The results of the literature search are presented as Fig. 1 (PRISMA diagram). The initial literature search generated 468 references. 328 studies were left for abstract screening after duplicated articles were removed. By dual-screening abstracts P.M and E.M, through the application of the inclusion and exclusion criteria, excluded 238 studies and 90 studies remained to be reviewed in full. Following the full text review, 76 articles were excluded, and a further 6 articles were excluded during data extraction due to the articles not meeting the inclusion criteria. Most excluded articles either did not include males, did not provide data on HPV-positivity or vaccination status, or were inappropriate study types (i.e., had low level evidence and rigour).
For the final inclusion, 7 articles remained. All 7 articles were published in English from 2017–2021. The included studies comprised 2 systematic reviews, 2 cross-sectional studies, 1 randomised controlled trial, 1 pre-post study with no control group and 1 prospective cohort study. Study characteristics can be seen as Fig. 2 and in more detail in Appendix 1. Risk of bias and quality assessment outcomes as described by the critical appraisal tools, are also summarised below.
Study Characteristics
Anil et al. carried out a cross-sectional study which showed significantly (P = 0.007) decreased levels of oral HPV infections in vaccinated (0%) compared to unvaccinated males (2.13%)24. The researchers obtained data from 2627 males and females in the US National Health and Nutrition Examination Survey 2011–2014, describing their oral HPV status and the HPV-vaccination status (Table 5). This study noted however, that due to low uptake overall among men, the effect of HPV-vaccination on oral HPV-positivity was 17% at a population level, but only 6.9% in men, highlighting the need for further uptake of HPV-vaccination in men24.
An ongoing prospective longitudinal cohort study into Indigenous Australians by Jamieson et al., demonstrated evidence of HPV-vaccination in only 8.3% of participants, but did not distinguish between males and females (Table 5).25 The researchers followed 910 individuals over 12 months obtaining data on HPV-positivity, HPV-vaccination as well as various other healthcare related data. They noted that 3.3% of males were positive for oral HPV16/18 and this increased to 3.9% at 12 months follow up. 25 Unfortunately this study did not distinguish between vaccinated and unvaccinated individuals when describing HPV-positivity, thus it is unclear whether lack of vaccination led to this percentage increase.25
Katz et al. in 2020, used a cross-sectional study format and interrogated the correlation of OPC with HPV-vaccination using hospital databases (Table 5) 26. They found a relative risk ratio increase of 23.8 (P = 0.0015) of developing oropharyngeal cancer in the male subgroup if they were not vaccinated26. Out of 607,322 males, 3013 had previously had OPC and 7732 were HPV vaccinated26. Of those with oropharyngeal cancer 1 had received the HPV vaccine and 3012 had not, suggesting that HPV vaccination could have reduced the incidence of OPC in this group 26.
An ongoing randomised controlled trial by MacCosham and colleagues is currently investigating whether HPV-vaccination can prevent HPV transmission among HPV discordant heterosexual couples (Table 5)27. They have so far recruited 167 couples and although the group have not reported any preliminary results yet, it appears to be a comprehensive and useful study capturing oral HPV results at baseline, and over the course of five follow up visits spanning one year, following randomisation to Gardasil or placebo27. Similarly, HPV positivity would be an indication of OPC incidence in the future. While the results are pending, the inclusion of this study was appropriate in this systematic review, given its relevance of the subject matter to the question at hand27.
A systematic review was published by Nielsen et al. in 2021, highlighting the effect of HPV-vaccination on oral HPV-positivity (Table 5)29. They included 9 relevant studies from the past 5 years, comprising of 48,777 participants, and found a significant decrease of oral HPV-positivity in those immunised with HPV-vaccinations in multiple studies and heterogenous populations29. They reported a mean Relative Prevention Percentage (RPP) of 83.9% following vaccination, from the cross-sectional studies, an RPP of 82.4% from the included randomised controlled trial and 83% in the longitudinal cohort study29.
Parker et al., in a single arm intervention trial, measured oral HPV16/18 antibodies at multiple time points post HPV-vaccination in males aged between 27–45 years (Table 5)30. They found that 93.2% and 72.1% had HPV16 and 18 antibodies respectively, detectable in oral gargles 7 months post HPV-vaccination30 The use of antibody levels to predict the potential development of HPV-associated OPC is a novel approach which differs from the other included studies who focus on oral HPV and this will be discussed further below.
In an important study, Tsentemeidou et al. in 2021, undertook a systematic review and meta-analysis examining the link between oral HPV-positivity and HPV-vaccination, particularly pertaining to the risk of developing OPC (Table 5)15. They included 4 studies in the meta-analysis (N = 13,285). Unfortunately, these papers did not distinguish between males and females in the HPV data in these studies which meant they were not suitable for inclusion in this systematic review. This meta-analysis overall showed that those who had received the vaccine had 80% less chance of having oral HPV16 compared to unvaccinated individuals (P < 0.0001) 15. The authors also argued for oral HPV16 positivity to be a surrogate marker for future risk of developing OPC15.
The included studies have given rise to the following themes: a link between HPV and OPC; a potential benefit to the vaccination of males to reduce rates of OPC and the likely cost-effectiveness of pangender HPV-vaccination15,24,25,26,27,28,29,30. These themes will be discussed further below.