Immunogenicity and Safety of Heterologous and Homologous Boosting With ChAdOx1-S and CoronaVac or a Formulation of SCB-2019 (COVID-19)

Study Overview
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Brief Summary
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SARS-CoV-2 is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, collectively called coronavirus disease-19 (COVID-19). SARS-CoV-2 has a high transmission rate, and severe cases of COVID-19 require admission to hospital intensive care units with the need for mechanical ventilation and associated high mortality. Currently cases continue to rise in many countries as the 'second and third waves' of SARS-CoV-2 infection evolve. The authorized vaccines and most vaccines in development are focused on the major antigenic target of the virus, the SARS-CoV-2 spike (S) protein. Authorization was granted in Brazil by ANVISA for the Fiocruz/Oxford-AstraZeneca ChAdOx1-S COVID-19 vaccine as a 2-dose homologous vaccination regimen, 28- to 84-days apart. Emergency Use Authorization (EUA) was also granted for Sinovac Biotech's CoronaVac vaccine as a 2-dose homologous vaccination regimen, 28 days apart. Further vaccines, using different platforms are approved or expected to be approved for use against SARS-CoV-2. Most of the vaccines are expected to be authorized as 2-dose, homologous vaccination series. SCB-2019 is Clover's adjuvanted recombinant SARS-CoV-2 trimeric S-protein subunit vaccine. The SCB-2019 antigen includes SARS-CoV-2 S protein as a trimer fused to Trimer-Tag and is produced in Chinese hamster ovary cells (CHO). SCB-2019 preserves the native trimeric structure of S-protein in the prefusion form and induces neutralizing antibodies to SARS-CoV-2. Trimer-Tag is derived from the fully-human C-propeptide domain of pro-collagen and is capable of self-trimerization, thus fusing any biologically-active proteins in-frame with Trimer-Tag. The resulting fusion proteins expressed in mammalian cells are secreted as disulfide bond-linked homotrimers. The immunogenicity and safety of different dose levels (3, 9, and 30 μg) SCB-2019 vaccine, administered as 2-dose regimen 21-days apart was assessed in a phase 1 clinical study. All dose levels were well-tolerated and induced neutralizing antibodies against S protein of the SARS-CoV-2 virus. Based on the results of that study, Clover selected 30 μg of SCB-2019 in combination with the CpG 1018/alum adjuvant system for further evaluation in the phase 2/3 clinical program as having the most favorable benefit/risk profile. The pivotal study (CLO-SCB-2019-003) included approximately 30,000 healthy participants and individuals with stable pre-existing chronic medical conditions, is being conducted in multiple countries, including in Brazil. The primary purpose of that study (CLO-SCB-2019-003) is to demonstrate the safety and efficacy of SCB-2019 in the prevention of COVID-19. The study showed efficacy. Heterologous boost vaccinations using different platforms may elicit immune responses of greater magnitude and breadth than can be achieved by priming or boosting with the same vaccine (He et al, 2021, Spencer et al., 2021). Also, given the anticipated challenges of vaccinating large proportions of the population, especially with respect to supply, out-of-stock situations, and potential misadministration, it is important for policy makers to have data on flexible vaccination schedules, where the third dose might be different from the priming platform. Protein-based adjuvanted vaccines have the advantage of being from a known and licensed technology that can produce high quantities of vaccine. Protein-based adjuvanted vaccines have also been shown to be highly immunogenic, both in the context of COVID-19 (Keech 2020; Richmond 2021) and other licensed vaccines (Skwarczynski 2016). The purpose of this study is to compare the immunogenicity and safety of heterologous and homologous booster schedules in individuals who received ChAdOx1-S or CoronaVac vaccination previously. The study will be performed in 2 stages - Stage 1 will serve to down-select one of the SCB-2019 formulations for boosting. Stage 2 will compare homologous and heterologous booster regimens in individuals who have received a 2-dose primary vaccination series of either ChadOx1-S or of CoronaVac.

Detailed Description
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This is a phase 2, randomized, controlled, observer-blinded, multi-center study to evaluate the immunogenicity and safety of heterologous and homologous vaccination series with ChAdOx1-S or CoronaVac COVID-19 vaccines and various formulations of adjuvanted recombinant SARS-CoV-2 trimeric S-protein subunit vaccine (SCB-2019). The study will be conducted in two stages.

Official Title
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An Observer-blinded, Randomized, Controlled, Phase 2 Study to Evaluate the Immunogenicity and Safety of Heterologous and Homologous Boosting With ChAdOx1-S and CoronaVac COVID-19 Vaccines or One Formulation of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) Determined in a lead-in Formulation Finding in Healthy Adults.

Conditions
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Covid19

Intervention / Treatment
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* Biological: ChAdOx1-S COVID-19 Vaccine(Fiocruz/Oxford-AstraZeneca)
* Biological: CoronaVac (Sinovac Biotech)
* Biological: Adjuvanted Recombinant SARS-CoV-2 TrimericS-protein Subunit Vaccine (SCB-2019 - Clover)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥18 years of age. Individuals are willing and able to comply with study requirements, including all scheduled visits, vaccinations, laboratory tests, and other study procedures. Individuals are willing and able to give an informed consent, prior to screening. Individuals who: • Received two dose of ChAdOx1-S vaccine 6 months (± 4 weeks) (Groups 1-4 of Stage 1 and Groups 5-7 of Stage 2) or CoronaVac 6 months (± 4 weeks) (Groups 8-10 of Stage 2) prior to recruitment in this study Healthy participants or participants with pre-existing medical conditions who are in a stable medical condition. A stable medical condition is defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 3 months before enrollment. Female participants are eligible to participate in the study if not pregnant, not breastfeeding, and at least 1 of the following criteria apply: Women of non-childbearing potential; Women of childbearing potential (WOCBP) must have a negative urine pregnancy test prior to study vaccination. A confirmatory serum pregnancy test may be conducted at the investigator's discretion. They must be using a highly effective licensed method of birth control for 30 days prior to the first vaccination and must agree to continue such precautions during the study until 90 days after the last study vaccination. Male participants must agree to employ acceptable contraception from the day of first dose of the study vaccine/comparator until 6 months after the last dose of the study vaccine/comparator and also refrain from donating sperm during this period.

Ages Eligible for Study
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Minimum Age: 18 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: Controlled, observer-blinded, Phase 2 Study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1 - Formulation-finding for SCB-2019 - Group 1<br>In Stage 1, immunogenicity and safety of three SCB-2019 formulations will be assessed in comparison with the ChAdOx1-S vaccine, in individuals who received two doses of ChAdOx1-S, 6 months (± 4 weeks) prior to recruitment. Participants (N=120) will be assigned to five groups for Stage 1 and receive doses as follows: Group 1: (N=30) Day 1: SCB-2019 (9 μg) alum; | Biological: Adjuvanted Recombinant SARS-CoV-2 TrimericS-protein Subunit Vaccine (SCB-2019 - Clover)<br>* Heterologous and Homologous Vaccination Series with ChAdOx1-S or CoronaVac COVID-19 Vaccines and Various Formulations of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) in Adults<br>|
| Experimental: Stage 1 - Formulation-finding for SCB-2019 - Group 2<br>In Stage 1, immunogenicity and safety of three SCB-2019 formulations will be assessed in comparison with the ChAdOx1-S vaccine, in individuals who received two doses of ChAdOx1-S, 6 months (± 4 weeks) prior to recruitment. Participants (N=120) will be assigned to five groups for Stage 1 and receive doses as follows: Group 2: (N=30) Day 1: SCB-2019 (9 μg) CpG 1018/alum; | Biological: Adjuvanted Recombinant SARS-CoV-2 TrimericS-protein Subunit Vaccine (SCB-2019 - Clover)<br>* Heterologous and Homologous Vaccination Series with ChAdOx1-S or CoronaVac COVID-19 Vaccines and Various Formulations of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) in Adults<br>|
| Experimental: Stage 1 - Formulation-finding for SCB-2019 - Group 3<br>In Stage 1, immunogenicity and safety of three SCB-2019 formulations will be assessed in comparison with the ChAdOx1-S vaccine, in individuals who received two doses of ChAdOx1-S, 6 months (± 4 weeks) prior to recruitment. Participants (N=120) will be assigned to five groups for Stage 1 and receive doses as follows: Group 3: (N=30) Day 1: SCB-2019 (30 μg) CpG 1018/alum; | Biological: Adjuvanted Recombinant SARS-CoV-2 TrimericS-protein Subunit Vaccine (SCB-2019 - Clover)<br>* Heterologous and Homologous Vaccination Series with ChAdOx1-S or CoronaVac COVID-19 Vaccines and Various Formulations of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) in Adults<br>|
| Experimental: Stage 1 - Formulation-finding for SCB-2019 - Group 4<br>In Stage 1, immunogenicity and safety of three SCB-2019 formulations will be assessed in comparison with the ChAdOx1-S vaccine, in individuals who received two doses of ChAdOx1-S, 6 months (± 4 weeks) prior to recruitment. Participants (N=120) will be assigned to five groups for Stage 1 and receive doses as follows: Group 4: (N=30) Day 1: ChAdOx1-S; | Biological: ChAdOx1-S COVID-19 Vaccine(Fiocruz/Oxford-AstraZeneca)<br>* Heterologous and Homologous Vaccination Series with ChAdOx1-S or CoronaVac COVID-19 Vaccines and Various Formulations of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) in Adults<br>|
| Experimental: Stage 2 - Homologous vs. Heterologous Booster Regimen - Group 5<br>For Stage 2, immunogenicity of heterologous booster vaccination schedule (ChAdOx1-S (Group 5-7) - selected formulation of SCB-2019 or CoronaVac and CoronaVac (Group 8-10) - selected formulation of SCB-2019 or ChAdOx1) vs. a 2-dose ChAdOx1-S or CoronaVac series will be assessed. Participants (N=400) will be randomly (2:1:1) distributed into 6 groups for Stage 2 and receive doses as follows: Group 5: (N=100) Day 1 (boost) -SCB-2019; | Biological: Adjuvanted Recombinant SARS-CoV-2 TrimericS-protein Subunit Vaccine (SCB-2019 - Clover)<br>* Heterologous and Homologous Vaccination Series with ChAdOx1-S or CoronaVac COVID-19 Vaccines and Various Formulations of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) in Adults<br>|
| Experimental: Stage 2 - Homologous vs. Heterologous Booster Regimen - Group 6<br>For Stage 2, immunogenicity of heterologous booster vaccination schedule (ChAdOx1-S (Group 5-7) - selected formulation of SCB-2019 or CoronaVac and CoronaVac (Group 8-10) - selected formulation of SCB-2019 or ChAdOx1) vs. a 2-dose ChAdOx1-S or CoronaVac series will be assessed. Participants (N=400) will be randomly (2:1:1) distributed into 6 groups for Stage 2 and receive doses as follows: Group 6: (N=50) Day 1 (boost) -ChAdOx1-S; | Biological: ChAdOx1-S COVID-19 Vaccine(Fiocruz/Oxford-AstraZeneca)<br>* Heterologous and Homologous Vaccination Series with ChAdOx1-S or CoronaVac COVID-19 Vaccines and Various Formulations of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) in Adults<br>|
| Experimental: Stage 2 - Homologous vs. Heterologous Booster Regimen - Group 7<br>For Stage 2, immunogenicity of heterologous booster vaccination schedule (ChAdOx1-S (Group 5-7) - selected formulation of SCB-2019 or CoronaVac and CoronaVac (Group 8-10) - selected formulation of SCB-2019 or ChAdOx1) vs. a 2-dose ChAdOx1-S or CoronaVac series will be assessed. Participants (N=400) will be randomly (2:1:1) distributed into 6 groups for Stage 2 and receive doses as follows: Group 7: (N=50) Day 1 (boost) -CoronaVac; | Biological: CoronaVac (Sinovac Biotech)<br>* Heterologous and Homologous Vaccination Series with ChAdOx1-S or CoronaVac COVID-19 Vaccines and Various Formulations of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) in Adults<br>|
| Experimental: Stage 2 - Homologous vs. Heterologous Booster Regimen - Group 8<br>For Stage 2, immunogenicity of heterologous booster vaccination schedule (ChAdOx1-S (Group 5-7) - selected formulation of SCB-2019 or CoronaVac and CoronaVac (Group 8-10) - selected formulation of SCB-2019 or ChAdOx1) vs. a 2-dose ChAdOx1-S or CoronaVac series will be assessed. Participants (N=400) will be randomly (2:1:1) distributed into 6 groups for Stage 2 and receive doses as follows: Group 8: (N=100) Day 1 (boost) -SCB-2019; | Biological: Adjuvanted Recombinant SARS-CoV-2 TrimericS-protein Subunit Vaccine (SCB-2019 - Clover)<br>* Heterologous and Homologous Vaccination Series with ChAdOx1-S or CoronaVac COVID-19 Vaccines and Various Formulations of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) in Adults<br>|
| Experimental: Stage 2 - Homologous vs. Heterologous Booster Regimen - Group 9<br>For Stage 2, immunogenicity of heterologous booster vaccination schedule (ChAdOx1-S (Group 5-7) - selected formulation of SCB-2019 or CoronaVac and CoronaVac (Group 8-10) - selected formulation of SCB-2019 or ChAdOx1) vs. a 2-dose ChAdOx1-S or CoronaVac series will be assessed. Participants (N=400) will be randomly (2:1:1) distributed into 6 groups for Stage 2 and receive doses as follows: Group 9: (N=50) Day 1 (boost) - ChAdOx1-S; | Biological: ChAdOx1-S COVID-19 Vaccine(Fiocruz/Oxford-AstraZeneca)<br>* Heterologous and Homologous Vaccination Series with ChAdOx1-S or CoronaVac COVID-19 Vaccines and Various Formulations of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) in Adults<br>|
| Experimental: Stage 2 - Homologous vs. Heterologous Booster Regimen - Group 10<br>For Stage 2, immunogenicity of heterologous booster vaccination schedule (ChAdOx1-S (Group 5-7) - selected formulation of SCB-2019 or CoronaVac and CoronaVac (Group 8-10) - selected formulation of SCB-2019 or ChAdOx1) vs. a 2-dose ChAdOx1-S or CoronaVac series will be assessed. Participants (N=400) will be randomly (2:1:1) distributed into 6 groups for Stage 2 and receive doses as follows: Group 10: (N=50) Day 1 (boost) - CoronaVac. | Biological: CoronaVac (Sinovac Biotech)<br>* Heterologous and Homologous Vaccination Series with ChAdOx1-S or CoronaVac COVID-19 Vaccines and Various Formulations of Clover Adjuvanted Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine (SCB-2019) in Adults<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity - Stage 1 | Immunogenicity is defined as the ability of cells/tissues to provoke an immune response and is generally considered to be an undesirable physiological response, as measured by ELISA (homologous strain) and virus neutralization assay (homologous and heterologous strains). | Day 1 | 
| Immunogenicity - Stage 1 | Immunogenicity is defined as the ability of cells/tissues to provoke an immune response and is generally considered to be an undesirable physiological response, as measured by ELISA (homologous strain) and virus neutralization assay (homologous and heterologous strains). | Day 15 | 
| Immunogenicity - Stage 1 | Immunogenicity is defined as the ability of cells/tissues to provoke an immune response and is generally considered to be an undesirable physiological response, as measured by ELISA (homologous strain) and virus neutralization assay (homologous and heterologous strains). | Day 29 | 
| Immunogenicity - Stage 2 | Immunogenicity is defined as the ability of cells/tissues to provoke an immune response and is generally considered to be an undesirable physiological response, as measured by ELISA (homologous strain) and virus neutralization assay (homologous and heterologous strains). | Day 1 | 
| Immunogenicity - Stage 2 | Immunogenicity is defined as the ability of cells/tissues to provoke an immune response and is generally considered to be an undesirable physiological response, as measured by ELISA (homologous strain) and virus neutralization assay (homologous and heterologous strains). | Day 15 | 
| Immunogenicity - Stage 2 | Immunogenicity is defined as the ability of cells/tissues to provoke an immune response and is generally considered to be an undesirable physiological response, as measured by ELISA (homologous strain) and virus neutralization assay (homologous and heterologous strains). | Day 180 | 
| Immunogenicity - Stage 2 | Immunogenicity is defined as the ability of cells/tissues to provoke an immune response and is generally considered to be an undesirable physiological response, as measured by ELISA (homologous strain) and virus neutralization assay (homologous and heterologous strains). | Day 360 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reactogenicity | Frequencies and percentages of participants experiencing local reactions and systemic solicited AEs; unsolicited AEs; SAEs; MAAEs and AESIs, will be summarized by vaccine group along with 95% CIs CI by the Clopper-Pearson method. | During 7 days after study vaccination | 
| Reactogenicity | Frequencies and percentages of participants experiencing local reactions and systemic solicited AEs; unsolicited AEs; SAEs; MAAEs and AESIs, will be summarized by vaccine group along with 95% CIs CI by the Clopper-Pearson method. | After 28 days after study vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Covid19, Immunogenicity, Vaccines