Review – Andrology

Human Papillomavirus Infection and Vaccination in Males

By: Eugenio Ventimigliaa b , Simon Horenblasc, Asif Muneerd and Andrea Saloniaa b

EU Focus, Volume 2 Issue 4, October 2016, Pages 355-362

Published online: 01 October 2016

Keywords: Human papillomavirus, Infection, Penile cancer, Genital warts, Vaccine

Abstract Full Text Full Text PDF (618 KB)



Human papillomavirus (HPV) is the commonest sexually transmitted pathogen in humans and is linked to the aetiopathogenesis for both benign and malignant disease in men.


To evaluate and summarise the evidence for HPV infection and vaccination in men.

Evidence acquisition

A search of Medline, PubMed, and Scopus was performed to identify articles published in English within the last 10 yr addressing HPV epidemiology, the natural history of HPV infection and its long-term consequences, and vaccination in men. Relevant studies were then screened, and the data were extracted, analysed, and summarised. The Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria were applied.

Evidence synthesis

HPV has an overall prevalence of >20% among men, although a minority of individuals develop external genital lesions (EGLs). The risk of acquiring a new HPV infection is robustly linked to sexual behaviour, with the most commonly infected sites being the prepuce, shaft, glans, corona, and scrotum. Of all cancer cases among men, 2% are attributable to HPV, and up to 50% of penile cancers are estimated to be either directly or indirectly driven by it, with HPV-16 the subtype most frequently isolated. Currently there are two different vaccines approved for men, with a good immunogenic profile and efficacy of up to 80% against EGLs; however, efficacy data regarding malignant lesions are still limited.


HPV, owing to its high prevalence and harmful consequences for men's health, has recently attracted considerable attention. Novel insights into the natural history of HPV infection, together with the successful development of several efficacious vaccines, have provided valuable tools in the prevention of HPV infections and their related consequences. HPV vaccination appears to be the only reliable method to provide protection against new HPV infections in men.

Patient summary

Human papillomavirus (HPV) infection is very common among sexually active men and can lead to more serious consequences, including cancer. Male vaccination is both a safe and efficacious option preventing both HPV infection and its long-term consequences.

Take Home Message

Human papillomavirus (HPV) infection is highly prevalent among sexually active men, and up to 50% of penile cancer cases are related to HPV infection. Male vaccination appears to be an effective option to prevent HPV infection and reduce the risk of HPV-driven cancers.

Keywords: Human papillomavirus, Infection, Penile cancer, Genital warts, Vaccine.

1. Introduction

Human papillomavirus (HPV) is recognised in the aetiopathogenesis of a number of conditions in men, including condylomata acuminata (also known as genital warts) as well as penile, oropharyngeal, and anal cancer [1]. More than 100 different HPV types have been described as being responsible for the broad range of diseases driven by HPV, with variable clinical manifestations and risk of tumourigenesis [1]. More specifically, approximately 40 different HPV types show a specific tropism for the anogenital region [2]; remarkably, they also represent the most common sexually transmitted pathogens among men and women in the USA, with an estimated 6.2 million new cases each year [3]. Although the main focus of HPV research was historically dedicated to cervical cancer in women, growing interest in the role of HPV in men has developed during the last two decades. Therefore, a better understanding of the natural history and possible treatment/preventive options for HPV-related anogenital disease are more important [4]. Since cervical cancer has been more extensively studied, the natural history has been translated to male HPV-related lesions, although the natural history of HPV is thought to differ between the two genders [5], as reflected in the epidemiology of HPV-related disease. In 2008, the incidence of anal cancers attributable to HPV was slightly higher among women than men, whereas the opposite trend was observed for oropharyngeal cancers [5]. Moreover, among men there is no such overwhelmingly prevalent clinical entity as cervical cancer, which accounts for more than five times all the incident cases of HPV-related cancer in men [5]. Nonetheless, HPV seroprevalence, which is usually higher in women than in men [6], decreases in women with increasing age, while it does not in men [7]. This again illustrates the need for different models to gain a general understanding of the whole disease pathway, which could lead to a different approach in terms of disease prevention and treatment. The advent of vaccines has revolutionised the paradigm of disease prevention in women, particularly in relation to cervical cancer, which has led to the view that the same concept can be used for men. Three highly effective and safe vaccines against HPV are currently available: a bivalent, a quadrivalent, and a nonavalent vaccine. There is increasing evidence supporting a rationale for using these vaccines to prevent both benign and malignant HPV-related lesions in both women and men [8]. HPV vaccines are not only able to elicit an effective immune response against HPV [9] but also appear to be effective against cervical, vaginal, vulvar, and anal dysplasia and against condyloma related to the specific HPV types covered by the vaccine in women [8]. In men, it has been shown that the quadrivalent vaccine reduces the onset of external genital lesions (EGLs), in particular condyloma [10], as well as rates of anal intraepithelial neoplasia among men who have sex with men [11]. Despite evidence suggesting that prevention of HPV infection will help to prevent or reduce anogenital and oropharyngeal cancers as well as virtually all HPV-related diseases, clinical studies specifically focusing on these areas are still lacking.

This review summarises the evidence currently available in terms of HPV infection in men, and analyses its prevalence, main clinical characteristics, natural history, and links to neoplasms. Moreover, a specific section is devoted to describing the state of the art of human vaccines against HPV.

2. Evidence acquisition

An initial search was carried out using the Medline, PubMed, and Scopus databases. We largely selected publications from the past 10 yr (2006–2016), but did not exclude commonly referenced and highly regarded older publications. Keywords included: male human papilloma virus OR male HPV AND prevalence OR incidence OR natural history OR cancer OR vaccine [Title/Abstract]. Abstracts were reviewed by the panel for relevance to the defined review question. If it was not clear from the abstract whether the paper might contain relevant data, the full paper was assessed. The references cited in all full-text articles were also assessed for additional relevant articles. Non-English articles were excluded from the analysis. With the consensus of the co-authors, the relevant studies were then selected and screened, and the data were extracted, analysed, and summarised after an interactive peer review process of the panel. The Preferred Reporting Items for Systematic Reviews and Meta-analysis flowchart was used to report the numbers of papers identified and included or excluded at each stage (Fig. 1).


Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-analysis flow diagram showing the outcome of the initial and additional searches resulting in the full studies included in the review.

3. Evidence synthesis

3.1. Epidemiology and natural history

HPV epidemiology gives a general overview of the magnitude and importance of the whole topic. Owing to the high rate of silent infections and asymptomatic carriers [6], a proper estimation of the prevalence is difficult to obtain. According to a systematic review by Dunne et al [6], HPV DNA can be detected in the anogenital region of 1.3-72.9% of men, depending on the individual study design, sampling method, and study population. Importantly, more than half of the studies they included reported an overall HPV prevalence >20%. A subanalysis for the site of action revealed that the prepuce, shaft, glans, corona, and scrotum were the anatomic locations more likely to harbour HPV DNA, whereas HPV prevalence in urine was <7%. More recently, a prospective cohort study including 290 US men aged 18–44 yr examined at baseline and every 6 mo (mean follow-up 15.5 mo) provided interesting insights into the natural history of HPV infection [12]. At baseline, the prevalence of any HPV type was 30%. Follow-up data led the authors to report a 12-mo incidence of new HPV infection of 29.2%, with a cumulative incidence of 42.3% (slightly higher for the oncogenic types). The median time to clearance (time necessary to determine complete regression in at least 50% of infected subjects) of any HPV infection was 5.9 mo, and at 12 mo approximately three men out of four initially positive no longer had any detectable HPV DNA. Notably, approximately 90% of the study population was circumcised and 40% did not use condoms. However, there is a paucity of data available outside the USA sharing similar results [13] and [14]. HPV type may play a major role in determining clearance kinetics, as HPV-16 takes approximately twice as long to clear compared to HPV-18 [15]. In general, the risk of acquiring a new HPV infection is robustly linked to sexual behaviour with both female and male sexual partners, as is the likelihood of HPV clearance. Having either more than ten lifetime female sexual partners or more than two recent male anal sex partners is an important predictor of both HPV infection and persistence [15]. If there are clinically relevant differences in HPV natural history between men and women, it is not clear whether age impacts on the clearance process. More specifically, considering a 12-mo period, the probability that a sexually active man will acquire a new genital HPV infection is 0.29–0.39 per 1000 person-months, similar to values reported for women [12] and [16]. Nevertheless, while the risk of a detectable HPV infection apparently decreases among women during their lifetime, men seem to have a stable risk of acquiring new HPV infections during advancing years [15].

A recent advance in our understanding of the natural history of HPV infection in men was provided by the HPV Infection in Men study. The authors aimed to determine the cumulative incidence rate of EGLs at 6, 12, and 24 mo among 1788 HPV-positive men [17]. Some 5% of the cohort developed EGLs, but <10% of these lesions were penile intraepithelial neoplasia (PeIN). Genital HPV-6, -11, and -16 infections were more likely to progress to PeIN; remarkably, those types would be theoretically preventable with the quadrivalent vaccine.

3.2. Screening and prevention strategies

Although the role and impact of HPV on general health have been widely recognised over the last few years, established strategies for prevention among men are still mostly lacking, although acceptable local general standards of care exist.

HPV infection is difficult to diagnose in the absence of clear clinical manifestations, which only occur in a minority of infected individuals [14]. The timing of both screening and prevention is intertwined with the aim of prevention itself: it is one thing to prevent HPV infection (and therefore its sequelae); it is another to try to prevent cancer once HPV has infected the host. Before the advent of vaccines, this second option was the only possible way to target cervical cancer in women, considering the long, and therefore screening-friendly, time lag from HPV infection to cancer (20–40 yr) [18]. Although vaccines have shown undoubted advantages in terms of disease prevention, the potential of HPV vaccination in terms of public health improvement is still far from realised, since HPV-related diseases remain a significant morbidity and mortality burden around the world [8]. Unfortunately, all the lessons learned from the female HPV-related perspective are not directly translatable to the male perspective. However, Bosch et al [18] identified some elements of an ongoing paradigm change in HPV-related cancer prevention that make the screening/prevention process more appealing for males: (1) the considerable burden of HPV-related disease in both sexes, even outside the anogenital sphere; (2) the tested efficacy of human vaccination not only in women but also in men [10]; (3) vaccine accessibility in less wealthy countries; and (4) outstanding results from recent and ongoing vaccine trials [19]. Moreover, a vaccination strategy is likely to be cost-effective, if not even cost-saving; this holds true particularly in settings without organised cervical screening programmes [20]. Although it seems that this paradigm is unstoppable, it will take a long time before it is implemented. This is rather worrying considering men have a lack of preventative strategies such as those for cervical cancers, whereby routine screening based on Pap smears and/or HPV nucleic acid detection technology will facilitate transition towards high-coverage vaccination [18]. To date, neither the European Association of Urology (EAU) [21] nor the National Comprehensive Cancer Network [22] guidelines on penile cancer provide any hint regarding screening and prevention. More precisely, the EAU guidelines state that there is currently no recommendation for HPV vaccination in males because of the different HPV-associated risk patterns for penile and cervical cancers [21]. Moreover, the American Cancer Society has no recommendations regarding the use of HPV vaccines in men [23], although the US Food and Drug Administration (FDA) approved the quadrivalent and nonavalent vaccines for use in boys to prevent anogenital HPV infection and, therefore, condyloma and cancers. Ideally, these vaccines should be administered before the onset of any sexual activity, and are approved for different age ranges. In this context, the quadrivalent vaccine is approved for ages 9–26 yr, and the nonavalent vaccine for ages 9–15 yr. In addition to this, the Advisory Committee on Immunization Practices (part of the US Centers for Disease Control and Prevention) recommends that boys and young men receive either the quadrivalent or nonavalent vaccine; in particular, boys at ages 11 and 12 yr should routinely be vaccinated. It also recommends vaccination of males aged 13–21 yr who have not already had all three doses [23]. Vaccinations may also be given to boys as young as 9 yr and to men between the ages of 22 and 26 yr [23]. In this regard, the only data available concerning male vaccination show efficacy for condyloma, but not for penile, perianal, or perineal intraepithelial neoplasia in the intention-to-treat population [10].

3.3. Cancer and HPV in men

In the USA, it was estimated that approximately 35 000 cases of cancer in 2009 were attributable to HPV infection, accounting for 3.3% and 2.0% of all cancer cases among women and men, respectively [24]. Although HPV has been implicated in the carcinogenesis of male anal, oropharyngeal, and penile cancer, for the specific purpose of this review we focus on the latter. Penile cancer is usually regarded as a rare disease in the Western world, but can account for up to 10% of all male cancers in less developed countries [25]. HPV is a risk factor in penile cancer pathogenesis, along with several other recognised risk factors such as poor penile hygiene, presence of lichen sclerosus, and phimosis. HPV DNA can be isolated in approximately 47% of penile cancers, with high risk HPV-16 and HPV-18 being the two commonest types isolated [26]. However, the mere coexistence of HPV DNA and cancer is undoubtedly not sufficient to support a pathogenic role for HPV in carcinogenesis: biological data have led the International Agency for Research on Cancer to consider just 12 HPV types (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, and -59) as group 1 human carcinogens [27]. More specifically, potential transformation can be inferred from the presence in infected cells of viral transcripts encoding the viral E6 and E7 oncoproteins; these E6 and E7 oncoproteins induce degradation of p53 and pRb tumour suppressor proteins, followed by abnormal expression of p16INK4a and cyclin D1 (Fig. 2) [28]. The consequent pattern of expressed genes and up- and downregulated proteins was recently used by Alemany et al [29] to report HPV prevalence in the largest series ever published of invasive penile cancers and penile high-grade squamous intraepithelial lesions (HGSILs) from 25 different countries worldwide. The authors were able to detect HPV DNA in one out of three cancers analysed, but this rate decreased to 22–27% when markers of HPV oncogenic activity were added. HPV-16 was the type most frequently detected, and substantial geographic differences were observed for Africa, Latin America, and Europe, with the lowest prevalence in Asia. From the histologic standpoint, lesions including those with warty-basaloid features had the highest HPV DNA prevalence. In contrast to what has been reported for other anatomic sites, HPV distribution in penile cancer does not seem to be influenced by age [29]. Little is known about the impact of HPV on the prognosis of penile cancer. Data suggest that high-risk HPV DNA presence in cancer specimens is associated with favourable 5-yr disease-specific survival when compared to HPV-negative cancers (96% vs 82%), with a hazard ratio of 0.2 after adjusting for stage, grade, lymphovascular invasion, and age [30].


Fig. 2

Oncogenic human papillomavirus (HPV) replicative cycle. Once a HPV viral particle enters the cell and becomes uncoated, viral DNA (red) self-replicates (a) thanks to cell polymerase (POL). The virus exploits the cell's machinery to synthetize viral structural proteins (b); the viral DNA (d) is eventually integrated into the cell genome (black). Newly synthesised viral DNA and structural proteins assemble to produce replicated viral particles (c). The integrated viral DNA allows for transcription of the viral proteins E6 and E7 (e), whose inhibitory action on p53 and pRb causes abrogation of cell-cycle checkpoints and, eventually, carcinogenesis.

Both the epidemiologic and biological relevance of HPV in penile cancer highlight the importance of adequate prevention strategies. Of importance, the nonavalent vaccine would theoretically protect against 85% of the HPV types detectable in penile cancer specimens, and up to 92% in penile HGSILs [29]. Unfortunately, data regarding the preventive efficacy of HPV vaccines in men are mostly limited to benign EGLs [10], arguing on one hand for more compelling evidence, but on the other hand limiting the explicit indication for vaccine use in this setting.

3.4. Vaccination

There are several valid arguments and benefits supporting a HPV vaccination strategy for men.

Vaccination in the HPV setting has to be primarily intended as preventive. There are at least five important reasons why prevention plays such an important role when dealing with HPV infection. First, from the epidemiologic standpoint, HPV is highly prevalent in both the male and female populations, and is the most common sexually transmitted disease in the sexually active population in the USA [3]. Second, the majority of infected individuals do not present with overt clinical signs of ongoing infection, and therefore can carry the virus unaware [14]. The third reason is related to the lack of general awareness about HPV infection and its consequences, even in developed countries with acceptable standards of care [31]. Fourth, there is no etiologic treatment available for HPV infection. This, along with the not uncommon chance of both persistence and re-infection, means that HPV has an almost inexhaustible reservoir. Finally, as a consequence of point 4, since HPV is actively involved in the pathogenesis of selected cancer histologies, a vaccine could theoretically prevent HPV-related carcinogenesis.

To date, three different HPV vaccines have been developed (Table 1): a bivalent vaccine covering HPV-16 and -18 (Cervarix, GSK, Rixensart, Belgium), a quadrivalent vaccine covering HPV-6, -11, -16, and -18 (Gardasil/Silgard, Merck, Kenilworth, NJ, USA), and, more recently, a nonavalent vaccine against HPV-6, -11, -16, -18, -31, -33, -45, -52, and -58 (Gardasil 9, Merck). All the three formulations include the recombinant HPV type-specific major capside protein, L1, which spontaneously self-assembles in HPV virus-like particles (VLPs), with several adjuvants eliciting a proper immune response that differs according to the vaccine type. All three vaccines are approved by both the FDA and European Medicines Agency (EMA). According to a World Health Organization position paper on HPV, HPV vaccines should be given via intramuscular injection into the deltoid area of the upper arm in three doses (at 0, 1 or 2, and 6 mo) for individuals aged >15 yr, or in two doses (0 and 6 mo) at age 9–15 yr [32]. Phase 3 trials revealed a very good safety profile, which was confirmed in large post-licensing safety studies [33]. These data were confirmed in the post-licensing setting [34], with an estimated incidence of adverse events following immunisation of 53.9 per 100 000 doses of HPV vaccine administered; the most frequently reported adverse events were syncope and local site reactions, accounting for the vast majority of the total number [33]. Early reports linked vaccine use to episodes of venous thromboembolism in young girls [35]; however, a recent study specifically addressing this issue found no association between venous thromboembolism and vaccination [36].

Table 1

Human papillomavirus vaccines available and indications by the main drug agencies supporting their use

VaccineHPV typesFood and Drug Administration indicationEuropean Medicines Agency indication
Cervarix16, 18Not indicated in menNot indicated in men
Gardasil6, 11, 16, 18– Boys and men aged 9–26 yr for the prevention of genital warts caused by HPV types 6 and 11
– Boys and men aged 9–26 yr for the prevention of anal cancer and associated precancerous lesions due to HPV types 6, 11, 16, and 18
Males aged from 9 yr to protect against the following conditions caused by specific HPV types:
– Precancerous lesions (growths) in the anus
– Anal cancers
– Genital warts
Gardasil 96, 11, 16, 18, 31, 33, 45, 52, 58Boys and men aged 9–26 yr for prevention of the following diseases:
– Anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58 (1.2)
– Genital warts (condyloma acuminata) caused by HPV types 6 and 11 (1.2)
– Anal intraepithelial neoplasia grades 1–3 caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58
Males from the age of 9 yr to protect against the following conditions caused by specific HPV types:
– Precancerous lesions (growths) in the anus
– Anal cancers
– Genital warts

Initial data regarding the efficacy of immunisation were surprisingly positive: antibody concentrations were one to four orders of magnitude higher than those measured in natural infections [37]. This, along with experimental evidence from an animal model [38], prompted the current assumption that HPV vaccines exert their protective role via neutralising antibodies [9]. Importantly, data on maintenance of the antigen-specific immune response are still lacking, as well as on possible underlying mechanisms. However, the general idea is that very low concentrations of antibodies should be protective [39].

The main effect exerted by vaccination is prevention of HPV infection before any exposure; therefore, it is routinely recommended during preadolescence (usually at 11–12 yr), although suggestions broadening the indications up to age are currently available [23]. Moreover, in males aged 10–15 yr, the immune response was not inferior compared with females aged 16–23 yr [40] and in males aged 9–15 yr compared to females aged 9–15 yr [41], with a seroconversion rate >99%. Similar results were reported for older males [42].

The recommendations by the main drug agencies mirror the aforementioned evidence (Table 1). In particular, the FDA approved the quadrivalent vaccine for the prevention of vaccine-specific HPV-related anal cancers and their precursors, and for vaccine-specific HPV-type genital warts in the age range 9–26 yr, with a three-dose schedule [43]. In the EU, the EMA approved the quadrivalent vaccine for the prevention of vaccine-type related anal lesions and of vaccine type–related genital warts (age ≥9 yr). For ages 9–13 yr, a two-dose vaccine schedule is approved; for individuals aged ≥14 yr, a three-dose vaccine schedule is approved [43]. In particular, for those aged 9–15 yr, immunobridging (equivalence of anti-HPV antibody concentrations) was the endpoint used to support licensing; for those aged 16–26 yr, the endpoint was disease (anal precursor lesions and genital warts) [43]. Few promising data [44] exist regarding males aged >26 yr, preventing any possible recommendation for this population. After showing a more than adequate immunologic outcome, the several vaccines tested proved to have noninferior prophylactic efficacy [8]. Among men, the quadrivalent vaccine is the only tested so far in an experimental setting [10]. In a randomised, placebo-controlled, double-blind trial enrolling 4065 men aged 16–26 yr without clinically detectable anogenital warts or genital lesions from 18 countries, Giuliano et al [10] found that the quadrivalent HPV vaccine prevented infection with HPV-6, -11, -16, and -18 and the development of related EGLs in males. The subjects were randomised to receive the vaccine or placebo and were followed up for a median period of 2.9 yr. In the intention-to-treat population, the vaccines had an observed efficacy of 60.2% in reducing the incidence of any genital lesion; analysis by lesion subtype revealed major effects on condylomata acuminata rather than on intraepithelial neoplasia. The efficacy was even higher (83.8%) in the per-protocol population (ie, those negative for HPV at baseline). The small numbers for the per-protocol population prevented any conclusion regarding intraepithelial neoplasia. The general idea that effective prevention of HPV infection will result in diminished clinical manifestations was indirectly corroborated by data from infection rates among unvaccinated Australian boys at a comparable age to women receiving the vaccine. The authors described a steep decrease in HPV detection in these subjects, unveiling potential insights in terms of herd immunity [45] and [46].

4. Conclusions

HPV is a highly prevalent infection among males, although the majority of infectious events are asymptomatic. Novel insights into the natural history of this disease and the successful development of several efficacious vaccines have provided valuable tools in the prevention of HPV infections and their related consequences. However, up until now there has been little high-level evidence supporting the use of vaccination in men to prevent the most feared consequence of HPV infection, which is the development of cancer. Despite all the advances and limitations, HPV vaccination appears to be the only reliable method to provide protection against new HPV infections and, probably, HPV-related cancers among men.

Author contributions: Eugenio Ventimiglia had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Ventimiglia, Horenblas, Muneer, Salonia.

Acquisition of data: Ventimiglia, Salonia.

Analysis and interpretation of data: Ventimiglia, Salonia.

Drafting of the manuscript: Ventimiglia, Salonia.

Critical revision of the manuscript for important intellectual content: Ventimiglia, Horenblas, Muneer, Salonia.

Statistical analysis: None.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: None.

Other: None.

Financial disclosures: Eugenio Ventimiglia certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.


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a Università Vita-Salute San Raffaele, Milan, Italy

b Division of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy

c Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands

d Department of Urology and NIHR Biomedical Research Centre, University College London Hospital, London, UK

Corresponding author. Division of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. Tel. +39 02 26435506; Fax: +39 02 26437298.

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