HPV-vaccination impact in Denmark: is the vaccine working?

1. Cervical cancer control in Denmark

Denmark has a high background risk of cervical cancer at an incidence level of 31 per 100,000 (World Standard Population) in the pre-screening period [1]. Fifty years’ of screening has helped to bring down this risk, and the incidence is now at 10 per 100,000 in line with the level in some other European countries, such as Norway. But the good effect of screening comes at a cost. In a population of only 5.8 million people, we currently take 400,000 cytology samples per year; 40,000 women undergo follow-up for abnormalities; and 6000 women – equivalent to every fifth women in a birth cohort – undergo conization [2].

The HPV-vaccination was therefore a highly appreciated new tool in control of cervical cancer in Denmark. The HPV-vaccine was marketed in 2006, but at a high price. In the population at large, HPV-vaccination therefore took off only after the vaccine was included in the childhood vaccination program, provided by the general practitioners free of charge for the girls. From October 2008, girls aged 13–15 years, born in 1993–1995, were offered vaccination; and from January 2009 vaccination was offered to all girls turning 12 years. From August 2012, a catch-up program was offered for women aged 19–26 years. Gardasil was used during the first 7 years of the Danish vaccination program; then Cervarix for 1.5 years, and from the autumn of 2017 Gardasil-9.

2. HPV-vaccination in Denmark: impact on cervical cancer risk

Precancerous lesions of the cervix uteri do not give rise to symptoms. The effect of HPV-vaccination can therefore be measured only after the vaccinated women have attended screening. We studied the outcome of screening in women born in 1993 after they were invited to their first screen in 2016, when they turned 23 years [3]. In this closed cohort, 92% had had at least one dose of HPV-vaccine. For comparison, we used women born in 1983, where no one had been HPV-vaccinated before first invitation to screening. The cohorts had the same screening coverage of 60%, approximately the same proportions with high school exams and based on available data the same average age of 16 years at sexual debut.

At first cytology screen, the detection rate for high-grade squamous intraepithelial lesion (HSIL) was 40% lower for women born in 1993 than for women born in 1983. This outcome is in line with what should be expected based on the randomized controlled trials on Gardasil [4]. In Denmark, women with HSIL are referred directly to a gynecologist for colposcopy and biopsies, and it is in the HSIL group that the majority of cervical intraepithelial lesions in need of treatment are expected to be found. However, there was a 40% higher detection rate of atypical cells of undetermined significance (ASCUS) in the vaccinated 1993 cohort than in the non-vaccinated 1983 cohort. This was surprising, as a 17% decrease should be expected based on the randomized controlled trials on Gardasil [4]. A shift in screening technology might be the reason for this unexpected finding. In 2006, where the majority of the 1983 cohort was screened, conventional cytology was the predominant screening technique in Denmark. In 2016, where the majority of the 1993 cohort was screened, all of Denmark had changed to liquid-based cytology mostly SurePath. For selected laboratories, we have found previously that the shift to SurePath was associated with an increase in the ASCUS detection rate in young women [5]. In Denmark, women below the age of 30 years with ASCUS are referred for repeated screening in 6 months, and only referred for a gynecologist if their cytology continues to be abnormal. We are currently collecting the follow-up data on cytology and histology from the women born in 1993.

Denmark offers good possibilities for evaluation of health interventions as all Danes are registered in the Central Population Register with a unique personal identification number, and all actions in the health sector are registered to these numbers. In order to make the correct use of these data, it is, however, necessary to know these data bases as well as the coverage may change; treatment codes may change, etc. In the evaluation of HPV-vaccination’s impact, we for instance had to exclude women from 1 out of 16 geographical areas, as the registration of cytology samples was not complete from this area back in time.

3. Long-term impact of HPV-vaccination in Denmark

HPV infection is not associated only with an increased risk of cervical cancer but also with cancer of the vulva and vagina (women), penis (men), anus, and oropharynx. The number of cancers in Denmark today causally associated with HPV is estimated to be 548 cases in women and 234 cases in men [2]. HPV-associated oropharyngeal cancers in men are on a rise [6], but the potentially preventable number of cancers is still higher in women than in men, because 1300–1900 cases of cervical cancer would have been expected in the absence of screening [2].

Modeling data indicate that due to the herd immunity, almost all women and men will be protected against HPV16 infection – and higher numbers for the other oncogenic HPV types – if 80% of girls are vaccinated [7]. At the start of HPV-vaccination in Denmark, this seemed to be an achievable aim as 80–90% of each birth cohort of girls had at least one dose of the vaccine. HPV-vaccination had higher coverage than cervical screening, where the coverage is 75%, and even the majority of daughters of non-screened women were vaccinated [8]. An early indicator of herd immunity in Denmark was a decline in genital warts in both women and men [9].

But things changed. In 2012, a number of cases of postural orthostatic tachycardia syndrome (POTS) and similar syndromes in young women were reported and hypothesized to be associated with HPV-vaccination [10]. These possible adverse effects were highlighted in a television documentary, and a negative attitude toward HPV-vaccination thus disseminated on social media. This was followed by a dramatic decrease in HPV-vaccination coverage from the previous 80–90% to 20–30%. In 2015 the European Medicines Agency (EMA) reviewed the literature and found no evidence for a causal association between HPV-vaccination and POTS and related syndromes [11]. Later studies in Denmark found girls reporting possible adverse effects to have been more frequent users of the health-care system than other girls even before the HPV-vaccination [12,13], indicating that factors other than the vaccination might have caused the syndromes.

Slowly the concern about possible side effects of HPV-vaccination subsided, and HPV-vaccination coverage increased. As an example, in June 2016 where all girls born in 2002 could have been vaccinated, this was the case for only 27%. In June 2018, this percentage had increased to 73%. This was a good development, but as the HPV-vaccine works best in HPV-naïve women, it was unfortunate that girls who could have been vaccinated at the age of 12 years were instead vaccinated at the age of 15–16 years, where more than one third of them are sexually active [14]. The initial, very good prospect from the start of HPV-vaccination in Denmark of reaching herd immunity was thus temporarily postponed for a 4–5 years’ period before HPV-vaccination regained momentum.

From the autumn of 2017, Gardasil-9 has been offered in the childhood vaccination program. A concerted effort StopHPV was initiated in spring 2017 by the Health Authorities, the Cancer Society, and the Medical Association to disseminate evidence on HPV-vaccination [15], including a website with answers to often-asked questions: YouTube film with women diagnosed with cervical cancer, and a Facebook group. Also, from the spring of 2018 boys attracted to boys are offered free vaccination as they will not benefit from the herd immunity generated by vaccination of girls. The Danish Health Authority is currently producing a health technology assessment looking at HPV-vaccination for all boys (Personal communication, Bolette Søborg, 2018).

4. Conclusion

Denmark is a high-risk country for cervical cancer. The incidence has in part been controlled by an extensive screening program, but this is not without cost. HPV-vaccination was therefore a valuable additional tool for control of cervical cancer in Denmark. When launched, the vaccination program gained wide support and 80–90% of targeted girls were vaccinated. Screening data from the very first HPV-vaccinated birth cohort indicate that the expectations from the randomized controlled trials on vaccine efficacy will be fulfilled. During the first years of the HPV-vaccination program, herd immunity seemed to be a realistic aim. But this was hampered by a dramatic decline in vaccination coverage following concern about possible side effects of vaccination. After a concerted effort by the health authorities, HPV-vaccination has now regained momentum and vaccination coverage has increased again.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed the receipt of lecture fees and support for conference participation from Sanofi Pasteur MSD.

Additional information

Funding

This work was financially supported by Kirsten and Freddy Johansen’s Fund.