers. But, whether such a polyvalent vaccine would result in immunological equivalence such that each component virus-like particle induced an antibody response that correlated with protection is unclear. In this issue of The Lancet Oncology, Villa and colleagues6 present results of a double-blind, placebo-controlled-efficacy trial of a quadrivalent (HPV types 6, 11, 16, and 18), aluminium-adjuvant vaccine in young women negative for HPV. In this study, concentrations of serum antibody to L1 in those assigned the vaccine were much the same for types 6, 11, and 18, but antibody concentrations against type 16 L1 virus-like particles were up to 1 log higher at both 7 months and 36 months after vaccination. As in previous reports, peak antibody concentrations were much higher in vaccinees than in seropositive non-vaccinated individuals at seroconversion, and these concentrations remained higher 36 months after vaccination, when antibody titres in the vaccinees had decreased. Despite the difference in antibody concentration, patients were protected against persistent infection with HPV 16 and 18, confirming data from previous trials. One patient in the vaccination group had verifiable HPV infection attributable to HPV 18. The antibody concentrations in this patient throughout the 36 months would have been of interest to know, because if this infection is from failure of the vaccine, then this patient could provide useful information of variables that correlate with protection.

Vaccines prevent disease not infection, and in this study no patients in the vaccinated group had CIN, whereas in the placebo group, seven had CIN and four had external genital warts. These results are consistent with previous data for protection against CIN induced by HPV 16 or 18, and raise hope that infections from HPV 6 and 11 can be similarly controlled. The apparent protection against disease induced by HPV 6 and 11 is encouraging, but larger trials will be needed before HPV 6 and 11 L1 virus-like particle vaccination can be confirmed to be protective. Endpoints for the efficacy of HPV 6 and 11 vaccines must, realistically, be disease endpoints, since the difficulties of adequately sampling widespread areas of anogenital skin for accurate assessment of the presence or absence of HPV DNA are formidable.

All trials to date of HPV vaccines have enrolled women, but genital HPV infections are mainly sexually transmitted and men will also need to be vaccinated if the whole population is to develop immunity. Interestingly, seroconversion rates in men with anogenital warts who are infected with HPV 6 or 11 are consistently lower than those in women,7,8 and trials of L1 virus-like-particle vaccines will need to also enrol men to confirm that responses are similar in men and women. Despite these caveats, we must be optimistic that the control of genital HPV infection, and morbidity and mortality associated with resultant disease is achievable-it could be the end of the affair with HPV.

MS is an ad-hoc consultant for Merck Vaccines, West Point, PA, USA; Sanofi Pasteur, France; and GlaxoKline Vaccines, Rixensart, Belgium, but is not a member of their scientific advisory boards and has no stock, share holdings, or patent interests in these companies. MS had a research collaboration with GlaxoKline Immunotherapeutics, age, UK, 1998-2004, on therapeutic HPV vaccines, which resulted in several publications

The Lancet 2004; 364:1731-1732

Vaccination against human papillomaviruses shows great promise

The Lancet November 2004; 364:1731-1732

Matti Lehtinen a and Jorma Paavonen b

a National Public Health Institute, Department of Infectious Disease Epidemiology, 00300 Helsinki, Finland

b Department of Obstetrics and Gynaecology, University of Helsinki, Helsinki, Finland

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.

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.9,10,11 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.

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