COVID-19 Vaccine (ChAdOx1 nCoV-19) Trial in South African Adults With and Without HIV-infection

Study Overview
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Brief Summary
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A Phase I/II, double-blinded, placebo-controlled, individually randomized trial to assess safety, immunogenicity and efficacy of the candidate Coronavirus disease (COVID-19) vaccine ChAdOx1 nCoV-19 in adults aged 18-65 years living with and without HIV in South Africa. The vaccine or placebo will be administered via an intramuscular injection into the deltoid muscle of the non-dominant arm.

Detailed Description
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A total of 2070 participants will be enrolled into the trial; 1970 HIV-uninfected and 100 people living with HIV. There will be 4 trial groups, group 1 (n=50; intensive safety & immunogenicity cohort, HIV negative), group 2a (n=250; safety, intense immunogenicity & efficacy), group 2b (n=1650; safety, immunogenicity & vaccine efficacy) and group 3 (n=100, intensive safety & immunogenicity cohort, HIV positive). Participants will be followed up for 12 months after enrollment.

Official Title
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An Adaptive Phase I/II Randomized Placebo-controlled Trial to Determine Safety, Immunogenicity and Efficacy of Non-replicating ChAdOx1 SARS-CoV-2 Vaccine in South African Adults Living Without HIV; and Safety and Immunogenicity in Adults Living With HIV

Conditions
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Coronavirus

Intervention / Treatment
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* Biological: ChAdOx1 nCoV-19
* Biological: Normal saline 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adults aged 18-65 years. Documented result of not being infected with HIV (including screening by a rapid HIV antibody test) within two weeks of randomization into the study for Group-1 and Group-2 participants only. Able and willing (in the Investigator's opinion) to comply with all study requirements. Willing to allow investigators review available medical records, and review all medical and laboratory records if participant is admitted to hospital with respiratory tract infection suspected or confirmed to be COVID-19. For females only, willingness to practice continuous effective contraception (see below) during the study and a negative pregnancy test on the day(s) of screening (within 14 days of randomization) or vaccination. For Group-3 only (i.e. HIV-infected), need to have been on anti-retroviral treatment for at least three months and HIV-1 viral load is <1,000 copies/ml within two weeks of randomization. Agreement to refrain from blood donation during the course of the study. Provide written informed consent. Exclusion Criteria: Planned receipt of any vaccine other (licensed or investigational) than the study intervention within 30 days before and after each study vaccination. Use of any unproven registered and unregistered treatments for COVID-19. Prior receipt of an investigational or licensed vaccine likely to impact on interpretation of the trial data (e.g. Adenovirus vectored vaccines, any coronavirus vaccines). Administration of immunoglobulins and/ or any blood products within the three months preceding the planned administration of the vaccine candidate. HBSAg positivity on the screening sample. Grade 2 or higher level of abnormality for FBC, U&E or LFT based on DAIDS Grading Criteria (Version 2.1, July 2017) History of allergic disease or reactions likely to be exacerbated by any component of the ChAdOx1 nCoV-19 vaccine. Any history of hereditary angioedema or idiopathic angioedema. Any history of anaphylaxis in relation to vaccination. Pregnancy, lactation or willingness/intention to become pregnant during the study. History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ). History of serious psychiatric condition likely to affect participation in the study. Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venipuncture. Any other serious chronic illness requiring hospital specialist supervision. Chronic respiratory diseases, including asthma Chronic cardiovascular disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological illness Seriously overweight (BMI ≥ 40 Kg/m2) Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 42 units every week. Suspected or known injecting drug abuse in the 5 years preceding enrollment. Any clinically significant abnormal finding on screening urinalysis. Any other significant disease, disorder or finding which may significantly increase the risk to the participant because of participation in the study, affect the ability of the participant to participate in the study or impair interpretation of the study data. History of laboratory confirmed COVID-19 illness or known contact with a person that was infected with SARS-COV-2. New onset of fever or a cough or shortness of breath in the 30 days preceding screening and/or enrollment Travel history to any other country with widespread epidemic since January 2020 In addition to above, Group 1 & 2 participants need to fulfill the following exclusion criteria: Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent severe infections and chronic use (more than 14 days) immunosuppressant medication within the past 6 months ( topical steroids are allowed). Any confirmed or suspected immunosuppressive or immunodeficient state (except HIV infection for Group-3), asplenia, recurrent severe infections and chronic use (more than 14 days) immunosuppressant medication within the past 6 months (topical steroids are allowed).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Four groups will be enrolled to receive either one or two doses of investigational vaccine or placebo. Follow up intensity and blood draws differ between groups
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1- IP<br>Participants (HIV-negative) will receive two doses of 5-7.5x10^10 vp ChAdOx1 nCoV-19 vaccine in deltoid of non-dominant arm, 28 days apart. Participants, investigators and outcome assessors will be blinded to intervention. Participants will have 11 routine visits over a 12 month period. | Biological: ChAdOx1 nCoV-19<br>* Dose of 5-7.5x10^10vp of ChAdOx1 nCoV-19<br>|
| Placebo Comparator: Group 1- placebo<br>Participants (HIV-negative) will receive two doses of Normal saline (0.9%) in deltoid of non-dominant arm, 28 days apart. Participants, investigators and outcome assessors will be blinded to intervention. Participants will have 11 routine visits over a 12 month period. | Biological: Normal saline 0.9%<br>* Normal saline 0.9% as placebo<br>|
| Experimental: Group 2a- IP<br>Participants (HIV-negative) will receive two doses of 5-7.5x10^10 vp ChAdOx1 nCoV-19 vaccine in deltoid of non-dominant arm, 28 days apart. Participants, investigators and outcome assessors will be blinded to intervention. Participants will have 7 (1-dose) or 9 (2 doses) routine visits over a 12 month period. | Biological: ChAdOx1 nCoV-19<br>* Dose of 5-7.5x10^10vp of ChAdOx1 nCoV-19<br>|
| Placebo Comparator: Group 2a- placebo<br>Participants (HIV-negative) will receive two doses of placebo in deltoid of non-dominant arm, 28 days apart. Participants, investigators and outcome assessors will be blinded to intervention. Participants will have 7 (1-dose) or 9 (2 doses) routine visits over a 12 month period. | Biological: Normal saline 0.9%<br>* Normal saline 0.9% as placebo<br>|
| Experimental: Group 2b- IP<br>Participants will receive two doses of 5-7.5x10^10 vp ChAdOx1 nCoV-19 vaccine in deltoid of non-dominant arm, 28 days apart. Participants, investigators and outcome assessors will be blinded to intervention. Participants will have 5 (1-dose) or 6 (2 doses) routine visits over a 12 month period. | Biological: ChAdOx1 nCoV-19<br>* Dose of 5-7.5x10^10vp of ChAdOx1 nCoV-19<br>|
| Placebo Comparator: Group 2b- placebo<br>Participants will receive two doses of placebo in deltoid of non-dominant arm, 28 days apart. Participants, investigators and outcome assessors will be blinded to intervention. Participants will have 5 (1-dose) or 6 (2 doses) routine visits over a 12 month period. | Biological: Normal saline 0.9%<br>* Normal saline 0.9% as placebo<br>|
| Experimental: Group 3- IP<br>Participants (HIV-positive) will receive two doses of 5-7.5x10^10 vp ChAdOx1 nCoV-19 vaccine in deltoid of non-dominant arm, 28 days apart. Participants, investigators and outcome assessors will be blinded to intervention. Participants will have 11 routine visits over a 12 month period. | Biological: ChAdOx1 nCoV-19<br>* Dose of 5-7.5x10^10vp of ChAdOx1 nCoV-19<br>|
| Placebo Comparator: Group 3- placebo<br>Participants (HIV-positive) will receive two doses of placebo in deltoid of non-dominant arm, 28 days apart. Participants, investigators and outcome assessors will be blinded to intervention. Participants will have 11 routine visits over a 12 month period. | Biological: Normal saline 0.9%<br>* Normal saline 0.9% as placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the incidence of adverse events (intervention-related and intervention-unrelated) in HIV-negative adults aged 18-65 year receiving candidate ChAdOx1 nCoV-19 vaccine or placebo (safety) | Number of solicited local and systemic reactogenicity signs and symptoms for 7 days following vaccination, and unsolicited adverse events for 28 days following vaccination. Assess occurrence of disease enhancement episodes and serious adverse events in year post vaccination | Up to 12 months post enrollment | 
| Determine if there is a reduction of severe and non-severe COVID-19 disease in HIV-negative adults who receive candidate vaccine ChAdOx1 nCoV-19 compared to placebo recipients (efficacy) | Virologically-confirmed COVID-19 clinical disease will be defined as an acute respiratory illness that is clinically consistent with COVID-19 disease, AND SARS-CoV-2 RT-PCR positivity. | Up to 12 months post enrollment | 
| Assess the incidence of adverse events (intervention-related and intervention-unrelated) in HIV-positive adults aged 18-65 year receiving candidate ChAdOx1 nCoV-19 vaccine or placebo (safety) | Number of solicited local and systemic reactogenicity signs and symptoms for 7 days following vaccination, and unsolicited adverse events for 28 days following vaccination. Assess occurrence of disease enhancement episodes and serious adverse events in year post vaccination | Up to 12 months post enrollment | 
| Assess cellular Immunogenicity of ChAdOx1 nCoV-19 in people living with HIV (immunogenicity) | Assessing the Interferon-gamma (IFN-γ) enzyme- linked immunospot (ELISpot) responses to SARS-CoV-2 spike protein and Th1 and Th2 cytokine response profile at 3-4 days after vaccination | Up to 12 months post enrollment | 
| Assess humoral immunogenicity of ChAdOx1 nCoV-19 in people living with HIV | Assessing Enzyme-linked immunosorbent assay (ELISA) or fluorescence based micro-bead immunosorbent assay on luminex platform to quantify antibodies against SARS-CoV-2 spike protein (seroconversion rates) and Virus neutralising antibody (NAb) assays against live and/or pseudotyped SARS-CoV-2 virus | Up to 12 months post enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess humoral Immunogenicity of ChAdOx1 nCoV-19 in HIV-negative adults (immunogenicity) | Assessing Enzyme-linked immunosorbent assay (ELISA) or fluorescence based micro-bead immunosorbent assay on luminex platform to quantify antibodies against SARS-CoV-2 spike protein (seroconversion rates) and Virus neutralising antibody (NAb) assays against live and/or pseudotyped SARS-CoV-2 virus | Up to 12 months post enrollment | 
| Assess cellular Immunogenicity of ChAdOx1 nCoV-19 in HIV-negative adults (immunogenicity) | Assessing the Interferon-gamma (IFN-γ) enzyme- linked immunospot (ELISpot) responses to SARS-CoV-2 spike protein and Th1 and Th2 cytokine response profile at 3-4 days after vaccination | Up to 12 months post enrollment |