The prevalence and natural history of HPV infection in the head and neck region has not been well established yet. Our prospective Finnish Family HPV cohort on HPV dynamics among family members has shown that HPV infection can be acquired vertically by the newborn before, during and after delivery, and HPV can be found both in the oral and genital mucosa (Sarkola et al. 2008; Rintala et al. 2004, 2005; Syrjänen et al. submitted). The site of the first HPV infection may be through oral mucosa more likely than the genital mucosa. These infections of the newborns create cell-mediated immunity (CMI) against HPV, including the T memory cells (Koskimaa et al. 2014, 2015). In adult life, HPV prevalence seems to be lower in oral mucosa than in the genital region (Chung et al. 2013). Studies using mouth rinses/gargles have found HPV prevalence ranging between 0.9 and 7.5 % (Edelstein et al. 2012; Gillison et al. 2012; Pickard et al. 2012; Smith et al. 2007; Summersgill et al. 2001). With mucosal swab samples and using more sensitive HPV detection methods, HPV prevalence is considerably higher (Kero et al. 2012, 2014; Rautava et al. 2012a, b).

Understanding the natural history of HPV infection in its whole, and the events leading to head and neck infection and cancer in particular, is the critical questions to be solved before conclusions can be drawn whether the current HPV vaccine strategies of adolescents also protect against HNSCC.

Oral cavity has its own specific environment including saliva. Saliva has secretory immunoglobulin A (sIgA) which is important in the control of infectious agents on oral mucosal surfaces. A study showed that low levels of sIgA could make the individual more susceptible to oral HPV infection (Gonçalves et al. 2006). Saliva could be a noninvasive testing alternative to serum testing for HPV antibodies (Cameron et al. 2003). Women with cervical neoplasia showed significantly more sIgA for HPV16 than women with no cervical neoplasia (Marais et al. 2006). However, opposite results were reported from Costa Rican women by Kemp and co-workers (2012). Immunoglobulin levels could be more site specific than compartmental between mucosal sites (Passmore et al. 2007). Women with a persistent oral HPV infection showed higher levels of salivary IgG and lysozyme than women with no oral HPV infection (Haukioja et al. 2014). In this study, smoking was a risk of persistent oral HPV infection. Prophylactic HPV vaccination has also been shown to induce neutralizing antibodies in saliva (Handisurya et al. 2016). An approach of mucosal HPV immunization has also been explored, because mucosal surfaces are the site of HPV infection (Kichaev et al. 2013). In Sweden, it was shown that after gradual introduction of public HPV vaccination during 2007–2012, between 2013 and 2014, when 73 % of the women were HPV vaccinated, but not necessarily before their sexual debut, oral HPV prevalence had dropped to 1.4 % as compared with 9.3 % in 2009–2011 (p < 0.00001) (Grun et al. 2015).

HPV-associated HNSCC, more specifically the incidence of oropharyngeal cancer, is dramatically increasing in industrialized countries (Gooi et al. 2016; Marur and Forastiere 2016), but there are no data on vaccine efficacy against oropharyngeal HPV infections (Chaturvedi et al. 2011). Table 2 summarizes the prevalence of HPV in HNSCCs derived from systematic reviews including meta-analyses. Because the most common oncogenic HPV genotypes (HPV16 and HPV18) found in the head and neck malignancies are the same as in cervical cancer, the question is: do prophylactic HPV vaccines effectively prevent HPV-related head and neck pathologies (Beachler et al. 2015; Herrero et al. 2013). However, HNSCCs may also harbor HPV genotypes that are not so common in genital malignancies (Rautava et al. 2012a, b). Moreover, Gardasil has demonstrated protection against genital warts and penile/vulvar/vaginal/anal neoplasia in addition to cervical cancer (Schiller et al. 2012; Garland and Smith 2010; Goldstone et al. 2013). Vaccination efficacy is lower when the subjects have already an ongoing HPV infection (Lu et al. 2011). These data suggest that vaccinating the males protects them also against most vaccine HPV-type-related anogenital diseases, which has led to registration and use of these vaccines for males in some countries (Palefsky et al. 2011; Giuliano et al. 2011). For men, immunization through the oral mucosa might be even more important than for women, because the largest mucosal area of men is in the oral cavity (Marais et al. 2006). Quadrivalent vaccination also induces neutralizing antibodies in oral mucosal fluids (Handisurya et al. 2016). Cost-effectiveness analysis has shown that HPV vaccination for boys aged 12 years could be a cost-effective strategy for the prevention of oropharyngeal carcinoma (Graham et al. 2015).

Today, there is no knowledge of the preceding lesions in the continuum of oropharyngeal carcinogenesis. However, it has been shown that HPV16 E6 antibodies are detectable 10 years prior to the detection of oropharyngeal cancer (Lang Kuhs et al. 2016; Anderson et al. 2015; Kreimer et al. 2013).

Therapeutic HPV vaccines could eliminate preexisting lesions and infected cells. Before using HPV vaccine in the treatment of a certain patient, there should be established HPV status and histological results. However, today there is no agreed standard method for HPV testing. Most therapeutic vaccines have been developed with HPV16, against its oncoproteins. Targets for therapeutic intervention are HPV E6 and E7 oncoproteins since they are expressed at all levels of the HPV-infected epithelium and play a role in the induction and maintenance of HPV-related cancer.

There are trials ongoing with several different molecular targets. A phase I dose escalation trial of MAGE-A3- and HPV16-specific peptide immunomodulatory vaccines GL-0810 and GL-0817 showed T cell and antibody responses in a majority of HNSCC patients (n = 16) (Zandberg et al. 2015). One consequence of E6/E7 over-expression in HPV-associated oropharyngeal cancer is a strong expression of the cellular protein p16^INK4a (Reuschenbach et al. 2016). A recent report of phase 1/2a first-in-human trial on HPV DNA vaccine against cyclin-dependent kinase inhibitor p16^INK4a showed induction of cellular and humoral immune responses in advanced tumors without severe toxicities (Reuschenbach et al. 2016). This study with 26 patients included seven HNSCCs. With a mouse model, local irradiation and Shiga Toxin B-based HPV vaccination for treatment of HNSCC have shown promising results and are approaching early-phase clinical trials (Mondini et al. 2015). In another study with mice, intradermal DNA vaccines forming E7 recombinant retroviral virus-like particles (pVLP-E7) cured mice with already established tumors when combined with toll-like receptor (TLR) 7 and TLR 9 agonists (Lescaille et al. 2013). Also the PD-1:PD-L1 pathway has shown a possibility of therapeutic blockade analyzing tissue samples from tonsillar carcinoma patients (Lyford-Pike et al. 2013). For comparison, quadrivalent vaccination effectiveness in low-risk HPV-induced respiratory papillomatosis has either shown no effect in children (Hermann and Weckx 2016) or prolonged the intervals between the surgical interventions (Hocevar-Boltezar et al. 2014).