Study on the Safety, Humoral Immune Response, and Memory B Cell Response Characteristics of Sequential 9-Valent HPV Vaccination

A Study on the Safety, Humoral Immune Response, and Memory B Cell Response Characteristics of Sequential Vaccination With 9-Valent Human Papillomavirus Vaccine (Escherichia Coli) and Bivalent HPV 16/18 Vaccine

This is a single-center, prospective, open-label, partially randomized, matched-controlled trial designed as a cohort study. The study plans to enroll 360 healthy female participants aged 18 to 45 years, divided into three groups: a three-dose sequential group, a two-dose sequential group, and a primary immunization group, with 120 participants in each group. All participants will be stratified by two age subgroups (18-26 years and 27-45 years) to ensure demographic balance across groups.

As blinding is not feasible in this study, a prospective, open-label, partially randomized, controlled trial design is adopted. A combination of randomized and non-randomized (i.e., partially randomized) enrollment methods is used to balance study feasibility with intergroup comparability.

Participants in the three-dose sequential group and the primary immunization group will receive one dose of the nine-valent HPV vaccine at months 0, 1, and 6, while those in the two-dose sequential group will receive the nine-valent HPV vaccine at months 0 and 6. Before the second and third doses, investigators must confirm that participants do not meet the criteria for early withdrawal or for postponement of the second and third doses. After each vaccination, a 30-minute safety observation will be conducted at the vaccination site to monitor for adverse events (AEs). Subsequently, the study visit procedures will be followed, including collection of solicited AEs within 7 days post-vaccination, unsolicited AEs within 30 days, and serious AEs (SAEs) throughout the study period. Participants will also complete other scheduled study visits, including safety observations and immunogenicity blood sampling at various time points before and after vaccination.

The study aims to evaluate the immune response characteristics and safety of sequential vaccination with different doses of the nine-valent HPV vaccine (three doses at 0, 1, 6 months and two doses at 0, 6 months) in healthy female participants who have previously completed vaccination with the bivalent HPV vaccine.

Inclusion Criteria:

• 1. Female volunteers, aged 18-45 years at the time of receiving the first trial vaccine dose;
• 2. Volunteers (and their legal guardians) are able to understand the study procedures and are capable of complying with protocol requirements (such as collecting biological samples, filling out diary cards, and attending follow-up visits on schedule), and have signed the informed consent form;
• 3. Adult female volunteers agree not to plan a pregnancy and to use effective contraception within 8 months after completing the first dose, or are women who have undergone tubal ligation, subtotal hysterectomy for benign lesions, or removal of benign ovarian tumors;

For participants in the sequential group, the following additional criteria must be met:

• 4. Previously completed the full three-dose schedule of XinKeNing, XiRuiShi, and WoZeHui [full three-dose schedule is defined as completing the second and third doses within 12 months after the first dose];
• 5. The interval between the last dose of XinKeNing, XiRuiShi, or WoZeHui and the enrollment date is ≥ 12 months.

Exclusion Criteria:

• 1. Axillary temperature > 37.0°C;
• 2. Positive urine pregnancy test in adult female volunteers, or being currently pregnant or breastfeeding;
• 3. Use of any other investigational or unregistered product (drug or vaccine) within 30 days prior to study vaccination, or planned use of other investigational or unregistered products or participation in another clinical study during the study period;
• 4. Long-term (continuous for more than 14 days) use of immunosuppressants or other immunomodulatory medications within 6 months prior to vaccination. Systemic administration of corticosteroid medications is excluded, while topical use (e.g., ointments, eye drops, inhalers, or nasal sprays) is permitted;
• 5. Use of immunoglobulins and/or blood products within 3 months prior to vaccination, or planned use within 7 months after the first dose, with the exception of emergency post-exposure use of tetanus immunoglobulin and rabies immunoglobulin;
• 6. Receipt of an inactivated vaccine within 7 days, or a live vaccine within 14 days, prior to study vaccination;
• 7. Experienced fever (axillary temperature ≥38.0°C) within 3 days prior to vaccination, or any serious acute illness requiring systemic antibiotic or antiviral therapy within the past 5 days, or taken medication containing antipyretic ingredients within the past 24 hours;
• 8. Previous vaccination with any HPV vaccine other than Cecolin, Cervarix, or Walvax;
• 9. Suffering from severe immunodeficiency diseases, severe primary diseases of vital organs, cancer (or precancerous lesions), autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, immunodeficiency caused by asplenia or splenectomy due to any reason, and other autoimmune diseases considered by the investigator to potentially affect the immune response);
• 10. History of severe allergies, including severe adverse reactions to previous vaccinations such as anaphylactic shock, acute urticaria, dyspnea, angioedema, or allergy to any component of the study vaccine (aluminum adjuvant, polysorbate, sodium dihydrogen phosphate, disodium hydrogen phosphate);
• 11. Asthma that has been unstable in the past two years, requiring emergency treatment, hospitalization, oral or intravenous corticosteroids;
• 12. Coagulation abnormalities or bleeding disorders;
• 13. Epilepsy, excluding febrile seizures under 2 years of age, alcohol-related seizures in the 3 years prior to abstinence, or simple epilepsy that has not required treatment in the past 3 years;
• 14. Any medical, psychological, social, occupational, or other conditions that, in the judgment of the investigator after reviewing the volunteer's medical history and relevant physical examination, may interfere with the conduct of the clinical study.