Abstract
Keywords
The GlaxoSmithKline Vaccine HPV007 Study Group reports a placebo-controlled (n = 1113; 560 in the vaccine group vs 553 in the placebo group) and a follow-up study (n = 776; 393 in the vaccine group vs 383 in the placebo group) [1]. These studies were carried out in 27 sites in three different countries (five in Brazil, five in Canada and 17 in the USA) to assess the efficacy of a prophylactic human papillomavirus (HPV) vaccine – HPV-16/18-AS04 adjuvanted vaccine. Cervical cancer is the second most common malignant disease in women worldwide, with the largest burden being in developing countries [2]. Some specific types, defined as ‘high risk’ HPV (type 16 and 18 being the most prevalent), have been identified as causative agents of cervical cancer and of its high-grade precursor lesions [3,4].
The prevalence of cervical HPV infection peaks among younger women in many populations, but it is unclear whether younger women are more vulnerable to incident HPV infection than older women or whether clearance is delayed [5]. Therefore, it is necessary to use a prophylactic vaccine in adolescent women before sexual debut. This study is interesting because it has been conducted in women who were naive to oncogenic HPV infection at the time of vaccination, and thus, these women represent the target population. The long-term duration of efficacy (up to 6.4 years) reported in these women suggests that antibody concentrations will remain high for many years – at least 20 years, as predicted by a mathematical model [6].
Results
In previous studies, the GlaxoSmithKline Study Group reported data on an intention- to-treat cohort [7,8]. In the present study, the analyses were carried out on the according-to-protocol cohort for efficacy for the virological end points (incident and persistent infection) and on the total vaccinated cohort for efficacy for the cytohistological end points.
In the according-to-protocol cohort, vaccine efficacy was 100% at the 6- and 12-month follow-ups, and in the total vaccinated cohort, vaccine efficacy remained high against incident HPV-16 or −18 infection for up to 6.4 years, achieving 100% of vaccine efficacy in cervical intraepithelial neoplasia grade I and II (CIN1 and CIN2). Moreover, vaccine efficacy was very high (96.7%) against cytological atypical squamous cells of undetermined significance associated with HPV-16/18, and 94.6% against low-grade squamous intraepithelial lesions. The analysis of cytohistological end points, independent of HPV DNA in the lesion, showed that vaccine efficacy against any cytological abnormal changes of atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions was 35.4% (95% CI: 17-6-49-5) and 39.4% (95% CI: 15 6–56-8), respectively, and vaccine efficacy against any CIN1-positive and CIN2-positive HPV was 50.3% (95% CI: 12.5-72.6) and 71.9% (95% CI: 20.6–91.9), respectively. The use of HPV-16/18-AS04 adjuvanted vaccine also conferred protection against HPV-45 and HPV-31 infections, which are the two oncogenic types most frequently associated with cervical cancer after HPV-16 and HPV-18, and are responsible for 10% of all cervical cancer cases [9]. This cross-protection against HPV-45/31 infection was also recorded during the 6.4-year follow-up, and vaccine efficacy for HPV-31 and HPV-45 was reported to be 59.8 and 77.7%, respectively. The safety profiles of the HPV vaccine and placebo were similar and the vaccine was well tolerated. There were serious adverse events in a few individuals, but no deaths.
Significance
Although we have known for a long time that HPVs are a family of viruses that are etiologically linked to a number of human diseases and cancers, there are no valid therapies for the infection at present. The only valid intervention is a prophylactic HPV vaccine that has proven efficacy and safety. Since antibody concentrations after natural infection are low and are doubtless insufficient to confer protection against the virus, the ideal vaccine has to induce high and sustained antibody titers. Indeed, HPV-16/18-AS04 adjuvanted vaccine, as was demonstrated in this study, produced high titers persisting for a long period together with a high presence of memory B cells. These findings were achieved by using the aluminum salt as an adjuvant, together with the immunostimulatory molecule, 3-O-desacyl-4 L-monophosphoryl lipid A [10]. The main goal for HPV vaccination is to maintain high antibody concentrations for long-term duration and in this report, 99% of the women remained seropositive for anti-HPV-16 and anti-HPV-18 IgG antibodies. After a peak response at month 7, there was a plateau between months 18 and 24 after vaccination, but antibody levels remained stable thereafter. During months 63–76, antibody concentrations against HPV-16 and HPV-18 were at least 13-fold and 12-fold higher, respectively, compared with those recorded after natural clearance of an infection. Indeed, during the follow-up, new cases of CIN2 were only recorded in the placebo group, proving that vaccine efficacy against precancerous cervical lesions was sustained over time with continuous exposure to infection and without other boosters of vaccination. This finding is also important because when such abnormal changes are identified, usual clinical practice dictates that women are referred for colposcopy, leading to anxiety and costs to the healthcare systems. Reduction of such follow-up and attendant treatment procedures would represent a vaccine benefit in addition to cervical cancer prevention. In conclusion, the data from the GlaxoSmithKline Vaccine HPV007 Study Group indicate that the window of protection after vaccination is more than 6 years; however, it is expected that it could be much longer, and a mathematical model indicates that protection could last for up to or more than 20 years.
Future perspective
It is extremely important that the worldwide population, in particular younger women, are educated regarding HPV and the HPV vaccine in order for individuals to make the appropriate decisions as to whether or not to vaccinate against this virus. Knowledge of HPV and of the HPV vaccine results is the only way to drive women towards making the right choice of undertaking HPV vaccination and, subsequently, reducing the incidence of cervical cancer. Although there is currently much attention surrounding HPV, observational studies are still necessary in order to sustain the safety and efficacy of the prophylactic HPV vaccine for a long time. Thus, the same GlaxoSmithKline Vaccine HPV007 Study Group is undertaking a separate follow-up study, continuing for up to 9.5 years after vaccination, in a subset of women from the present study. However, owing to the long latency period between infection and cancer, the benefits of a prophylactic vaccination would only be visible after decades [11,12] and, thus, it is fundamental to consider therapeutic vaccines or other therapies for already HPV-infected patients. Moreover, owing to the actual elevated costs, the use of these vaccines in developing countries is problematic. For these reasons, in the future, research should address both therapeutic vaccines and low-cost production technologies [13].
Executive summary
Cervical cancer is the second most common cause of death by cancer among women worldwide, and human papillomaviruses (HPVs) are the infectious agents responsible for the neoplastic transformation of the cervical epithelium. The two HPVs most frequently associated with malignancies are types 16 and 18.
Assessment of the efficacy of HPV-16/18-AS04 adjuvanted vaccine has been carried out in previous reports. In the evaluated study discussed in this articlle, a primary analysis of the efficacy was carried out on the according-to-protocol cohort for efficacy for virological end points (incident and persistent infection) and on the total vaccinated cohort for efficacy for cytohistological end points.
In an according-to-protocol cohort, vaccine efficacy was found to be 100% at the 6-and 12-month follow-ups, and in the total vaccinated cohort, vaccine efficacy remained high against incident HPV-16 or −18 infection for up to 6.4 years. No new cases of cervical intraepithelial neoplasia grade II were recorded in the vaccine group.
The greatest source of uncertainty with respect to the potential effect of HPV vaccines is the duration of the immune response; HPV-16/18-AS04 adjuvanted vaccine, by inducing high antibody concentrations against HPV16/18 for a long-term duration, may be considered to be the right answer.
Footnotes
The works of Francesca Paolini and Aldo Venuti are partially supported by the Italian Ministry of Health and Lega Italiana Lotta Tumori (LILT). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.