In 30 years, gender-neutral vaccination eradicates oncogenic human papillomavirus (HPV) types while screening eliminates HPV-associated cancers

Worldwide HPV-vaccination policy has not been fixed yet. Thus, it is important to note that if the World Health Organization (WHO [1]) and national governments only dared to think bigger, eradication of the most important high-risk (hr), oncogenic human papillomavirus (HPV) types 16/18/31/45 [2] from the 2010 birth cohorts onwards could materialize in 30 years (Figure 1(c,d)). With current HPV-vaccination coverage [3], this can in the Nordic countries, like eradication of mumps/ measles/rubella [Pauli Leinikki pers.commun], be achieved with gender-neutral vaccination as shown by our community-randomized implementation trial [4–6]. In comparison, with girls-only vaccination, similar reduction of hrHPV prevalence (i.e. eradication) is not foreseeable even in 100 years (Figure 1(a,b)) [3–7]. However, with the double-level of protection from gender-neutral vaccination and revised screening, accelerated elimination of all 600,000 HPV-associated cancers and 400,000 related deaths annually is within reach. Here, the biggest concern among the HPV-associated cancers is cervical cancer that largely affects developing countries.

Figure 1. Mathematical model [5,6] based prediction on the impact of implementing human papillomavirus (HPV) vaccination with 80% coverage according to the girls-only (a and b) vs. gender-neutral (c and d) strategy on HPV16 incidence in women (left) and men (right) by age and calendar time (years).

Vaccination is efficacious against both HPV infections and HPV-associated cancers [4,8]. HPV vaccines have further proven to be safe when evaluating onset of autoimmune diseases, fertility, and adverse pregnancy outcomes [9,10]. However, apart from the case in 22 countries, vaccination coverage is generally low (<50%) [3], and even the desired 80% to 90% coverage of girls-only vaccination strategy would never serve the entire populations. According to our model, parameterized with population-based Finnish contact structure and HPV prevalence data (for details, see [5] and the references therein) and assumptions overlapping our community-randomized effectiveness trial results [5], girls-only vaccination will permanently leave all males and unjustly deprived women [11] susceptible to hrHPV-infections (Figure 1(a,b)) and HPV-associated cancers. Protection of the unvaccinated females and males via herd effect by vaccinating part of both males and females starts to come into effect already in less than 5 years if the gender-neutral vaccination coverage reaches 40%. Unlike girls-only vaccination, the gender-neutral vaccination-derived herd effect includes also HPV16 infection which is a notoriously hard target due to its persistence [4,7]. By 70% to 80% vaccination coverage, the gender-neutral strategy would eradicate HPV16 and other hrHPV types from the HPV-vaccinated birth cohorts in 30 years (Figure 1(c,d)) [4–6].

Screening alone cannot stem the tide of the epidemics of HPV16 and subsequent associated cervical cancer in fertile-aged women driven by the sexual revolution [12]. Neither intensive opportunistic nor organized cervical screenings have been able to prevent the incidence of cervical cancer from tripling in fertile-aged Finnish women during the last 30 years from 2.6 to 7.5 cases/100.000 women years (Table 1, Figure 2). This not only demonstrates how incompetent cervical screening is in tackling HPV infection and associated cervical cancer epidemics but critically also the fragility of the WHO-defined cervical cancer elimination red-line (4 cases/100.000 women years).

Figure 2. Incidence of invasive cervical cancer (/100,000 women) in Finnish fertile-aged women (<40 years of age) during 1953–2018 (NORDCAN 2.0 https://nordcan.iarc.fr/en/ Database version 9.0 accessed on 11/07/202 [21]). The red dotted line indicates the cervical cancer elimination threshold specified by the WHO. The blue dots indicate the observed crude rate of each year.

Table 1. Incidence (age-specific incidence rates per 100,000 women) of cervical cancer in 20–39-year-old Finnish women over 60 years (NORDCAN)

	Age
Period	20–24	25-29	30–34	35-39	20–39
1954–1958	0.1	2.9	10.1	29.5	10.4
1959–1963	0.4	2.0	9.4	23.6	8.9
1964–1968	0.7	3.1	7.4	21.1	7.7
1969–1973	0.3	1.9	5.6	12.4	4.3
1974–1978	0.4	2.3	4.1	4.8	2.7
1979–1983	0.8	2.2	4.2	4.7	3.0
1984–1988	0.4	2.3	2.8	4.6	2.6
1989–1993	0.6	1.6	4.1	5.0	2.9
1994–1998	0.9	3.5	6.6	8.7	5.2
1999–2003	0.4	5.0	10.6	8.5	6.3
2004–2008	1.2	4.3	10.2	11.0	6.7
2009–2013	2.6	5.3	8.6	13.3	7.4
2014–2018	1.0	4.6	10.7	13.4	7.5

In the foreseeable future, HPV-vaccination coverage is likely to remain low to moderate in several EU countries [5]. Amidst HPV16 and imminent other hrHPV epidemics [12,13], such limited girls-only vaccination coverage (unlike the gender-neutral strategy) will leave the unvaccinated young women and men devoid of herd effect-derived protection [4–7]. Concomitantly, the decrease of HPV16/18 prevalence that follows even ineffective vaccination strategies is jeopardizing the predictive value of cervical screening [14,15]. Thus, while notable proportions of female birth cohorts would be protected by gender-neutral HPV vaccination directly and/or indirectly via herd effect, there is an urgent need for new screening strategies with less not more screening visits and HPV-independent cellular methylation marker-based triage [16,17]. Our randomized trials (www.clinicaltrialsgov.com: NCT02149030/NCT04755517 [18,19]) investigating the impact of infrequent vs. frequent screening in HPV-vaccinated women of screening age are soon providing proof of the infrequent screening concept [17]. The usefulness of such methylation marker triage in HPV-vaccinated women with cervical intraepithelial neoplasia will also be assessed in this setting.

While cervical cancer is mostly linked with hrHPV types 16/18/31/45 [2], oropharyngeal squamous cell carcinomas (OPSCCs) are up to 90% HPV16 positive [2]. The rapid increase in the HPV-OPSCC incidence, therefore, follows closely that of the HPV16 epidemics. Notably, even in the affluent countries, HPV-vaccination alone cannot rapidly tackle the ongoing epidemics of OPSCC (such as those in the USA and Nordic countries [20,21]). Up to 50 unvaccinated birth cohorts are too old to benefit from the sound primary prophylaxis and the associated herd effect provided by gender-neutral HPV vaccination which is now available for the younger birth cohorts. These birth cohorts could therefore benefit from complementary OPSCC screening. However, the lack of known precancerous lesions is posing a difficulty for screening of occult OPSCC.

The new measures outlined above to eradicate hrHPV-infections and eliminate cervical cancer may have the following caveats: (1) higher cancer risks among undefined unvaccinated subpopulations where background hrHPV incidence is higher, (2) the age peak of the hrHPV incidence is likely to shift upwards, (3) possible waning of vaccine-induced protective antibodies after the first sustainable 12 years [4], and (4) rapid replacement of vaccine HPV types with non-vaccine HPV types [17]). However, the ongoing randomized, population-based trial will tackle these caveats by monitoring the effectiveness and impact and possible adverse effects of these measures. Finally, with ample vaccine supply, unlikely infection pressure from unvaccinated older birth cohorts on vaccinated birth cohorts could be reduced by catch-up vaccination.

In conclusion, we do not accept girls-only vaccination strategy as a goal. Even high (read impossible outside school-based programs) girls-only vaccination is not enough against all hrHPV types. Furthermore, temporary constraints in vaccination supply is not an excuse to pursue the unfounded strategy. Undaunted proof on the outstanding impact of the gender-neutral vaccination [4–6] is pivotal for hrHPV eradication. Furthermore, emerging data on the impact of new screening modalities on HPV-associated cancer incidence in vaccinated and unvaccinated Finnish birth cohorts from the population-based cancer registry will hopefully provide a roadmap to effective control and the fastest possible elimination of all HPV-associated cancers.

Author contribution statement

All the authors have contributed to the conceptualization, interpretation of the scientific literature, writing, and editing for intellectual content in the preparation of this review article.

Declaration of Interests

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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

This short piece is dedicated to Professor Pauli Leinikki, steering committee chairman of the Finnish Community-Randomized Trial on the Effectiveness of Different HPV Vaccination Strategies on his 80th birthday.

Additional information

Funding

This manuscript was funded by Cancer Foundation Finland and the Jane and Aatos Erkko Foundation and the Horizon 2020 RISCC-network.