Trial no.:	PACTR202009726132275	Date of Approval:	14/09/2020
Trial Status:	Registered in accordance with WHO and ICMJE standards

TRIAL DESCRIPTION

Public title

A Study Looking at the Safety and Effectiveness of a COVID-19 Vaccine Plus Adjuvant in South African Adults

Official scientific title

A Phase 2A/B, Randomized, Observer-blinded, Placebo-controlled Study to Evaluate the Efficacy, Immunogenicity, and Safety of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine (SARS-CoV-2 rS) With Matrix-M1™ Adjuvant in South African Adult Subjects Living Without HIV; and Safety and Immunogenicity in Adults Living With HIV. COVID-19

Brief summary describing the background and objectives of the trial

This is a study to evaluate the safety and effectiveness of a COVID-19 vaccine plus adjuvant in healthy HIV-negative and HIV-positive adults. A vaccine causes the body to have an Immune response that can help improve the body's reaction to reinfection by the virus, and reduce the severity of symptoms. An adjuvant is something that can make a vaccine work better. This study will look at the body's immune response to see if the adjuvant affects the body's immune response. Participants in the study will randomly be assigned to receive the SARS-CoV-2 rS vaccine plus adjuvant, or to receive placebo. Each participant in the study will receive a total of two intra-muscular injections over the course of the study.

Type of trial

RCT

Acronym (If the trial has an acronym then please provide)

Disease(s) or condition(s) being studied

Infections and Infestations

Sub-Disease(s) or condition(s) being studied

COVID-19

Purpose of the trial

Prevention: Vaccines

Anticipated trial start date

30/07/2020

Actual trial start date

20/08/2020

Anticipated date of last follow up

30/09/2020

Actual Last follow-up date

Anticipated target sample size (number of participants)

4404

Actual target sample size (number of participants)

Recruitment status

Recruiting

Publication URL

Secondary Ids	Issuing authority/Trial register

STUDY DESIGN
Intervention assignment	Allocation to intervention	If randomised, describe how the allocation sequence was generated	Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms	Masking	If masking / blinding was used
Factorial: participants randomly allocated to either no, one, some or all interventions simultaneously	Randomised	Simple randomization using a randomization table created by a computer software program	Central randomisation by phone/fax	Masking/blinding used	Care giver/Provider,Outcome Assessors,Participants

INTERVENTIONS
Intervention type	Intervention name	Dose	Duration	Intervention description	Group size	Nature of control
Experimental Group	Cohort 1 HIV negative	SARS-CoV-2 rS 5 μg 5 μg, administered by intramuscular injection on Day 0 and Day 21, ideally in alternating deltoids.	Single injection	Biological/Vaccine: SARS-CoV-2 rS 5 μg. Other Names: severe acute respiratory syndrome coronavirus 2 recombinant spike protein nanoparticle vaccine. Biological/Vaccine: Matrix-M1 50 μg, administered with SARS-CoV-2 rS. Other Names: Adjuvant.	2082
Control Group	Cohort 1 HIV negative	Placebo Administered by intramuscular injection on Day 0 and Day 21	Single Injection	Placebo: Sodium chloride 0.9% (BP, sterile)	2082	Placebo
Experimental Group	Cohort 2 HIV positive	Biological/Vaccine: SARS-CoV-2 rS 5 μg, administered by intramuscular injection on Day 0 and Day 21	Single injection	Biological/Vaccine: SARS-CoV-2 rS 5 μg. Other Names: severe acute respiratory syndrome coronavirus 2 recombinant spike protein nanoparticle vaccine. Biological/Vaccine: Matrix-M1 50 μg, administered with SARS-CoV-2 rS. Other Names: Adjuvant.	120
Control Group	Cohort 2 HIV positive	Placebo administered by intramuscular injection on Day 0 and Day 21	Single injection	Sodium chloride 0.9% (BP, sterile)	120	Placebo

ELIGIBILITY CRITERIA
List inclusion criteria	List exclusion criteria	Age Category	Minimum age	Maximum age	Gender
All subjects: • Body mass index (BMI) of 17 to 40 kg/m². • Provides informed consent prior to study participation and is willing to comply with study procedures, including potential home visits. • Women of child-bearing potential must agree not to have sexual intercourse with men, or must consistently use an agreed method of contraception from at least 21 days prior to enrolment in the study, through 6 months after the last vaccination. HIV-negative subjects only: Documentation of HIV-negative test result by a method approved in South Africa. • Healthy at study screening, as determined by the investigator. HIV-positive subjects only: • Documentation of HIV-positive test result by a method approved in South Africa. • Receiving highly active antiretroviral therapy (HAART) and has been using the same regimen for at least 8 weeks before screening. Changes in antiretroviral dosage within 8 weeks of entering the study are allowed, as are exchanges in pharmacological formulations. • Medically stable at screening, as determined by the investigator. • Have a HIV-1 viral load < 1000 copies/mL within 45 days of randomization in the stud	• Any current acute illness requiring medical or surgical care, or chronic illness (excluding HIV in HIV-positive subjects) that requires changes in medication in the past 2 months indicating that chronic illness/disease is not stable. • Chronic disease, including: a. hypertension (elevated blood pressure [BP]) ≥ grade 2 (systolic BP ≥ 160 mmHg; and/or diastolic BP ≥ 100 mmHg) according to the South African Hypertension Society’s Practice Guidelines; b. congestive heart failure with a history of an acute exacerbation of any severity in the prior 2 years; c. chronic obstructive pulmonary disease (COPD) with a history of an acute exacerbation of any severity in the past 2 years. Stable coronary heart disease is NOT exclusionary; d. evidence of unstable coronary artery disease in the past 3 months, as determined by the investigator; e. asthma requiring regular/chronic control medication; f. Type 1 and 2 diabetes (adult onset) requiring treatment with insulin; g. chronic kidney disease/renal insufficiency; h. Chronic gastrointestinal and hepatic diseases; i. chronic neurological diseases (such as multiple sclerosis, dementia, transient ischemic attacks, Parkinson's disease, degenerative neurological conditions, neuropathy, epilepsy, or a history of stroke or previous neurological disorder within the past 12 months with residual symptoms). Subjects with a history of migraine or chronic headaches, or nerve root compression that have been stable on treatment for the last 4 weeks are not excluded. • Participation in research involving an investigational product (drug/biologic/device) within 45 days prior to first study vaccination. • Prior receipt of investigational or approved COVID-19 vaccine at any time. • History of a diagnosis of suspected or confirmed COVID-19. • Received influenza (flu) vaccination within 14 days prior to first study vaccination; or any other vaccine within 4 weeks prior to first study vaccination; or planned vaccination with 5 weeks after first st	80 and over: 80+ Year,Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Middle Aged: 45 Year(s)-64 Year(s)	18 Year(s)	85 Year(s)	Both

ETHICS APPROVAL

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

03/08/2020

University of the Witwatersrand Human Research Ethics Committee

Ethics Committee Address
Street address	City	Postal code	Country
31 Princess of Wales Terrace Parktown, Johannesburg	Johannesburg	2193	South Africa

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

01/10/2020

University of Cape Town Faculty of Health Sciences Human Research Ethics Committee

Ethics Committee Address
Street address	City	Postal code	Country
Groote Schuur Hospital	Cape Town	7925	South Africa

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

28/09/2020

University of Cape Town Faculty of Health Sciences Human Research ethics Committee

Ethics Committee Address
Street address	City	Postal code	Country
Groote Schuur Hospital	Cape Town	7925	South Africa

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

05/10/2020

University of the Witwatersrand Human Research Ethics Committee

Ethics Committee Address
Street address	City	Postal code	Country
31 Princess of Wales Terrace	Johannesburg	2193	South Africa

OUTCOMES
Type of outcome	Outcome	Timepoint(s) at which outcome measured
Primary Outcome	Total number of HIV- participants with first COVID-19 infection and mild, moderate or severe symptoms COVID-19 confirmed by PCR. Symptoms include respiratory (new onset cough, new onset rapid breathing, new onset shortness of breath, sore throat, loss of smell, nasal congestion, runny nose) and non-respiratory (fever, myalgia, chills, loss of taste, headache, diarrhea, tiredness, nausea or vomiting, loss of appetite).	Day 28
Primary Outcome	Total number of HIV- participants with first COVID-19 infection and mild or moderate symptoms COVID-19 confirmed by PCR. Symptoms include respiratory (new onset cough, new onset rapid breathing, new onset shortness of breath, sore throat, loss of smell, nasal congestion, runny nose) and non-respiratory (fever, myalgia, chills, loss of taste, headache, diarrhea, tiredness, nausea or vomiting, loss of appetite). Moderate symptoms are ≥1 of fever plus any 2 COVID-19 symptoms for ≥3 days, high fever for ≥3 days, any evidence of significant lower respiratory tract infection. Severe symptoms are ≥1 of tachypnea, resting heart rate ≥125 beats per minute, oxygen saturation ≤93% on room air or PAO#/FiO#, high flow oxygen therapy/non--invasive ventilation/non-invasive positive pressure ventilation, mechanical ventilation or extracorporeal membrane oxygenation, ≥1 major organ system dysfunction or failure, admission to an ICU, death.	Day 28
Primary Outcome	Number of HIV- participants with solicited adverse events (AEs) following first vaccination	Day 0 to Day 7
Primary Outcome	Number of HIV+ participants with solicited adverse events (AEs) following first vaccination	Day 0 to Day 7
Primary Outcome	Number of HIV- participants with solicited adverse events (AEs) following second vaccination	Day 21 to Day 28
Primary Outcome	Number of HIV+ participants with solicited adverse events (AEs) following second vaccination	Day 21 to Day 28
Primary Outcome	Percentage of HIV- participants with solicited adverse events (AEs) following first vaccination	Day 0 to Day 7
Primary Outcome	Percentage of HIV+ participants with solicited adverse events (AEs) following first vaccination	Day 0 to Day 7
Primary Outcome	Percentage of HIV- participants with solicited adverse events (AEs) following second vaccination	21 to Day 28
Primary Outcome	Percentage of HIV+ participants with solicited adverse events (AEs) following second vaccination	Day 21 to Day 28
Primary Outcome	Number of HIV+ participants with unsolicited adverse events (AEs)	Thru day 35
Primary Outcome	Percentage of HIV+ participants with unsolicited adverse events (AEs)	Thru day 35
Primary Outcome	Serum IgG antibody levels specific for COVID-19 in HIV+ participants	Day 35
Secondary Outcome	Total number of HIV- participants with first COVID-19 infection with any symptoms COVID-19 confirmed by PCR. Mild symptoms are ≥1 of fever, new onset cough, ≥2 COVID-19 respiratory/nonrespiratory symptoms, and does not meet criteria for moderate or severe symptoms. Moderate symptoms are ≥1 of fever plus any 2 COVID-19 symptoms for ≥3 days, high fever for ≥3 days, any evidence of significant lower respiratory tract infection. Severe symptoms are ≥1 of tachypnea, resting heart rate ≥125 beats per minute, oxygen saturation ≤93% on room air or PAO#/FiO#, high flow oxygen therapy/non--invasive ventilation/non-invasive positive pressure ventilation, mechanical ventilation or extracorporeal membrane oxygenation, ≥1 major organ system dysfunction or failure, admission to an ICU, death.	Up to 12 months after last vaccination day 21
Secondary Outcome	Total number of HIV+ participants with first COVID-19 infection with any symptoms COVID-19 confirmed by PCR. Mild symptoms are ≥1 of fever, new onset cough, ≥2 COVID-19 respiratory/nonrespiratory symptoms, and does not meet criteria for moderate or severe symptoms. Moderate symptoms are ≥1 of fever plus any 2 COVID-19 symptoms for ≥3 days, high fever for ≥3 days, any evidence of significant lower respiratory tract infection. Severe symptoms are ≥1 of tachypnea, resting heart rate ≥125 beats per minute, oxygen saturation ≤93% on room air or PAO#/FiO#, high flow oxygen therapy/non--invasive ventilation/non-invasive positive pressure ventilation, mechanical ventilation or extracorporeal membrane oxygenation, ≥1 major organ system dysfunction or failure, admission to an ICU, death.	Up to 12 months after last vaccination day 21
Secondary Outcome	Total number of HIV- participants with first COVID-19 infection requiring hospitalization	Up to 12 months after last vaccination day 21
Secondary Outcome	Incidence of virologically confirmed COVID-19 infection in HIV- participants	Up to 12 months after last vaccination day 21
Secondary Outcome	Incidence of virologically confirmed COVID-19 infection in HIV+ participants	Up to 12 months after last vaccination day 21
Secondary Outcome	Maximum severity score of COVID-19 infection in HIV- participants. Should COVID-19 illness scoring be substantially validated at the time of study start, application of the standard scoring may be applied.	Up to 12 months after last vaccination day 21
Secondary Outcome	Maximum severity score of COVID-19 infection in HIV+ participants. Should COVID-19 illness scoring be substantially validated at the time of study start, application of the standard scoring may be applied.	Up to 12 months after last vaccination day 21
Secondary Outcome	COVID-19 symptom duration in HIV- participants	Up to 12 months after last vaccination day 21
Secondary Outcome	COVID-19 symptom duration in HIV+ participants	Up to 12 months after last vaccination day 21
Secondary Outcome	Serum IgG antibody levels specific for COVID-19 in HIV- participants (post-first dose). Measured by ELISA using geometric mean titers (GMT) or seroconversion rate (SCR)	Day 21
Secondary Outcome	Serum IgG antibody levels specific for COVID-19 in HIV+ participants (post-first dose). Measured by ELISA using geometric mean titers (GMT) or seroconversion rate (SCR)	Day 21
Secondary Outcome	Serum IgG antibody levels specific for COVID-19 in HIV- participants (post-second dose). Measured by ELISA using geometric mean titers (GMT) or seroconversion rate (SCR)	Day 35
Secondary Outcome	Serum IgG antibody levels specific for COVID-19 in HIV+ participants (post-second dose). Measured by ELISA using geometric mean titers (GMT) or seroconversion rate (SCR)	Day 35
Secondary Outcome	Serum IgG antibody levels specific for COVID-19 in HIV- participants. Measured by ELISA using geometric mean titers (GMT) or seroconversion rate (SCR)	Up to 6 months after last vaccination day 21
Secondary Outcome	Serum IgG antibody levels specific for COVID-19 in HIV+ participants. Measured by ELISA using geometric mean titers (GMT) or seroconversion rate (SCR)	Up to 6 months after last vaccination day 21
Secondary Outcome	Change from baseline in serum IgG antibody levels specific for COVID-19 in HIV- participants at Day 35. Measured by ELISA	Baseline and Day 35
Secondary Outcome	Change from baseline in serum IgG antibody levels specific for COVID-19 in HIV+ participants at Day 35. Measured by ELISA	Baseline and Day 35
Secondary Outcome	Change from baseline in serum IgG antibody levels specific for COVID-19 in HIV- participants. Measured by ELISA	Baseline and 6 months after last vaccination day 21
Secondary Outcome	Change from baseline in serum IgG antibody levels specific for COVID-19 in HIV+ participants. Measured by ELISA	Baseline and 6 months after last vaccination day 21
Secondary Outcome	Epitope-specific immune responses to COVID-19 protein receptor binding domain in HIV- participants. Measured by serum titers in an ACE2 receptor binding inhibition assay	Up to 12 months after last vaccination day 21
Secondary Outcome	Epitope-specific immune responses to COVID-19 protein receptor binding domain in HIV+ participants. Measured by serum titers in an ACE2 receptor binding inhibition assay	Up to 12 months after last vaccination day 21
Secondary Outcome	Change in neutralizing antibody activity in HIV- participants at Day 35	Baseline and Day 35
Secondary Outcome	Change in neutralizing antibody activity in HIV+ participants at Day 35	Baseline and Day 35
Secondary Outcome	Change in neutralizing antibody activity in HIV- participants	Baseline and 6 months after last vaccination day 21
Secondary Outcome	Change in neutralizing antibody activity in HIV+ participants	Baseline and 6 months after last vaccination day 21
Secondary Outcome	Number of HIV- participants with MAAEs, AESI or SAE. Assessed by MedDRA classification, severity score and relatedness	Up to 12 months after last vaccination day 21
Secondary Outcome	Number of HIV+ participants with MAAEs, AESI or SAE. Assessed by MedDRA classification, severity score and relatedness	Up to 12 months after last vaccination day 21
Secondary Outcome	Percentage of HIV- participants with MAAEs (Medically Attended Adverse Events), AESI (Adverse Events of Special Interest) or SAEs (Serious Adverse Events). Assessed by MedDRA classification, severity score and relatedness	Up to 12 months after last vaccination day 21
Secondary Outcome	Percentage of HIV+ participants with MAAEs (Medically Attended Adverse Events), AESI (Adverse Events of Special Interest) or SAEs (Serious Adverse Events). Assessed by MedDRA classification, severity score and relatedness	Up to 12 months after last vaccination day 21

RECRUITMENT CENTRES
Name of recruitment centre	Street address	City	Postal code	Country
Respiratory and Meningeal Pathogens Research Unit RMPRU	Chris Hani Baragwanath Academic Hospital, Chris Hani Road, Soweto	Johannesburg	2013	South Africa
Setshaba Research Centre	2088 Block H	Soshanguve	0152	South Africa
Wits RHI Shandukani Research Centre	Hillbrow Health Precinct Klein Street	Johannesburg	2001	South Africa
University of Cape Town Lung Institute and Centre for Lung Infection and Immunity	George Street Observatory	Cape Town	7700	South Africa
Soweto Clinical Trials Centre	Sycamore Street Soweto	Johannesburg	1818	South Africa
South African Tuberculosis Vaccine Initiative	Brewelskloof Hospital Haarlem Street	Worcester	6850	South Africa
Josha Research	28 East Burger Street	Bloemfontein	9300	South Africa
Umlazi Clinical Research Site	Mangosuthu Highway	Umlazi	4066	South Africa
Verulam Clinical Research Site South African Medical Research Council HIV Prevention Research Unit	31-33 Wick Street	Verulam	4340	South Africa
KwaPhila Health Solution	26 Charles Strachan Road	Durban	4091	South Africa
Durban International Clinical Research Site Enhancing Care Foundation	Umbilo Road	Durban	4013	South Africa
The Aurum Institute Pretoria Clinical Research Centre	6 Mark Shuttleworth Street	Pretoria	0087	South Africa
Madibeng Centre for Research	40 Pienaar Street	Brits		South Africa
Limpopo Clinical Research Initiative	11 Van der Bijl street	Thabazimbi	0380	South Africa
Peermed CTC Merk Kempton	Cnr Voortrekker and Monument Rd	Kempton Park	1619	South Africa
Mzansi Ethical Research Centre	184 Cowen Ntuli street	Middelburg	1055	South Africa

FUNDING SOURCES
Name of source	Street address	City	Postal code	Country
Bill and Melinda Gates Foundation	440 5th Ave N	Seattle	WA 98109	United States of America

SPONSORS
Sponsor level	Name	Street address	City	Postal code	Country	Nature of sponsor
Primary Sponsor	Novavax Inc	21 Firstfield Road	Gaithersburg	MD 20878	United States of America	Commercial Sector/Industry

COLLABORATORS
Name	Street address	City	Postal code	Country

CONTACT PEOPLE
Role	Name	Email	Phone	Street address
Principal Investigator	Shabir Madhi	madhis@rmpru.co.za	+27119899891	Chris Hani Baragwanath Academic Hospital Chris Hani Road
City	Postal code	Country	Position/Affiliation
Johannesburg	2013	South Africa	Respiratory and Meningeal Pathogens Research Unit and MRC Vaccines and Infectious Diseases Analytics Research Unit
Role	Name	Email	Phone	Street address
Public Enquiries	Gary Albert	GAlbert@Novavax.com	+12402684000	21 Firstfield Road
City	Postal code	Country	Position/Affiliation
Gaithersburg	MD 20878	United States of America	Central Contact Person
Role	Name	Email	Phone	Street address
Scientific Enquiries	Vivek Shinde	vshinde@novavax.com	+12402684000	21 Firstfield Road
City	Postal code	Country	Position/Affiliation
Gaithersburg	MD 20878	United States of America	Study Chair

REPORTING
Share IPD	Description	Additional Document Types	Sharing Time Frame	Key Access Criteria
Yes	At a minimum, summary results or a link to summary results will be provided within the trial registration record.	Clinical Study Report,Study Protocol	This will be done within 12 months of the study completion date.	Based on the data sharing agreement with the funder, which is in progress
URL	Results Available	Results Summary	Result Posting Date	First Journal Publication Date
Not available at present	No
Result Upload 1:	Result Upload 2:	Result Upload 3:	Result Upload 4:	Result Upload 5:

Result URL Hyperlinks	Link To Protocol
Result URL Hyperlinks

Changes to trial information
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Trial Information	Official scientific title	26/08/2020	Term COVID-19 added as per WHO request for ease of record identification	A Phase 2A/B, Randomized, Observer-blinded, Placebo-controlled Study to Evaluate the Efficacy, Immunogenicity, and Safety of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine (SARS-CoV-2 rS) With Matrix-M1™ Adjuvant in South African Adult Subjects Living Without HIV; and Safety and Immunogenicity in Adults Living With HIV	A Phase 2A/B, Randomized, Observer-blinded, Placebo-controlled Study to Evaluate the Efficacy, Immunogenicity, and Safety of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine (SARS-CoV-2 rS) With Matrix-M1™ Adjuvant in South African Adult Subjects Living Without HIV; and Safety and Immunogenicity in Adults Living With HIV. COVID-19
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Reporting	IPD description	04/09/2020	Information not previously provided.		At a minimum, summary results or a link to summary results will be provided within the trial registration record.
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Reporting	IPD-Sharing time frame	04/09/2020	Information not previously provided.		This will be done within 12 months of the study completion date.
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Reporting	Key access criteria	04/09/2020	Information not previously provided.		Based on the data sharing agreement with the funder, which is in progress
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Reporting	IPD URL	04/09/2020	Information not previously provided.		Not available at present
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Reporting	Study protocol document	04/09/2020	Information not previously provided.		Study Protocol, Clinical Study Report
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Reporting	Results Available	04/09/2020	Information not previously provided.	No	No
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Intervention	Intervention List	14/10/2020	Increase in the total sample size of the study from 2,904 to a minimum of approximately 3,200 to a maximum of approximately 4,404 subjects	Experimental Group, Cohort 1 HIV negative, SARS-CoV-2 rS 5 μg 5 μg, administered by intramuscular injection on Day 0 and Day 21, ideally in alternating deltoids., Single injection, Biological/Vaccine: SARS-CoV-2 rS 5 μg. Other Names: severe acute respiratory syndrome coronavirus 2 recombinant spike protein nanoparticle vaccine. Biological/Vaccine: Matrix-M1 50 μg, administered with SARS-CoV-2 rS. Other Names: Adjuvant., 1332,	Experimental Group, Cohort 1 HIV negative, SARS-CoV-2 rS 5 μg 5 μg, administered by intramuscular injection on Day 0 and Day 21, ideally in alternating deltoids., Single injection, Biological/Vaccine: SARS-CoV-2 rS 5 μg. Other Names: severe acute respiratory syndrome coronavirus 2 recombinant spike protein nanoparticle vaccine. Biological/Vaccine: Matrix-M1 50 μg, administered with SARS-CoV-2 rS. Other Names: Adjuvant., 2082,
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Intervention	Intervention List	14/10/2020	Increase in the total sample size of the study from 2,904 to a minimum of approximately 3,200 to a maximum of approximately 4,404 subjects	Control Group, Cohort 1 HIV negative, Placebo Administered by intramuscular injection on Day 0 and Day 21, Single Injection, Placebo: Sodium chloride 0.9% (BP, sterile) , 1332, Placebo	Control Group, Cohort 1 HIV negative, Placebo Administered by intramuscular injection on Day 0 and Day 21, Single Injection, Placebo: Sodium chloride 0.9% (BP, sterile) , 2082, Placebo
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Eligibility	Age group	14/10/2020	Increase in the upper limit of the eligible age to < 85 years in Cohort 1 only, with an effort to enroll a target of 10 25% of subjects ≥ 65 to <85 years of age. RATIONALE: older adults represent an important risk group to be prioritized in the early rollout of COVID-19 vaccine deployment globally because this population is at increased risk serious COVID-19 outcomes	Adolescent: 13 Year-18 Year, Adult: 19 Year-44 Year, Middle Aged: 45 Year(s)-64 Year(s), Aged: 65+ Year(s)	Adolescent: 13 Year-18 Year, Adult: 19 Year-44 Year, Middle Aged: 45 Year(s)-64 Year(s), Aged: 65+ Year(s), 80 and over: 80+ Year
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Eligibility	Maximum age	14/10/2020	Increase in the upper limit of the eligible age to < 85 years in Cohort 1 only, with an effort to enroll a target of 10 25% of subjects ≥ 65 to <85 years of age. RATIONALE: older adults represent an important risk group to be prioritized in the early rollout of COVID-19 vaccine deployment globally because this population is at increased risk serious COVID-19 outcomes	64 Year(s)	85 Year(s)
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Eligibility	Exclusion criteria	14/10/2020	Exclusion Criteria (Section 4.2) were broadened or clarified as follows: o Broaden the eligibility criteria by providing the actual blood pressure values that define hypertension according to the South African Hypertension Society Practice Guidelines (Exclusion Criterion 2a). This exclusion criterion now references local South African Hypertension Society Guidelines and allow for mild Grade 1 hypertension. o Broaden the eligibility criteria by defining congestive heart failure (Exclusion Criterion 2b). Mild congestive heart failure without history of exacerbation in the prior 2 years is now allowed. o Clarify that stable coronary heart disease was not exclusionary (Exclusion Criterion 2d). o Broaden the eligibility criteria by defining asthma (Exclusion Criterion 2e). Mild, intermittent asthma not requiring chronic control medication is now allowed. o Add type 1 diabetes to the exclusion criteria since type 1 diabetes subjects require insulin and clarified that non-insulin dependent type 2 diabetes subjects were not exclusionary (Exclusion Criterion 2f). o Clarify chronic neurological diseases (Exclusion Criterion 2i). o Added that the use of inhaled glucocorticoids was permitted (Exclusion Criterion 8).	• Any current acute illness requiring medical or surgical care, or chronic illness (excluding HIV in HIV-positive subjects) that requires changes in medication in the past 2 months indicating that chronic illness/disease is not stable. • Chronic disease, including: a. hypertension uncontrolled for age; b. congestive heart failure; c. chronic obstructive pulmonary disease (COPD) with a history of an acute exacerbation of any severity in the past 2 years; d. evidence of unstable coronary artery disease in the past 3 months, as determined by the investigator; e. asthma; f. Type 2 diabetes (adult onset) requiring treatment with insulin; g. chronic kidney disease/renal insufficiency; h. Chronic gastrointestinal and hepatic diseases; i. chronic neurological diseases (such as multiple sclerosis, dementia, transient ischemic attacks, Parkinson's disease, degenerative neurological conditions, neuropathy, epilepsy, or a history of stroke or previous neurological disorder within the past 12 months with residual symptoms). Subjects with a history of migraine or chronic headaches, or nerve root compression that have been stable on treatment for the last 4 weeks are not excluded. • Participation in research involving an investigational product (drug/biologic/device) within 45 days prior to first study vaccination. • Prior receipt of investigational or approved COVID-19 vaccine at any time. • History of a diagnosis of suspected or confirmed COVID-19. • Received influenza (flu) vaccination within 14 days prior to first study vaccination; or any other vaccine within 4 weeks prior to first study vaccination; or planned vaccination with 5 weeks after first study vaccination. • Any autoimmune or immunodeficiency disease/condition (excluding HIV in HIV-positive patients). • Chronic (more than 14 days continuous) administration of immunosuppressant, systemic glucocorticosteroids, or other immune modifying drug • Received immunoglobulin, blood-derived products, or other immunosuppressan	• Any current acute illness requiring medical or surgical care, or chronic illness (excluding HIV in HIV-positive subjects) that requires changes in medication in the past 2 months indicating that chronic illness/disease is not stable. • Chronic disease, including: a. hypertension (elevated blood pressure [BP]) ≥ grade 2 (systolic BP ≥ 160 mmHg; and/or diastolic BP ≥ 100 mmHg) according to the South African Hypertension Society’s Practice Guidelines; b. congestive heart failure with a history of an acute exacerbation of any severity in the prior 2 years; c. chronic obstructive pulmonary disease (COPD) with a history of an acute exacerbation of any severity in the past 2 years. Stable coronary heart disease is NOT exclusionary; d. evidence of unstable coronary artery disease in the past 3 months, as determined by the investigator; e. asthma requiring regular/chronic control medication; f. Type 1 and 2 diabetes (adult onset) requiring treatment with insulin; g. chronic kidney disease/renal insufficiency; h. Chronic gastrointestinal and hepatic diseases; i. chronic neurological diseases (such as multiple sclerosis, dementia, transient ischemic attacks, Parkinson's disease, degenerative neurological conditions, neuropathy, epilepsy, or a history of stroke or previous neurological disorder within the past 12 months with residual symptoms). Subjects with a history of migraine or chronic headaches, or nerve root compression that have been stable on treatment for the last 4 weeks are not excluded. • Participation in research involving an investigational product (drug/biologic/device) within 45 days prior to first study vaccination. • Prior receipt of investigational or approved COVID-19 vaccine at any time. • History of a diagnosis of suspected or confirmed COVID-19. • Received influenza (flu) vaccination within 14 days prior to first study vaccination; or any other vaccine within 4 weeks prior to first study vaccination; or planned vaccination with 5 weeks after first st
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	14/10/2020	To achieve increased subject numbers		Josha Research, 28 East Burger Street, Bloemfontein, 9300, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	14/10/2020	To achieve recruitment of increased subject numbers		Umlazi Clinical Research Site, Mangosuthu Highway, Umlazi, 4066, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	14/10/2020	To achieve recruitment of increased subject numbers		Verulam Clinical Research Site South African Medical Research Council HIV Prevention Research Unit, 31-33 Wick Street, Verulam, 4340, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	14/10/2020	To achieve recruitment of increased subject numbers		KwaPhila Health Solution, 26 Charles Strachan Road, Durban, 4091, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	14/10/2020	To enable recruitment of increased subject numbers		Durban International Clinical Research Site Enhancing Care Foundation, Umbilo Road, Durban, 4013, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	14/10/2020	To enable recruitment of increased subject numbers		The Aurum Institute Pretoria Clinical Research Centre, 6 Mark Shuttleworth Street, Pretoria, 0087, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	14/10/2020	To enable recruitment of increased subject numbers		Madibeng Centre for Research, 40 Pienaar Street, Brits, , South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	14/10/2020	To enable recruitment of increased subject numbers		Limpopo Clinical Research Initiative, 11 Van der Bijl street , Thabazimbi, 0380, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Ethics	Ethics List	14/10/2020	Initial approval for UCT site		TRUE, University of Cape Town Faculty of Health Sciences Human Research Ethics Committee , Groote Schuur Hospital, Cape Town, 7925, South Africa, , 01 Oct 2020, 0214066626, hrec-enquiries@uct.ac.za, 12319_12775_4737.pdf
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Ethics	Ethics List	14/10/2020	Initial approval for UCT site		TRUE, University of Cape Town Faculty of Health Sciences Human Research ethics Committee, Groote Schuur Hospital, Cape Town, 7925, South Africa, , 28 Sep 2020, +27214066626, hrec-enquiries@uct.ac.za, 12319_12776_4737.pdf
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Ethics	Ethics List	15/10/2020	Approval of Protocol amendment. Version 3.0/Amendment 2 dated 09 September 2020		TRUE, University of the Witwatersrand Human Research Ethics Committee, 31 Princess of Wales Terrace, Johannesburg, 2193, South Africa, , 05 Oct 2020, +27112749200, jennifer.palmer@witshealth.co.za, 12319_12778_4737.pdf
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Trial Information	Target no of participants	01/12/2020	Increase in the total sample size of the study from 2,904 to a minimum of approximately 3,200 to a maximum of approximately 4404 subjects. All additional subjects will be added to Cohort 1 (HIV-negative subjects). RATIONALE: the increase in sample size will allow a more rapid accumulation of efficacy endpoints to help accelerate the timing of the endpoint-driven efficacy analysis (and in turn accelerate vaccine development), and to account for the declining intensity of the COVID-19 epidemic in South Africa.	2904	4040
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	01/12/2020	Additional investigator site to meet enrollment numbers		The Aurum Institute Pretoria Clinical Research Centre, 6 Mark Shuttleworth Street, Pretoria, 0087, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	01/12/2020	Additional investigator site to meet enrollment numbers		Peermed CTC Merk Kempton, Cnr Voortrekker and Monument Rd, Kempton Park, 1619, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	01/12/2020	Duplicate	The Aurum Institute Pretoria Clinical Research Centre, 6 Mark Shuttleworth Street, Pretoria, 0087, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Recruitment Centre	RecruitmentCentre List	01/12/2020	To meet target recruitment numbers		Mzansi Ethical Research Centre, 184 Cowen Ntuli street, Middelburg, 1055, South Africa
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Trial Information	Target no of participants	01/12/2020	Increase in the total sample size of the study from 2,904 to a minimum of approximately 3,200 to a maximum of approximately 4404 subjects. All additional subjects will be added to Cohort 1 (HIV-negative subjects). RATIONALE: the increase in sample size will allow a more rapid accumulation of efficacy endpoints to help accelerate the timing of the endpoint-driven efficacy analysis (and in turn accelerate vaccine development), and to account for the declining intensity of the COVID-19 epidemic in South Africa.	4040	4404

Pan African Clinical Trials Registry