Efficacy, Immunogenicity and Safety of BBIBP-CorV Vaccine Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

Study Overview
=================
Brief Summary
-----------------
To expand the access and delivery of COVID-19 Vaccines in Africa (ECOVA), the investigators will conduct a phase 3, individually randomized, observer-blind, controlled (influenza vaccine) trial to evaluate the safety and efficacy of the BBIBP-CorV vaccine against any severe acute respiratory syndrome 2 (SARS-CoV- 2) infection among adults 18 years and older. The BBIBP-CorV vaccine is an inactivated SARS-CoV-2 vaccine (Vero cell) manufactured by the Beijing Institute of Biological Products (BIBP), China National Biotec Group (CNBG), Sinopharm, Beijing, People's Republic of China and received emergency use authorization (EUA) from World Health Organization (WHO).

Detailed Description
-----------------
The investigators will conduct a randomized, observer-blind, controlled, phase 3 trial will be conducted to assess the safety, immunogenicity and efficacy of two doses of intramuscular BBIBP-CorV vaccine, followed by a booster dose, in adults 18 years of age and older. . Study Arms 1 and 2 will have two groups: group 1 - HIV-uninfected receiving BBIBP-CorV or Flu Quadrivalent; group 2 - HIV-infected receiving BBIBP-CorV or Flu Quadrivalent. Arm 3 will have 1 group - HIV-uninfected co-administration group receiving both vaccines. The randomization will be stratified by HIV status. Active surveillance for covid-19 will be carried out and immunogenicity will be assessed for a subset of population.

Official Title
-----------------
A Phase 3, Randomized, Observer-blind, Controlled Trial to Assess the Efficacy, Immunogenicity and Safety of BBIBP-CorV Vaccine Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

Conditions
-----------------
COVID-19 Disease

Intervention / Treatment
-----------------
* Biological: BBIBP-CorV - Inactivated SARS-CoV-2 vaccine (Vero cell)
* Biological: influenza season quadrivalent Influenza Vaccine (Flu Quadrivalent)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female and male adults aged 18 years and older (Arm 1-Group 1 and Arm 2-Group 1) and 18-65 years (Arm 1 - Group 2, Arm 2-Group 2 and Arm3-Group1) at the time of consent. Residing within the Beira and Maputo health region and planning to stay for the study duration. HIV-negative test result at the day of screening for participants in Group 1, in Arms 1, 2 and 3 HIV-positive and on anti-retroviral treatment for at least six months for participants in Group 2, in Arms 1 and 2 Female volunteers of childbearing potential with a negative pregnancy test on the day(s) of screening and vaccination, practicing/willing to practice continuous effective contraception recommended by the national health system up to four weeks after the third vaccination. Able and willing to comply with all study requirements, based on the assessment of the investigator. Provide written informed consent before any trial procedure. Exclusion Criteria: Pregnant, lactating, or with intention to become pregnant during the study. Planned receipt of any investigational vaccine than the study intervention within 28 days before and after each study vaccination. Active COVID-19 infection at the time of enrollment History of allergic reactions or anaphylaxis to previous immunization or allergies to any components of the vaccines. History of bleeding disorder, or prior history of significant bleeding or bruising following intramuscular injections or venipuncture (for the immunogenicity subset and HIV infected participants). Any other finding which in the opinion of the investigators would increase the risk of an adverse outcome from participation in the trial or result in incomplete or poor quality data.

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
Interventional Model Description: A randomized, observer-blind, controlled, phase 3 trial will be conducted to assess the safety, immunogenicity and efficacy of two doses of intramuscular BBIBP-CorV vaccine, followed by a booster dose, in adults 18 years of age and older.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: BBIBP-CorV<br>Study Arms 1 will have two groups: group 1 - HIV-uninfected receiving BBIBP-CorV; group 2 - HIV-infected receiving BBIBP-CorV . | Biological: BBIBP-CorV - Inactivated SARS-CoV-2 vaccine (Vero cell)<br>* The Inactivated SARS-CoV-2 vaccine (Vero cell)- BBIBP-CorV manufactured by Beijing Institute of Biological Products (BIBP), China National Biotec Group (CNBG), Sinopharm, Beijing, People's Republic of China Dose formulation: A liquid formulation containing 4μg total protein with aluminum hydroxide adjuvant (0·45 mg/mL) per 0·5 mL (2-dose schedule followed by a booster dose). Mode of Administration: Intramuscular Storage Conditions: 2 to 8 degree Celsius<br>|
| Experimental: Arm 2: Flu Quadrivalent<br>Study Arms 2 will have two groups: group 1 - HIV-uninfected receiving Flu Quadrivalent; group 2 - HIV-infected receiving Flu Quadrivalent. The Flu Quadrivalent is recommended as a single dose for adults, the second and the booster doses for Arm 2 will be placebo. | Biological: influenza season quadrivalent Influenza Vaccine (Flu Quadrivalent)<br>* The southern hemisphere for the 2021 influenza season quadrivalent Influenza Vaccine (Flu Quadrivalent) Dose formulation: Purified Inactivated Influenza Virus Antigen H1N1, H3N2, Yamagata and Victoria (single dose, 0.5ml for adults) Mode of Administration: Intramuscular Storage Conditions: 2 to 8 degree Celsius<br>|
| Experimental: Arm 3: BBIBP-CorV and Flu Quadrivalent (Co-administration)<br>Arm 3 will have 1 group - HIV-uninfected co-administration group receiving both study vaccines. | Biological: BBIBP-CorV - Inactivated SARS-CoV-2 vaccine (Vero cell)<br>* The Inactivated SARS-CoV-2 vaccine (Vero cell)- BBIBP-CorV manufactured by Beijing Institute of Biological Products (BIBP), China National Biotec Group (CNBG), Sinopharm, Beijing, People's Republic of China Dose formulation: A liquid formulation containing 4μg total protein with aluminum hydroxide adjuvant (0·45 mg/mL) per 0·5 mL (2-dose schedule followed by a booster dose). Mode of Administration: Intramuscular Storage Conditions: 2 to 8 degree Celsius<br>Biological: influenza season quadrivalent Influenza Vaccine (Flu Quadrivalent)<br>* The southern hemisphere for the 2021 influenza season quadrivalent Influenza Vaccine (Flu Quadrivalent) Dose formulation: Purified Inactivated Influenza Virus Antigen H1N1, H3N2, Yamagata and Victoria (single dose, 0.5ml for adults) Mode of Administration: Intramuscular Storage Conditions: 2 to 8 degree Celsius<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protection conferred by BBIBP-CorV vaccine against any COVID-19 disease | Protection conferred by BBIBP-CorV vaccine against any COVID-19 disease measured as the reduction in incidence of Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) confirmed COVID-19 disease in the BBIBP-CorV vaccine arm (s) compared to the control arm, 7 days after the second dose of study intervention | Up to two years follow up from the date of enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of solicited adverse events, unsolicited adverse events and serious adverse events and adverse events of special interest (AESIs) | Incidence of local solicited adverse events within 7 days and systemic solicited adverse events within 14 days of each vaccination, unsolicited adverse events within 28 days of each vaccination, serious adverse events and adverse events of special interest (AESIs) throughout the duration of the study according to the Brighton collaboration list for COVID-19 vaccine studies | local solicited adverse events within 7 days and systemic solicited adverse events within 14 days of each vaccination, unsolicited adverse events within 28 days of each vaccination | 
| Protection conferred by BBIBP-CorV vaccine against symptomatic COVID-19 disease | Protection conferred by BBIBP-CorV vaccine against symptomatic COVID-19 disease caused by variants of concerns (VoCs) measured as the reduction in incidence of RT-PCR-confirmed symptomatic COVID-19 disease caused by variants of concerns (VoCs) in the BBIBP-CorV vaccine arm (s) compared to the control arm, 7 days after the second dose of study intervention. | Till two years follow up from the date of enrollment | 
| Protection conferred by BBIBP-CorV vaccine against asymptomatic SARS-CoV-2 infection (any SARS-CoV-2 variant) | Protection conferred by BBIBP-CorV vaccine against asymptomatic SARS-CoV-2 infection (any SARS-CoV-2 variant) measured as the reduction in incidence of RT-PCR-confirmed asymptomatic COVID-19 disease in the BBIBP-CorV vaccine arm (s) compared to the control arm 7 days after the second dose of study intervention. | Till two years follow up from the date of enrollment | 
| Protection conferred by BBIBP-CorV vaccine against severe COVID-19 disease and COVID-19 associated death | Protection conferred by BBIBP-CorV vaccine against severe COVID-19 disease and COVID-19 associated death, measured as the reduction in incidence of RT-PCR-confirmed severe COVID-19 hospitalization and death in the BBIBP-CorV vaccine arm (s) compared to the control arm. | Till two years follow up from the date of enrollment | 
| Geometric Mean Titers (GMT) and Geometric Mean Fold Rise (GMFR) of anti-SARS-CoV-2 neutralizing antibody in subset of participants | Geometric Mean Titers (GMT) and Geometric Mean Fold Rise (GMFR) of anti-SARS-CoV-2 neutralizing antibody in subset of participants, at Visit 2 (Day 0) , Visit 4 (day 28) , Visit 6 (day 56), Visit 7 (day 112), Visit 9 (day 140) Visit 10 (day 280) and Visit 11 (day 700) | Till two years follow up from the date of enrollment | 
| Incidence of solicited adverse events, unsolicited adverse events and serious adverse events and adverse events of special interest (AESIs) in HIV-infected adults | Incidence of local solicited adverse events within 7 days and systemic solicited adverse events within 14 days of each vaccination, unsolicited adverse events within 28 days of each vaccination, serious adverse events and adverse events of special interest (AESIs) according to Brighton Collaboration list for COVID-19 vaccine studies throughout the duration of the study in HIV-infected adults as compared to equal number of HIV-uninfected adults receiving the BBIBP-CorV vaccine and in HIV-infected adults receiving the control vaccine | Till two years follow up from the date of enrollment | 
| Geometric Mean Titers (GMT) and Geometric Mean Fold Rise (GMFR) of anti-SARS-CoV-2 neutralizing antibody in subset of participants in HIV-infected adults | Geometric Mean Titers (GMT) and Geometric Mean Fold Rise (GMFR) of anti-SARS-CoV-2 neutralizing antibody in subset of participants, at Visit 2 (Day 0) , Visit 4 (day 28) , Visit 6 (day 56), Visit 7 (day 112), Visit 9 (day 140) Visit 10 (day 280) and Visit 11 (day700) in HIV-infected adults as compared to in HIV-uninfected adults receiving the BBIBP-CorV vaccine and in HIV-infected adults receiving the control vaccine | Till two years follow up from the date of enrollment | 
| SARS-CoV-2 sequence variants among HIV-infected and HIV-uninfected, BBIBP-CorV vaccine and placebo recipients | SARS-CoV-2 sequence variants among HIV-infected and HIV-uninfected, BBIBP-CorV vaccine and placebo recipients | Till two years follow up from the date of enrollment | 
| Geometric Mean Titers (GMT) and Geometric Mean Fold Rise (GMFR) of anti-SARS-CoV-2 neutralizing antibody in the Arm 3 as compared to Arm 1 and 2 (subset participants). | Geometric Mean Titers (GMT) and Geometric Mean Fold Rise (GMFR) of anti-SARS-CoV-2 neutralizing antibody in the Arm 3 as compared to Arm 1 and 2 (subset participants), at Visit 2 (Day 0) , Visit 4 (day 28) , Visit 6 (day 56), Visit 7 (day 112), Visit 9 (day 140) Visit 10 (day 280) and Visit 11 (day 700) | Till two years follow up from the date of enrollment | 
| Incidence of adverse event (AE) after each vaccination, serious adverse event (SAE), adverse events of special interests (AESIs) according to Brighton Collaboration list for COVID-19 vaccine studies among participants receiving the study vaccines. | Incidence of adverse event (AE) after each vaccination, serious adverse event (SAE), adverse events of special interests (AESIs) according to Brighton Collaboration list for COVID-19 vaccine studies throughout the duration of the study. | Till two years follow up from the date of enrollment | 
| Humoral and cellular immune responses of HIV-infected participants as compared to HIV-uninfected vaccine and control arms (subset participants of Arms 1 and 2) | Humoral and cellular immune responses of HIV-infected participants as compared to HIV-uninfected vaccine and control arms (subset participants of Arms 1 and 2) at Visit 2 (Day 0) , Visit 4 (day 28) , Visit 6 (day 56), Visit 7 (day 112), Visit 09 (day 140) Visit 10 (day 280) and Visit 11 (day 700). | Till two years follow up from the date of enrollment | 
| Geometric Mean Titers (GMT) and Geometric Mean Fold Rise (GMFR) of anti-SARS-CoV-2 neutralizing antibody following booster dose of BBIBP-CorV vaccine | Geometric Mean Titers (GMT) and Geometric Mean Fold Rise (GMFR) of anti-SARS-CoV-2 neutralizing antibody at Visit 7 (day 112), Visit 09 (day 140) Visit 10 (day 280) and Visit 11 (day 700) following booster dose of BBIBP-CorV vaccine. | Till two years follow up from the date of enrollment | 
| Incidence of solicited adverse events, unsolicited adverse events and serious adverse events and adverse events of special interest (AESIs) among HIV uninfected adults. | Incidence of local solicited adverse events within 7 days and systemic solicited adverse events within 14 days of booster dose, unsolicited adverse events within 28 days of booster dose and serious adverse events, and adverse events of special interest (AESIs) according to Brighton Collaboration list for COVID-19 vaccine studies throughout the duration of the study among HIV uninfected adults in the BBIBP-CorV vaccine arm (s) compared to the control arm. | Till two years follow up from the date of enrollment |