Study on Combined Vaccination With SARS-CoV-2 Inactivated Vaccine and Quadrivalent Influenza Vaccine

Study Overview
=================
Brief Summary
-----------------
This study is an open-label, single-center, randomized phase IV clinical trial of the SARS-CoV-2 inactivated vaccine manufactured by Sinovac Research & Development Co., Ltd. The purpose of this study is to evaluate the safety and immunogenicity of concomitant administration of the SARS-CoV-2 Inactivated Vaccine (Vero cell) with Quadrivalent Influenza Vaccine in adults aged from 18 to 59 Years

Detailed Description
-----------------
This study is an open-label, single-center, randomized phase IV clinical trial of the SARS-CoV-2 inactivated vaccine (Vero cell) manufactured by Sinovac Research & Development Co., Ltd. The purpose of this study is to evaluate the safety and immunogenicity of concomitant administration of the SARS-CoV-2 Inactivated Vaccine (Vero cell) with Quadrivalent Influenza Vaccine in adults aged from 18 to 59 Years. 480 healthy adults as participants are randomly assigned into two groups in the ratio 1:1. The first group was the combined immunization group, which is randomly divided into two subgroups, 120 subjects in each group. The combined immunization subgroup Ⅰ receive SARS-CoV-2 inactivated vaccine &Quadrivalent Influenza Vaccine on day 0 and SARS-CoV-2 inactivated vaccine (second dose) on day 28.The combined immunization subgroup Ⅱ receive SARS-CoV-2 inactivated vaccine on day 0 and SARS-CoV-2 inactivated vaccine (second dose) & Quadrivalent Influenza Vaccine on day 28. The second group was the non combined immunization group，which receive SARS-CoV-2 inactivated vaccine (first dose) on day 0, Quadrivalent Influenza Vaccine on day 14 and SARS-CoV-2 inactivated vaccine (second dose) on day 28.

Official Title
-----------------
A Study to Evaluate the Safety and Immunogenicity of Concomitant Administration of the SARS-CoV-2 Inactivated Vaccine (Vero Cell) With Quadrivalent Influenza Vaccine in Adults Aged From 18 to 59 Years

Conditions
-----------------
COVID-19, Influenza

Intervention / Treatment
-----------------
* Biological: Two doses of inactivated SARS-CoV-2 vaccine at the schedule of day 0,28 and one dose Quadrivalent Influenza Vaccine on day 0 or day 28.
* Biological: Two doses of inactivated SARS-CoV-2 vaccine at the schedule of day 0,28 and one dose Quadrivalent Influenza Vaccine on day 14.


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy adults aged 18-59 years; The subject can understand and voluntarily sign the informed consent form; Proven legal identity Exclusion Criteria: Travel history / residence history of communities with case reports within 14 days; History of contact with a SARS-CoV-2 infection (positive in nucleic acid test) within 14 days; Have contacted patients with fever or respiratory symptoms from communities with case reports within 14 days; Two or more cases of fever and / or respiratory symptoms in a small contact area of volunteers, such as home, office etc. within 14 days; History of SARS-CoV-2 infection; History of asthma, history of allergy to the vaccine or vaccine components, or serious adverse reactions to the vaccine, such as urticaria, dyspnea, and angioedema; Congenital malformations or developmental disorders, genetic defects, severe malnutrition, etc.; Autoimmune disease or immunodeficiency / immunosuppression; Severe chronic diseases, severe cardiovascular diseases, hypertension and diabetes that cannot be controlled by drugs, liver or kidney diseases, malignant tumors, etc.; Severe neurological disease (epilepsy, convulsions or convulsions) or mental illness; Thyroid disease or history of thyroidectomy, spleenlessness, functional spleenlessness, spleenlessness or splenectomy resulting from any condition; Diagnosed abnormal blood coagulation function (eg, lack of blood coagulation factors, blood coagulopathy, abnormal platelets) or obvious bruising or blood coagulation; Immunosuppressive therapy, cytotoxic therapy, inhaled corticosteroids (excluding allergic rhinitis corticosteroid spray therapy, acute noncomplicated dermatitis superficial corticosteroid therapy) in the past 6 months; Physical examination has clinically significant abnormal hematology and biochemistry laboratory test results that exceed the reference value range (only applicable to phase I clinical trials): Blood routine test: white blood cell count, hemoglobin, platelet count; Detection of blood biochemical indicators: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), creatinine (CR), fasting blood glucose; Urine routine index: urine protein (PRO); History of alcohol or drug abuse; Receipt of blood products within in the past 3 months; Receipt of other investigational drugs in the past 30 days; Receipt of attenuated live vaccines in the past 14 days; Receipt of inactivated or subunit vaccines in the past 7 days; Acute diseases or acute exacerbation of chronic diseases in the past 7 days; Axillary temperature >37.0°C; Already pregnant (including a positive urine pregnancy test) or are breastfeeding, planning to get pregnant within 3 months; According to the investigator's judgment, the subject has any other factors that are not suitable for participating in the clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combined immunization group<br>The combined immunization group is randomly divided into two subgroups, 120 subjects in each group. The combined immunization subgroup Ⅰ receive SARS-CoV-2 inactivated vaccine (Vero cell)&Quadrivalent Influenza Vaccine on day0 and SARS-CoV-2 inactivated vaccine (Vero cell) (second dose) on day 28.The combined immunization subgroup Ⅱ receive SARS-CoV-2 inactivated vaccine (Vero cell) on day 0 and SARS-CoV-2 inactivated vaccine (Vero cell) (second dose) & Quadrivalent Influenza Vaccine on day 28. | Biological: Two doses of inactivated SARS-CoV-2 vaccine at the schedule of day 0,28 and one dose Quadrivalent Influenza Vaccine on day 0 or day 28.<br>* The inactivated SARS-CoV-2 vaccine was manufactured by Sinovac Research & Development Co., Ltd., with a antigen content of 600SU/0.5ml. The Quadrivalent Influenza Vaccine manufactured by Sinovac Biotech Co.,Ltd. including 4 antigens H1N1, H3N2, BV and BY, 15μg for each, 0.5ml per dose.<br>|
| Experimental: Non combined immunization group<br>The non combined immunization group receive SARS-CoV-2 inactivated vaccine (Vero cell)(first dose) on day 0, Quadrivalent Influenza Vaccine on day 14 and SARS-CoV-2 inactivated vaccine (Vero cell)(second dose) on day 28. | Biological: Two doses of inactivated SARS-CoV-2 vaccine at the schedule of day 0,28 and one dose Quadrivalent Influenza Vaccine on day 14.<br>* The inactivated SARS-CoV-2 vaccine was manufactured by Sinovac Research & Development Co., Ltd., with a antigen content of 600SU/0.5ml. The Quadrivalent Influenza Vaccine manufactured by Sinovac Biotech Co.,Ltd. including 4 antigens H1N1, H3N2, BV and BY, 15μg for each, 0.5ml per dose.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety index-incidence of adverse reactions within 7 days after each dose | Incidence of adverse reactions within 7 days after each dose | Day 0-7 after each dose vaccination | 
| Immunogenicity index-seroconversion rates of neutralizing antibody against SARS-CoV-2 | Neutralizing antibody assay will be performed using the micro-neutralization method. Seroconversion will be defined as a change from seronegative (<1:8) to seropositive (≥1:8), or ≥4 fold increase from baseline. | The 28th day after the second dose vaccination of the inactivated SARS-CoV-2 vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety index-incidence of adverse reactions within 56 days after the first dose vaccination | Incidence of adverse reactions within 56 days after the first dose vaccination | Day 0-56 after the first dose vaccination | 
| Safety index-incidence of serious adverse events | SAE will be collected throughout the clinical trial. | Day 0-56 after the first dose vaccination | 
| Immunogenicity index-seropositive rates of neutralizing antibody against SARS-CoV-2 | Neutralizing antibody assay will be performed using the micro-neutralization method, and subjects with a antibody titer ≥1:8 will defined as seropositive. | The 28th day after each dose vaccination | 
| Immunogenicity index-geometric mean titer (GMT) of neutralizing antibody against SARS-CoV-2 | Neutralizing antibody assay will be performed using the micro-neutralization method. | The 28th day after each dose vaccination | 
| Immunogenicity index-geometric mean ratio (GMR) of neutralizing antibody against SARS-CoV-2 | Neutralizing antibody assay will be performed using the micro-neutralization method. Ratio of post-vaccination titer divided by baseline titer will be calculated. | The 28th day after each dose vaccination | 
| Immunogenicity index-seroconversion rates of influenza HI antibodies | Seroconversion will be defined as a change from seronegative (<1:10) to protective (≥1:40), or ≥4 fold increase from baseline(≥1:10). | The 28th day after the vaccination | 
| Immunogenicity index-protective rates of influenza HI antibodies | The standard of reaching the protective rate is that the antibody titer ≥1:40. | The 28th day after the vaccination | 
| Immunogenicity index-geometric mean titer (GMT) of influenza HI antibodies | influenza HI antibodies assay will be performed using the micro hemagglutination inhibition test | The 28th day after the vaccination | 
| Immunogenicity index-geometric mean ratio (GMR) of influenza HI antibodies | influenza HI antibodies assay will be performed using the micro hemagglutination inhibition test | The 28th day after the vaccination |