HPV vaccination in Italy: perspectives after 1-year experience.

Since January 2008, the Italian Regions, in accordance with their organizational programme, have launched the offer of free human anti-papillomavirus vaccine (HPV) to 12-year-olds, with the possibility to extend this offer to other age groups. With the beginning of this vaccination campaign, a widespread scientific debate developed concerning certain aspects which are still disputed. In our opinion, therefore, it was decided worthwhile making a review of articles appearing in the literature over the last year, in particular reports published after the onset of commercialisation, in the attempt to gather together useful elements that would contribute to improve the vaccination strategies. Development, therefore, of a vaccine to reduce the impact of the infection, in terms of morbidity and mortality, has now become of prime importance as far as concerns public health worldwide. The European Medicines Evaluation Agency (EMEA) has authorized the use of 2 anti-HPV vaccines: since September 2006, a quadrivalent vaccine (Gardasil®, Sanofi Pasteur MSD) containing Virus-like Particles (VLPs) of the HPV-16, HPV-18, HPV-6 and HPV-11 genotypes, produced in Saccharomyces cerevisiae and with an amorphous alluminium hydroxyphosphate sulphate (AAHS) adjuvant and, since September 2007, a bivalent vaccine (Cervarix®, GlaxoSmithKline) containing VLPs of the HPV-16 and HPV-18 genotypes, produced in insect cell lines and with the AS04 (aluminium and monophosphoryl-lipid A hydroxy adjuvant). Since 2006, Gardasil®, has also been granted approval by the Food and Drug Administration (FDA) in the United States. Treatment indications* for both these products are aimed at prevention of cervical precancerous lesions and cervical cancer caused by HPV 16 and 18, which are held responsible for approximately 70% of all cases of cervical carcinoma [1]; Gardasil® is used, furthermore, in the prevention of lesions correlated with HPV 6 and 11, responsible for 70-90% of genital condylomas and 10-20% of low grade of Cervical Intraepithelial Neoplasia (CIN 1). Evidence that HPV 6 and 11 are associated with CIN 1 lesions confirms the significant frequency of these types in women with borderline cytological evidence, such as, abnormal Paptest, atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells of undetermined significance (AGUS) [2-5]. Gardasil® indications also include prevention of precancerous genital lesions at vulva (VIN 2/3) and vagina (VAIN 2/3) level. In this respect, one of the aims in the pharmaceutical development of vaccines was, indeed, that of extending the number of viral types of HPV in order to prevent the related pathological conditions, taking into consideration primarily cervical cancer, but not overlooking other tumours of the female genital tract and the early disorders, such as condylomas and low grade lesions correlated with the various viral types. The treatment used in the management of these lesions involves high costs which are not necessary and could, therefore, be limited with the use of a primary prevention programme [6, 7]. As far as concerns the host immune response, anti-HPV vaccines have been produced with an adjuvant in order to increase antibody response: it is well known, however, that the protection induced by these, even if mediated by the humoral response, cannot be correctly evaluated only by means of the immunological data, but need to be related to prevention of clinical lesions. As mentioned in the technical notes of these two products, no minimal antibody level has been identified as associated with protection against CIN, grades 2 and 3, or against persistent infection associated with the types of virus contained in the vaccine. Also for this reason, World Health Organisation (WHO) recommended undertaking clinical developments with clinical-histological endpoints, aimed at the definition of “precursors” as the surrogate of carcinoma, based upon precise observations focused on the biological behaviour of the intra-epithelial lesions (CIN 1, 2 and 3) [8]. In clinical studies involving young women, both vaccines were found to be efficacious as far as concerns primary and secondary endpoints associated with the types of HPV contained [9]; moreover, Gardasil® was demonstrated to be highly efficacious in the prevention of vaginal/ vulvar and genital condyloma lesions [10]. On the other hand, these two preparations do not appear to have any significant effect upon clearance levels and progression of the cervical infections caused by HPV [9], thus confirming their preventive rather than their therapeutic role. Furthermore, there is evidence of cross protection towards viral strains not directly contained in the quadrivalent preparation thus confirming the difficulty encountered in interpreting the mechanisms of the immune response and Key words