Evaluation of Immunogenicity and Safety of Combined Immunization of COVAX (Produced in Wuhan) and PPV23 / IIV4

Study Overview
=================
Brief Summary
-----------------
Subjects will be recruited and divided into 3 groups: Experimental Group (468 subjects): 1st dose : combined vaccination of COVAX+PPV23, 2nd dose: combined vaccination of COVAX+IIV4; Control Group A (468 subjects): 1st dose: COVAX only, 2nd dose: COVAX only; Control Group B (468 subjects): 1st dose: PPV23 only, 2nd dose: IIV4 only. Blood samples will be collected 3 times: before the 1st dose of vaccinatioin; before the 2nd dose of vaccination; 28 days after the 2nd dose of vaccination. The immunogenicity and safety of both experimental and control groups will be analyzed.

Detailed Description
-----------------
This randomized, parallel, controlled study is designed to evaluate the immunogenicity and safety of simultaneously immunization of COVAX + PPV23 and COVAX + IIV4. 1404 subjects are divided into 3 groups, including 1 experimental group and 2 control groups (control group A and B). Each group includes 468 subjects respectively. Experimental Group (468 subjects) will receive: 1st dose : combined vaccination of COVAX+PPV23, 2nd dose: combined vaccination of COVAX+IIV4; Control Group A (468 subjects) will receive: 1st dose: COVAX only, 2nd dose: COVAX only; Control Group B (468 subjects) will receive: 1st dose: PPV23 only, 2nd dose: IIV4 only. Specifically, each group will be divided again. Each 468-subject group is divided again into 2 age-based subgroups: (1) 18-59 years old; (2) ≥60 years old. Each subgroup includes 234 subjects respectively. Blood samples will be collected 3 times: (1) before the 1st dose of vaccinatioin; (2) before the 2nd dose of vaccination; (3) 28 days after the 2nd dose of vaccination. To evaluate the immunogenicity, the investigators will detect and compare the neutralizing antibody levels, the seroconversion rates and antibody geometric mean concentrations. The safety of all groups will be monitored as well.

Official Title
-----------------
A Randomized, Controlled, Multicenter Phase 4 Clinic Trial to Evaluate the Immunogenicity and Safety of Combined Immunization of Inactivated SARS-CoV-2 Vaccines (Vero Cell) (COVAX) (Produced in Wuhan) and 23-valent Pneumococcal Polysaccharide Vaccine (PPV23) or Quadrivalent Inactivated Influenza Vaccine (IIV4)

Conditions
-----------------
Influenza, Human, Pneumonia, Pneumococcal, COVID-19 Pneumonia

Intervention / Treatment
-----------------
* Biological: COVAX+PPV23;COVAX+IIV4
* Biological: COVAX only (1st and 2nd dose)
* Biological: PPV23 for the 1st dose and IIV4 for the 2nd dose


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ≥18 years old when enrolled; Participants signing the informed consent; Being able to participate in all planned follow-ups and accomplish all research procedures including completing a diary card and coming back for interview; Having not been administered any pneumonia vaccine or COVID-19 vaccine, and having not been administered an influenza vaccine in the current season before enrollment; ≥14 days from the most recent vaccination; Before enrollment, the body temperature is ≤37.0C as confirmed by medical history and clinical examination. Exclusion Criteria: Having a history of COVID-19 or a positive nucleic acid test for COVID-19; Having a history or a family history of allergy, convulsion, epilepsy, brain disease, or mental illness; Being allergic to any component of vaccines, or having a history of severe allergic reaction to any vaccine; Having immunodeficiency disorder, during treatment of malignant tumor, having immunodeficiency induced by immunosuppressants (oral steroid hormones) or HIV, or having a family member with close contact who suffers from congenital immune disorder; Having injection of non-specific immunoglobulin within 1 month prior to enrollment; Having acute febrile illness or communicable disease; Having a history of confirmed thrombocytopenia or other coagulation disorders, which may cause contraindications for a subcutaneous injection; Having severe chronic disease or acute exacerbation of chronic disease, or having uncontrolled hypertension or diabetes; Having various infectious, pyogenic, or allergic skin diseases; Women in pregnancy or lactation or participants who plan for a baby within 3 months after vaccination should delay the vaccination; Having any condition that may affect trial assessment as determined by researchers. Exclusion criteria for the second dose: Having any serious adverse event related to the first dose vaccination; After vaccination, having systemic adverse reaction or allergic reaction with a severity of grade 3 or higher as determined by researchers; Having a newly emerging condition that meets the exclusion criteria for the first dose; Having any condition that may affect trial assessment as determined by researchers.

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>Experimental Group (468 subjects) will receive: 1st dose : combined vaccination of COVAX+PPV23; 2nd dose: combined vaccination of COVAX+IIV4 | Biological: COVAX+PPV23;COVAX+IIV4<br>* 1st dose : combined vaccination of COVAX+PPV23; 2nd dose: combined vaccination of COVAX+IIV4<br>|
| Active Comparator: Control group A<br>Control Group A (468 subjects) will receive: 1st dose: COVAX only; 2nd dose: COVAX only | Biological: COVAX only (1st and 2nd dose)<br>* 1st dose: COVAX only; 2nd dose: COVAX only<br>|
| Active Comparator: Control group B<br>Control Group B (468 subjects) will receive: 1st dose: PPV23 only; 2nd dose: IIV4 only | Biological: PPV23 for the 1st dose and IIV4 for the 2nd dose<br>* 1st dose: PPV23 only; 2nd dose: IIV4 only<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seroconversion rate (COVAX) | the rate of positive seroconversion against coronavirus | Results obtained 28 days after the first dose (= right before the second dose) | 
| Seroconversion rate (COVAX) | the rate of positive seroconversion against coronavirus | Results obtained after the second dose of vaccination (= 56 days after the first dose, or 28 days after the second dose) | 
| Neutralizing antibody level (COVAX) | neutralizing antibody level against coronavirus | Baseline (before vaccination) results | 
| Neutralizing antibody level (COVAX) | neutralizing antibody level against coronavirus | Results obtained 28 days after the first dose (= right before the second dose) | 
| Neutralizing antibody level (COVAX) | neutralizing antibody level against coronavirus | Results obtained after the second dose of vaccination (= 56 days after the first dose, or 28 days after the second dose) | 
| Seropositive rate (IIV4) | the rate of positive seroconversion against influenza A (H3N2, H1N1) type and B (BY, BV) type viruses | Baseline (before vaccination) results | 
| Seroconversion rate (IIV4) | the rate of positive seroconversion against influenza A (H3N2, H1N1) type and B (BY, BV) type viruses | Results obtained 28 days after the first dose (= right before the second dose) | 
| Seroconversion rate (IIV4) | the rate of positive seroconversion against influenza A (H3N2, H1N1) type and B (BY, BV) type viruses | Results obtained after the second dose of vaccination (= 56 days after the first dose, or 28 days after the second dose) | 
| Hemmagglution inhibition antibody level (IIV4) | Hemmagglution inhibition antibody levels against influenza A (H3N2, H1N1) type and B (BY, BV) type viruses | Baseline (before vaccination) results | 
| Hemmagglution inhibition antibody level (IIV4) | Hemmagglution inhibition antibody levels against influenza A (H3N2, H1N1) type and B (BY, BV) type viruses | Results obtained 28 days after the first dose (= right before the second dose) | 
| Hemmagglution inhibition antibody level (IIV4) | Hemmagglution inhibition antibody levels against influenza A (H3N2, H1N1) type and B (BY, BV) type viruses | Results obtained after the second dose of vaccination (= 56 days after the first dose, or 28 days after the second dose) | 
| Seroconversion rate (PPV23) | the rate of positive seroconversion against 23 pneumococcal serotypes | Results obtained 28 days after the first dose (= right before the second dose) | 
| Seroconversion rate (PPV23) | the rate of positive seroconversion against 23 pneumococcal serotypes | Results obtained after the second dose of vaccination (= 56 days after the first dose, or 28 days after the second dose) | 
| Neutralizing antibody level (PPV23) | Neutralizing antibody level against 23 pneumococcal serotypes | Baseline (before vaccination) results | 
| Neutralizing antibody level (PPV23) | Neutralizing antibody level against 23 pneumococcal serotypes | Results obtained 28 days after the first dose (= right before the second dose) | 
| Neutralizing antibody level (PPV23) | Neutralizing antibody level against 23 pneumococcal serotypes | Results obtained after the second dose of vaccination (= 56 days after the first dose, or 28 days after the second dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events following vaccination | analyse the incidence of adverse events following immunization, both solicited and unsolicited | 0-6 months |