Preface

I have been involved with studies on the causes and control of cervical neoplasia for close to 45 years. Evidence that helps rejecting the non-causal association between herpes simplex virus type 2 (HSV-2) and cervical cancer [1-3], and confirms the association between previous infection with human papillomavirus type 16 (HPV16) and development of cervical cancer later in life [4, 5] emerged 30-40 years ago. Like other cancers, cervical cancer is a multi-etiological disease. In a number of our cohort studies it was possible to set order among independent pieces of the puzzle like smoking [6] and infection with Chlamydia trachomatis [7], or interacting pieces like non-oncogenic HPV types 6/11 [8, 9] and HLA-type [10]. Chapter I of this book ends with a suggestion: Data from our Nordic cohort study setting that successfully participated in dissolving the etiology of cervical cancer should now be used to evaluate the performance of artificial intelligence in causal inferencing up to change of paradigma. This is now timely also to understand and tackle the cervical cancer epidemic that has been ongoing among fertile-aged Finnish women over the last 25 years [11].

Prophylactic vaccination against a defined infectious cause of human cancer followed by elimination of the cancer is not only the ultimate proof of related causality, but also the most efficient means to alleviate, even abolish the given infection-associated cancer-burden. Proving hepatitis B-virus (HBV) vaccine efficacy against hepatocellular carcinoma took 25 years [12]. Our active, from the beginning population-based, participation to phase II to phase IV trials that involved HPV-vaccine development, licensure, and implementation of HPV vaccination have produced safety, immunogenicity and efficacy data for both the bivalent and quadrivalent vaccines (for a review see Lehtinen and Dillner [13]). Besides providing reliable and uniquely sensitive safety data our population-based approach with health-registry linkages provided long-term (up to 15 years) immunogenicity follow-up for a head-to-head comparison of the licensed HPV vaccines [14, 15]. First evidence on the efficacy of the HPV vaccine against human cancer was provided, this time in 10 years from the vaccine licensure [16] and also from the above-mentioned population-based setting as described in Chapter II.

The bivalent and quadrivalent HPV vaccines were the first highly efficacious vaccines licensed against sexually transmitted infections and their sequelae, including HPV-associated immediate precancerous lesions [17-21]. The implementation of these vaccines into national vaccination programs has, however, been a disappointment with global HPV vaccination coverage in the targeted female age-groups being 12%, and not more than 43% in high-income countries, where vaccine price should not be an issue [22]. It is obvious that the WHO campaign to eliminate cervical cancer by 2030 is bound to fail unless new scientifically sound approaches are soon implemented. Chapter III describes in detail the Finnish community-randomized trial on the impact of different HPV vaccination strategies. Comparing the gender-neutral and girls-only vaccination of early adolescent birth cohorts we have proven the superb effectiveness of gender-neutral vaccination in the introduction of herd effect against HPV types 16/18/31/33/35 in less than four years post-vaccination [23-25].

Following already moderate gender-neutral HPV vaccination coverage, the ecological niche of the vaccine HPV types 16/18 becomes essentially vacated in four to eight years [26]. Various epidemiological approaches to identify the replacement of the vaccine types with non-vaccine, high-risk HPV types either in vaccinated women [27, 28] or unvaccinated women [29-31] have been unequivocal to say the least. This may have been because of the extremely short follow-up time for a single non-vaccine HPV type to take over the vacated ecological niche [32]. However, an ecological approach managed to disclose abrupt changes in the overall HPV type-distribution and documented replacement of HPV-vaccine types in the vacated ecological niche already four years post gender-neutral vaccination [26]. Chapter IV elaborates on how and why the ecological tools used were more suitable than conventional epidemiological tools when trying to disclose what was and is happening in the HPV population biology following prophylactic vaccination.

There is an imminent danger that the Swiss cheese model applies to preventative measures against cervical cancer. Females, who do not get vaccinated as adolescents are prone to be the least active participants in organized cervical cancer screening [33]. However, the HPV vaccination-derived herd effect extends protection also to the marginalized females. Besides the remaining high-risk HPV types identified in cervical lesions of the fully vaccinated sexually active population may have considerably lower progression potential [34, 35]. Chapter V elaborates on new possibilities in HPV-independent triage of cervical precancer in HPV-vaccinated women and women, who have been under herd protection and acquired cervical infections from non-vaccine HPV types only [35].

Non-cervical HPV-associated cancers comprise one of the last black boxes in terms of population-attributable fractions of vaccine HPV types. Especially, the rapidly increasing HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) calls for attention since it is already now as common as cervical cancer in a number of Western countries [36], and in the foreseeable future in a number of other countries as well. While prophylactic vaccination of HPV naïve birth cohorts is the ultimate solution also to HPV-associated OPSCC there are 30 to 50 young adult and middle-aged, most notably male birth cohorts that would benefit from effective screening of the disease. Most likely due to the anatomic location of the tumour, serological screening of HPV-OPSCC is possible due to the early appearance of HPV16 E6 protein antibodies 10 to 30 years before clinical diagnosis of the tumour. Chapter VI describes in detail the planned screening trial that again makes use of the Finnish cohort study setting with serum samples to be screened, which had already been taken 10 to 30 years ago [37].

In the post-vaccination era, when gender-neutral HPV vaccination has been implemented we are approaching the eradication of the most important oncogenic HPV types [11, 23]. This is qualitatively different from the WHO-pursued [38] elimination of cervical cancer below a certain low incidence (4/100.000) threshold. Finland is a striking example of how easily a country can slide above these arbitrary incidence thresholds. [11, 39]. How to reliably document impact and sustainability of such different public health interventions as prophylactic HPV vaccination, and screening and treatment of precancerous cervical lesions has not been solved yet [22]. On the contrary, the resilience of prophylactic HPV vaccination programs is being assessed as elaborated in the Endgame chapter.