Elsevier

Vaccine

Volume 24, Issues 27–28, 7 July 2006, Pages 5571-5583
Vaccine

Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18

https://doi.org/10.1016/j.vaccine.2006.04.068Get rights and content

Abstract

Human papillomavirus (HPV) infection causes cervical cancer and genital warts. Young women (1106) were randomized to receive one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 virus-like particle (VLP) vaccine or one of two placebo formulations. The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naïve and previously infected subjects. All three formulations were highly immunogenic. At Month 2 (postdose 1), among women with vaccine-type antibodies at baseline, vaccine-induced anti-HPV responses were ∼12- to 26-fold higher than those observed in baseline-naïve women, suggesting an anamnestic response. Following an initial, similar sized decline, anti-HPV responses plateaued and remained stable through end-of-study (3.0 years). No vaccine-related serious adverse experiences were reported.

Introduction

Human papillomavirus (HPV) infection is a cause of cervical cancer and genital warts [1], [2], [3], [4], [5], [6]. HPV infection is also associated with the development of anal, vulvar, vaginal, and penile cancers. The oncogenicity of HPV is mediated by the HPV E6 and E7 proteins, which induce accelerated and disordered cellular proliferation resulting in pre-cancerous epithelial lesions. Such lesions can progress to invasive cancer.

HPV infection is one of the most common sexually transmitted diseases worldwide [5], [6], [7]. The lifetime risk of HPV infection for sexually active males and females is approximately 50% [7]. An estimation of worldwide cancer incidence and mortality for 2002 showed that persistent HPV infection had caused about 500,000 cases of cervical cancer [8]. Despite organized screening programs using the Papanicolaou (Pap) test, approximately 35,000 women died from this disease in the USA and Europe [8]. While Pap testing reduces mortality from cervical neoplasia, it does not prevent HPV infection or development of pre-cancerous lesions such as high-grade cervical intraepithelial neoplasia 2/3 (CIN 2/3) and persistent low-grade lesions (CIN 1), all of which require treatment. A recent study has estimated that in the United States alone, cervical HPV-related disease accounts for a total health care cost of $3.4 billion (in 2002 dollars) [9]. Another non-negligible complication of genital HPV infection is anogenital warts, which affect approximately 1% of sexually active individuals between the ages of 15 and 50 years old [10].

Of the approximately 40 distinct HPV types that are known to infect the anogenital epithelium, only a small number cause the majority of disease. HPV Types 16 and 18 cause approximately 70% of all cervical cancer cases worldwide [3]. HPV 6 and 11 cause a majority of genital warts (men and women) [11]. HPV 6, 11, 16 or 18 are found in approximately a third of low-grade cervical lesions [12]. Thus, an effective HPV (Types 6/11/16/18) vaccine would target HPV types that cause about 70% of cervical cancers and high-grade pre-cancerous lesions, about a third of low-grade dysplastic lesions, and a majority of genital wart cases. Such a vaccine has the potential to substantially reduce the burden of clinical HPV disease in both men and women.

HPV is a small, non-enveloped, double-stranded DNA virus. The HPV L1 capsid protein, when expressed in yeast cells, forms non-infectious virus-like particles (VLPs) that resemble native virions [13]. Recent Phase I and II clinical trials have demonstrated that HPV vaccines based on the HPV L1 capsid protein are generally well-tolerated and induce neutralizing anti-HPV responses [14], [15], [16], [17], [18], [19], [20], [21], [22]. These trials served as the basis for evaluating a quadrivalent HPV vaccine targeting HPV 6/11/16/18.

Recently, we described results from a Phase II study designed to select one of three formulations of quadrivalent HPV (Types 6/11/16/18) L1 VLP vaccine for use in Phase III studies. This 3-year, randomized, placebo-controlled trial showed that the formulation comprising the lowest dose of HPV 6, 11, 16 and 18 L1 VLPs was generally well-tolerated and reduced the combined incidence of persistent HPV 6, 11, 16 or 18 infection or related genital disease by 90%, compared to placebo [20]. In this study, subjects with vaccine-type antibodies or DNA at baseline were eligible for vaccination. This design feature allowed for an assessment of the tolerability, immunogenicity, and efficacy of the quadrivalent HPV (Types 6/11/16/18) L1 VLP vaccine in women who had presumably already been infected with vaccine HPV types prior to enrollment. This report extends previous findings by presenting immunogenicity and tolerability results for all three doses of quadrivalent vaccine. These data provide the rationale for selecting the quadrivalent HPV vaccine dose used in Phase III studies. In addition, an exploratory analysis of the immunogenicity of this Phase III formulation in HPV 6, 11, 16, or 18-naïve and previously infected women, is presented.

Section snippets

Vaccine

The active quadrivalent vaccine consists of a mixture of four recombinant HPV type-specific VLPs (Merck Research Laboratories, West Point, PA) composed of the L1 major capsid proteins of HPV 6, 11, 16 and 18 synthesized in Saccharomyces cerevisiae [20]. The four VLP types were purified and adsorbed onto a proprietary amorphous aluminum hydroxyphosphate sulfate adjuvant (AAHS), also referred to as Merck Aluminum Adjuvant (MAA). The two placebo formulations contained the same adjuvant and were

Baseline demographics

The baseline demographic characteristics were generally well-balanced among the five vaccination groups (Table 1). These 13–24 year-old women were predominantly Caucasians and approximately 25% (277/1106) were current smokers. The mean age at first sexual intercourse was between 16 and 17 for each vaccination group. Over 60% (707/1106) of subjects reported fewer than 3 lifetime sexual partners at enrollment. The percentages of subjects who used barrier, behavior, hormonal, and other

Discussion

The duration of protection afforded by vaccines represents a critical test of their utility as public health interventions. Some vaccines induce long-term immunity. Others require the administration of booster doses. Experience with hepatitis B vaccine may provide some guidance on long-term immunity raised by HPV vaccination since these two vaccines are similar in design. Vaccine-induced antibody against hepatitis B wanes over the course of several years, but re-exposure to antigen results in a

Acknowledgements

We would like to thank Sheri Kelly, Derek Puchalski, Jeff Van Doren, Patricia Boerckel, Joanne Erick, Dan Sylvester, DeeMarie Skulsky, Christine Roberts, Amha Tadesse, Timothy Hamilton, Robert Wittrock, Michael Sharer, Elizabeth Orlow Else, Liesje Germ, Mary Biersack, and Weli Li for their expert technical assistance in performing the HPV serology and PCR assays. We also thank Darcy Hille for assistance in the preparation of this manuscript. Source of funding: Merck Research Laboratories, a

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  • Cited by (0)

    1

    Now at Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, USA.

    2

    Now at Moffitt Cancer Center, Tampa, FL, USA.

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