Immunogenicity and safety of Gardasil among mid-adult aged men (27–45 years)—The MAM Study
Introduction
Human papillomavirus (HPV) infects the squamous epithelium of both genders, leading to anogenital condyloma acuminata and cancers of the penis, anus, and oropharynx in men [1]. In any 12-month period, the probability of a sexually active man acquiring a new genital HPV infection is 0.29–0.39 per 1000 person-months [2], [3], [4], comparable to estimates reported for women. However, unlike women, the rate of acquisition of new genital HPV infections in men remains constant with increasing age [5]. Correspondingly, an older median age at diagnosis of HPV-related cancers is observed in men compared to women. Underlying these differences by gender in HPV natural history with age may be differences in the immune response to natural HPV infection between the sexes. The proportion of men who are HPV seropositive is lower than that reported in women [5]. Among men and women who are HPV seropositive, antibody titers are higher in women compared to men, and antibodies to natural infection do not appear to provide protection against subsequent HPV infection in men, while partial protection is noted among women [6], [7]. This lower immune response to natural infection may partially explain the overall higher prevalence of HPV infections observed in men and the sustained incidence and prevalence of HPV infection at multiple anatomic sites (anal, genital, oral) observed across the lifespan of men.
HPV vaccination may be the only reliable method to provide protection against new HPV infections in men. As previously shown, the quadrivalent HPV (types 6/11/16/18) vaccine, Gardasil, was efficacious in preventing persistent anogenital HPV infection and external genital lesions caused by HPV 6/11/16/18 in men ages 16–26 years [8]. No previous studies have assessed whether healthy mid-adult aged men, those who are at higher risk of HPV-related cancers, could also benefit from HPV vaccination. Therefore, as a first step in evaluating the potential benefit of vaccinating mid-adult aged men, we conducted a single-arm HPV vaccine trial to assess the safety and immunogenicity of Gardasil in men ages 27–45 years.
Section snippets
Study population
This investigator-initiated clinical trial required the filing of an Investigational New Drug (IND) application with the Food and Drug Administration, as Gardasil is not currently approved for males over the age of 26. Seventy-five (75) participants each from the US (Tampa, FL) and Mexico (Cuernavaca) study sites were recruited from a cohort of men who completed ten biannual visits of follow-up in the ongoing prospective natural history study of HPV Infection in Men (The HIM Study). Men were
Results
As shown in Table 1, the median age of trial participants was 36 years (range: 27–45 years). Most men were white (45.3%) or of mixed race (43.3%), married (44.7%), and had completed some college at a minimum. Significant differences by country of residence were observed for all socio-demographic factors except reports of ever having sex with a man. At MAM Study enrollment, a small percentage of men had detectable levels of anti-HPV 6 (18.0%), 11 (6.0%), 16 (13.3%), or 18 (7.3%) antibodies in
Discussion
The quadrivalent HPV vaccine is safe and induces HPV antibodies against HPV 6, 11, 16, and 18 in 100% of vaccinated men ages 27–45 years. Consistent with prior HPV vaccine trials of females and males younger than 27, men in this mid-adult age group who had pre-existing HPV antibodies demonstrated higher antibody titers following vaccination than did men who were seronegative prior to vaccination [10], [11]. High antibody levels in response to vaccine were robust across country of residence, age
Conclusions
In conclusion, results from this Phase II trial of Gardasil demonstrate that the vaccine is safe and highly immunogenic among mid-adult aged men. These data support further study of HPV vaccination in mid-adult men to evaluate durability of the antibody response and efficacy against persistent HPV infections, particularly at the oral cavity where there is a near absence of data.
Conflict of interest statement
A.R.G. received a grant (IISP39265) from Merck and is a consultant for Merck. For the remaining authors, no conflicts of interest were declared.
Acknowledgements
This research was supported in part by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp.
The authors thank Merck Research Laboratories for supplying the quadrivalent HPV vaccine. We also thank those individuals who made significant contributions to this study, including Christine Gage, Andrea Bobanic, Kayoko Kennedy, Kathy
References (22)
- et al.
Randomized trial of HPV4 vaccine assessing the response to HPV4 vaccine in two schedules among Peruvian female sex workers
Vaccine
(2012) - et al.
Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study
Lancet
(2014) - et al.
Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study
Lancet
(2011) - et al.
Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study
Lancet
(2013) Human papillomaviruses
(2007)International HPV incidence among men ages 18–70 years
- et al.
Age-specific prevalence, incidence, and duration of human papillomavirus infections in a cohort of 290 US men
J Infect Dis
(2008) - et al.
Genital human papillomavirus infection in men: incidence and risk factors in a cohort of university students
J Infect Dis
(2007) - et al.
EUROGIN 2014 roadmap: differences in human papillomavirus infection natural history, transmission and human papillomavirus-related cancer incidence by gender and anatomic site of infection
Int J Cancer
(2015) - et al.
Prevalence of HPV infection among men: a systematic review of the literature
J Infect Dis
(2006)
Seroprevalence of human papillomavirus type 16 infection in the United States
J Infect Dis
Cited by (49)
Increases in human papillomavirus vaccine coverage over 12 months among a community-recruited cohort of gay, bisexual, and other men who have sex with men in Canada
2022, VaccineCitation Excerpt :The upper age limit for publicly-funded programs is based on the clinical trial used to authorize HPV vaccine for GBM that was conducted among sexually-inexperienced, young males aged 16–26 years [7]. More recent studies including GBM older than 27 years of age confirm optimal timing of HPV vaccination at younger ages, but also suggest some potential benefit in older men, even if they were more sexually experienced or had evidence of prior infection at the time of vaccination [48–50]. However, vaccine effectiveness studies to confirm clinical benefit in this age group are ongoing and public funding of HPV vaccination for older males is likely not cost effective at a population level [39,46].
Recommendations for prevention of infection in systemic autoimmune rheumatic diseases
2022, Reumatologia ClinicaDecision support needs for shared clinical decision-making regarding HPV vaccination among adults 27–45 years of age
2021, Patient Education and CounselingIncreases in HPV-16/18 antibody avidity and HPV-specific memory B-cell response in mid-adult aged men post-dose three of the quadrivalent HPV vaccine
2021, VaccineCitation Excerpt :A p value of ≤ 0.05 was considered significant. All men that received three doses of the quadrivalent HPV vaccine developed HPV-16 and HPV-18 antibodies [7]. The three doses of the quadrivalent vaccine also induced a significant increase in antibody avidity and thus, antibody affinity maturation at month 7 (Fig. 1).
Human Papillomavirus Vaccination Prevalence Among Adults Aged 19–45 Years: An Analysis of the 2017 National Health Interview Survey
2020, American Journal of Preventive Medicine