A Phase 3, International, Multi-center, Randomized, Double-blind, Placebo-controlled Clinical Trial to Study the Efficacy, Immunogenicity, and Safety of the 9vHPV Vaccine, a Multivalent L1 Virus-like Particle Vaccine, in the prevention of oral persistent infection with HPV Types 16, 18, 31, 33, 45, 52, or 58 in adult males, 20 to 45 years of age

The primary objective of this clinical trial is to demonstrate that a 3-dose regimen of the **9-valent human papillomavirus (9vHPV) vaccine** will reduce the incidence of oral persistent infection related to **human papillomavirus (HPV)** types 16, 18, 31, 33, 45, 52, and 58 for 6 months (± 1-month window) or longer, compared with placebo in males aged 20 to 45 years. This is clinically relevant as it addresses the prevention of oral persistent infections caused by high-risk HPV types, which are associated with an increased risk of oropharyngeal cancers.

The secondary objectives include:

• Demonstrating that the 9vHPV vaccine will reduce the incidence of HPV 6/11-related oral persistent infection for 6 months (± 1-month window) or longer compared with placebo in the same demographic.
• Summarizing antibody responses, including Geometric Mean Titer (GMT) and seroconversion percentages, to each of HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 at Month 7.
• Evaluating the safety and tolerability of the 9vHPV vaccine when administered to males aged 20 to 45 years.

The clinical trial involves a total of **4538 participants**, specifically targeting **males** aged **20 to 45 years**. The study population is composed of individuals who are in good physical health, as determined by medical history and physical examination. Participants were selected based on their ability to provide informed consent and their agreement to maintain contact with study personnel. The trial focuses on the **prevention of oral persistent infection** caused by specific types of **human papillomavirus (HPV)**, namely types 16, 18, 31, 33, 45, 52, and 58. Participants are required to have had at least one lifetime sexual partner. The trial does not include female subjects or vulnerable populations. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, immunogenicity, and safety of the 9-valent human papillomavirus (9vHPV) vaccine in preventing oral persistent infection with specific HPV types in adult males aged 20 to 45 years. The trial involves a 3-dose regimen of the 9vHPV vaccine, with the primary objective of reducing the incidence of HPV types 16, 18, 31, 33, 45, 52, and 58-related oral persistent infections over a period of 6 months. The study is expected to conclude by October 2024, with recruitment having commenced in February 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, health status, and consent. Following successful screening, participants will be randomized to receive either the 9vHPV vaccine or a saline placebo. The study includes follow-up visits to monitor the participants' health, collect data on the incidence of HPV-related infections, and assess the immunogenic response to the vaccine. The end-of-study visit will evaluate the overall outcomes and safety of the intervention.

The expected duration of participant involvement is approximately 6 months, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with study procedures. The trial's primary endpoint is the incidence of HPV-related 6-month persistent oral infection, while secondary endpoints include the incidence of HPV 6/11-related infections, geometric mean titers of HPV antibodies, seroconversion rates, and the occurrence of adverse events such as injection-site reactions and fever.

The clinical trial involves the administration of **Gardasil 9**, a **suspension for injection** containing the **Human Papillomavirus 9-valent Vaccine (Recombinant, adsorbed)**. This vaccine is designed to prevent oral persistent infection with specific HPV types, including 16, 18, 31, 33, 45, 52, and 58. The active substances in Gardasil 9 are virus-like particles of the L1 protein from various HPV types, produced in yeast cells (**Saccharomyces cerevisiae**). The vaccine is administered intramuscularly in a 0.5 ml dose per injection, with a total of three doses given over a six-month period. The maximum total dose is 1.5 ml. The vaccine is manufactured by Merck Sharp & Dohme BV and is authorized under the marketing authorization number EU/1/15/1007/001.

The trial also includes a **saline placebo** for V503, which serves as the comparator treatment. The placebo is administered in the same manner as the experimental vaccine, via intramuscular injection. The use of a placebo allows for a double-blind study design, ensuring that neither the participants nor the investigators know which treatment is being administered, thereby reducing bias. The placebo is used to evaluate the efficacy and safety of the Gardasil 9 vaccine by comparing outcomes between the treatment and placebo groups.

The efficacy of the 9-valent human papillomavirus vaccine (9vHPV) in preventing oral persistent infection with specific HPV types will be assessed in this clinical trial. The primary endpoint for evaluating efficacy is the incidence of **Human Papillomavirus (HPV)16/18/31/33/45/52/58-related 6-month Persistent Oral Infection**. Secondary endpoints include the incidence of HPV 6/11-related 6-month persistent oral infection, geometric mean titers to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 antibodies at month 7, and the percentage of participants who seroconvert to these HPV types. Additionally, the percentage of participants with at least one solicited injection-site adverse event and those with elevated temperature (fever) will be recorded.

The trial is designed as a Phase 3, international, multi-center, randomized, double-blind, placebo-controlled study. The main objective is to demonstrate that a 3-dose regimen of the 9vHPV vaccine reduces the incidence of HPV-related oral persistent infection in males aged 20 to 45 years. Efficacy assessments will be conducted at specified timepoints, including month 7 for antibody titers. The trial will utilize validated laboratory tests to measure antibody levels and assess seroconversion rates. Data collection will be systematic and adhere to the trial's protocol to ensure the reliability and validity of the efficacy outcomes.