Phase IIIb Clinical Trial of Quadrivalent Recombinant Human Papillomavirus Vaccine (Hansenulapolymorpha) for Age/Immunization Schedule Bridging

A Randomized, Open-label, Non-inferiority Phase IIIb Clinical Trial to Evaluate the Immunogenicity Age/Schedule Bridging Between Adolescent Girls Aged 9-14 Years Receiving a 2-dose Regimen or Adolescent Girls Aged 9-17 Years Receiving a 3-dose Regimen of a Quadrivalent Recombinant Human Papillomavirus (HPV) Vaccine (Hansenula Polymorpha) and Women Aged 18-35 Years.

This vaccine was jointly developed by Chengdu Institute of Biological Products Co., Ltd. and National Vaccine and Serum Institute, China, is co-sponsoring this clinical trial.

This trial plans to enroll 1,800 female subjects aged 9-35 years, 450 in each of the 18-25 years old 3-dose group, 26-35 years old 3-dose group, 9-17 years old 3-dose group and 9-14 years old 2-dose group.

All subjects in the 9-14 years old 2-dose group will be injected with 2 doses of the experimental vaccine in the deltoid muscle of the upper arm according to the 0-6 month immunization schedule. Subjects in the non-immune persistence subgroup will need to complete 6 on-site visits and subjects in the immune persistence subgroup will need to complete 13 on-site visits ; All subjects in the 9-17 years old 3-dose group and the 18-35 years old 3-dose group will be injected with 3 doses of the experimental vaccine in the deltoid muscle of the upper arm according to the 0, 2, and 6 month immunization schedule. Subjects in the non-immune persistence subgroup will need to complete 9 on-site visits and subjects in the immune persistence subgroup will need to complete 16 on-site visits

Inclusion Criteria:

• Females aged 9-35 years at the time of enrollment;
• Subjects aged 9-17 years at the time of enrollment and at least one legal guardian are informed and willing to participate, sign the informed consent form and can provide valid identity documents; subjects aged 18-35 years at the time of enrollment are informed and willing to participate, sign the informed consent form and can provide valid identity documents;
• Subjects are able to understand the research procedures and cooperate with the requirements of the clinical trial to participate in regular follow-up;
• Female subjects of childbearing age have a negative urine pregnancy test on the day of enrollment, are not breastfeeding and have no fertility plans within 7 months after enrollment; have taken effective contraceptive measures since the end of the last menstruation until enrollment, and agree to continue to use effective contraceptive measures within 7 months after participating in the study (effective contraceptive measures include: oral contraceptives, injections or implants, sustained-release local contraceptives, hormone patches, intrauterine devices (IUDs), sterilization, abstinence, condoms (male), diaphragms, cervical caps, etc.);
• Body temperature ≤37.0℃ (axillary temperature) on the day of enrollment.

Exclusion Criteria:

First dose exclusion criteria

• Those who have received a commercially available HPV vaccine in the past or plan to receive a commercially available HPV vaccine during the study; or have participated in other HPV vaccine clinical trials and have received the vaccine/placebo;
• Those who have a history of cervical lesions that are likely to be related to HPV infection (such as abnormal cervical cancer screening, CIN disease history); Those who have a history of hysterectomy or pelvic radiotherapy; Patients who have a history of external genital diseases that are likely to be related to HPV infection (such as vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, and genital warts);
• Those who have a history of severe allergic reactions to any vaccine or drug (including yeast) that require medical intervention, such as anaphylactic shock, allergic laryngeal edema, allergic purpura, thrombocytopenic purpura, local allergic necrosis reaction (Arthus reaction), etc.Or individuals with a known hypersensitivity to any of the components of the test vaccine (L-histidine, sodium chloride, aluminum hydroxide, and water for injection);
• Those who have impaired immune function or have been diagnosed with congenital or acquired immunodeficiency, human immunodeficiency virus (Human Immunodeficiency Virus). Virus, HIV) infection, lymphoma, leukemia, systemic lupus erythematosus (SLE), rheumatoid arthritis, juvenile rheumatoid arthritis (JRA), inflammatory bowel disease or other autoimmune diseases;
• Those who have received long-term (≥14 days) immunomodulatory therapy (including immune enhancers and immunosuppressants) within 1 year prior to vaccination or within 7 months after enrollment, such as oral or injectable systemic glucocorticoid therapy (≥14 days, dose ≥2 mg/kg/day or ≥20 mg/day prednisone or equivalent prednisone dose), are permitted to use topical medications (such as ointments, eye drops, inhalers or nasal sprays), but topical medications must not exceed the dose recommended in the instructions or have any signs of systemic exposure;
• Any immunoglobulin or blood products within 3 months before vaccination or planned within 7 months after enrollment;
• Those who have received a non-live vaccine within 14 days prior to vaccination, or a live vaccine within 28 days prior to vaccination;
• Acute onset or use of antipyretic, analgesic and antiallergic drugs (such as acetaminophen, ibuprofen, aspirin, loratadine, cetirizine, etc.) 3 days before vaccination, or acute attack of chronic diseases;
• History of convulsions (except febrile convulsions), or history or family history of epilepsy, encephalopathy, mental illness;
• Past or current severe (such as emergency treatment, surgical treatment, etc.) heart disease (such as congenital heart disease, etc.), liver and kidney disease (such as chronic hepatitis or suspected active hepatitis, nephrotic syndrome, uremia, etc.), complications of diabetes, malignant tumors, etc.;
• Elevated blood pressure measured by on-site physical examination (9-15 years old: systolic blood pressure ≥100+1.5×age (years) mmHg and/or diastolic blood pressure ≥65+age (years) mmHg; 16-26 years old: systolic blood pressure ≥140mmHg and/or diastolic blood pressure ≥90mmHg);
• Participating in clinical studies of other investigational or unmarketed products (drugs, vaccines and medical devices) within 3 months before vaccination or planning to participate in the study period;
• Asplenia or functional asplenia, or splenectomy caused by any circumstances;
• Suffering from thrombocytopenia or other coagulation disorders that may be contraindications to intramuscular injection;
• Any other factors that the researcher believes make the subject unsuitable for participation in clinical trials.

Subsequent doses of vaccination should be postponed if any of the following conditions occur. Delays should ideally be made within the prescribed time window:

• Axillary temperature >37.0℃ before vaccination;
• Received any immunoglobulin or blood products within 3 months prior to vaccination;
• Received a non-live vaccine within 14 days prior to vaccination, or a live vaccine within 28 days prior to vaccination;
• Acute onset of illness or use of antipyretics, analgesics, and antihistamines (such as acetaminophen, ibuprofen, aspirin, loratadine, cetirizine, etc.) within 3 days prior to vaccination, or an acute exacerbation of a chronic disease;
• Any other reason deemed necessary for postponement by the investigator.

If any of the following situations occur, the researcher will terminate the subsequent doses of vaccination for the subject.

• Positive urine pregnancy test before vaccination (on the day of vaccination); Note: If the subject chooses to terminate the pregnancy, at least 6 weeks after the end of the pregnancy and can submit medical evidence of termination of pregnancy (such as imaging reports or relevant medical records, etc.), the researcher can continue to vaccinate if it is considered that the subject can continue to vaccinate; if the subject chooses to continue the pregnancy, the subsequent doses of vaccination will not be administered.
• Newly discovered or newly occurring situations that meet the first dose exclusion criteria 1, 2, 3, 4, 9, 10, 13, and 14;
• After vaccination, adverse reactions related to vaccination are evaluated and considered unsuitable for continued vaccination;
• Any other reasons that the researcher assesses to terminate vaccination.