Immunogenicity and safety of Gardasil among mid-adult aged men (27–45 years)—The MAM Study

doi:10.1016/j.vaccine.2015.08.072

Vaccine

Volume 33, Issue 42, 13 October 2015, Pages 5640-5646

https://doi.org/10.1016/j.vaccine.2015.08.072 Get rights and content

Highlights

•
The quadrivalent HPV vaccine was administered to mid-adult men ages 27–45 years.
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100% of men seroconverted to each of the four HPV vaccine components.
•
Immune response to vaccine in men ages 27–45 was comparable to that in younger men.
•
Antibody response did not differ by age group or sexual orientation.
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No serious adverse events attributable to vaccination were observed.

Abstract

Background

The quadrivalent (types 6/11/16/18) human papillomavirus (HPV) vaccine, Gardasil, has demonstrated efficacy against persistent HPV infection and associated anogenital disease in males. The goal of this Phase II trial was to establish the immunogenicity and safety of Gardasil among mid-adult men ages 27–45 years.

Methods

One hundred and fifty men from Tampa, FL, US, and Cuernavaca, Mexico who met eligibility criteria (male, 27–45 years old, completed four years of follow-up in the HPV Infection in Men (HIM) natural history study) were enrolled. Subjects completed four visits over seven months, with Gardasil administered at Day 1 and Months 2 and 6. Sera were collected at Day 1 (pre-vaccination) and Month 7 (one month post-dose three). Anti-HPV6, 11, 16, and 18 IgG levels were determined by competitive Luminex immunoassay.

Findings

100% of men seroconverted to each of the four HPV vaccine components, and the vaccine was generally well-tolerated. Antibody responses to vaccine did not differ by age group or sexual orientation, regardless of HPV type, and were significantly higher at Month 7 among men who entered the trial seropositive for HPV 6 or 11.

Interpretation

The immune response to HPV vaccination in men ages 27–45 was comparable to that observed in younger men, in whom clinical efficacy was demonstrated. Further trials to assess the efficacy of HPV vaccines to prevent persistent HPV infections in mid-adult men are needed.

Funding

Merck & Co. Inc. was the main sponsor of this trial (IISP39256) and provided the study product.

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

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Immunogenicity and safety of Gardasil among mid-adult aged men (27–45 years)—The MAM Study

Highlights

Abstract

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study population

Results

Discussion

Conclusions

Conflict of interest statement

Acknowledgements

Vaccine

Lancet

Lancet

Lancet

Human papillomaviruses

International HPV incidence among men ages 18–70 years

Age-specific prevalence, incidence, and duration of human papillomavirus infections in a cohort of 290 US men

J Infect Dis

Genital human papillomavirus infection in men: incidence and risk factors in a cohort of university students

J Infect Dis

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

Prevalence of HPV infection among men: a systematic review of the literature

J Infect Dis

Seroprevalence of human papillomavirus type 16 infection in the United States

J Infect Dis