This clinical trial is a single-blind, randomised study to determine the reactogenicity and immunogenicity of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) vaccine (Pfizer-BioNTech) as booster dose in adults, who have previously received either Sinopharm (BBIBP-CorV®), AstraZeneca (ChAdOx1-S, or Vaxzevria®) or Sputnik V (Gam-COVID-Vac®) as their primary doses 6 to 9 months earlier. Both standard and fractional doses will be tested. Participants are healthy adults aged 18 years or older, with no upper age limit. Procedures will be implemented to ensure participants of all ages (aged 18 and above) are included and that there is an even age distribution (\<50 and ≥50 years) in each group. There will be a total of 6 groups (Sinopharm-standard dose Pfizer, Sinopharm-fractional dose Pfizer, AstraZeneca-standard dose Pfizer, AstraZeneca-fractional dose Pfizer, Sputnik - standard dose Pfizer, Sputnik - fractional dose Pfizer), with 200 participants per group for Sinopharm and 100 for AstraZeneca and Sputnik.
As per brief summary
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
601
Tozinameran is a single-stranded, 5'-capped messenger RNA (mRNA) produced using a cellfree in vitro transcription from the corresponding DNA templates, encoding the viral spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Dose - 30 µg in 0.3 ml. Liquid for injection. Single dose.
Tozinameran is a single-stranded, 5'-capped messenger RNA (mRNA) produced using a cellfree in vitro transcription from the corresponding DNA templates, encoding the viral spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Dose - 15 µg in 0.15 ml. Liquid for injection. Single dose.
District Health Centre
Ulaanbaatar, Mongolia
Seroresponse
Serum samples collected at 28-days post booster vaccination from all groups will be evaluated for SARS-CoV-2 specific IgG antibodies using IgG ELISA. The primary endpoint is the seroresponse rate at the Day-28 visit. The seroresponse rate at the individual level is defined as either a ≥4-fold rise in binding antibodies at the Day-28 visit compared to baseline (pre-vaccination) with a titre of \<200 BAU/ml, a ≥2-fold rise among participants with a baseline (pre-vaccination) titre of \>200 BAU/ml, or a ≥4-times the lower limit of detection if baseline levels are lower than the limit of detection.
Time frame: 28-days post booster vaccination
Solicited Grade 3 or 4 Local or Systemic Reaction
Questionnaire to document solicited reactions is developed specifically for this study. Data will be reported as the proportion of participants who report grade 3 or 4 reactions by each intervention arm. Solicited reactions such as pain, tenderness, erythema/redness, induration, swelling, fever, nausea, vomiting, headache, fatigue/malaise, myalgia, arthralgia, diarrhea, enlarged lymph nodes will be collected from the participants 7 days post-vaccination.
Time frame: 7 days post booster vaccination
Seroresponse by Priming Vaccine Strata
Serum samples collected at 28-days post booster vaccination from all groups will be evaluated for SARS-CoV-2 specific IgG antibodies using IgG ELISA. The primary endpoint is the seroresponse rate at the Day-28 visit. The seroresponse rate at the individual level is defined as either a ≥4-fold rise in binding antibodies at the Day-28 visit compared to baseline (pre-vaccination) with a titre of \<200 BAU/ml, a ≥2-fold rise among participants with a baseline (pre-vaccination) titre of \>200 BAU/ml, or a ≥4-times the lower limit of detection if baseline levels are lower than the limit of detection. Priming strata (previously COVID vaccination): AstraZeneca (ChAdOx1-S, or Vaxzevria®); Sinopharm (BBIBP-CorV®); Sputnik V (Gam-COVID-Vac®)
Time frame: 28-days post booster vaccination
SARS-CoV-2 Specific IgG Antibodies at Day-28
Serum samples collected at 28-days post booster vaccination from all groups will be evaluated for SARS-CoV-2 specific IgG antibodies using IgG ELISA.
Time frame: 28-days post booster vaccination
SARS-CoV-2 Specific IgG Antibodies at Day-28 by Priming Vaccine Strata
Serum samples collected at 28-days post booster vaccination from all groups will be evaluated for SARS-CoV-2 specific IgG antibodies using IgG ELISA. Priming strata (previously COVID vaccination): AstraZeneca (ChAdOx1-S, or Vaxzevria®); Sinopharm (BBIBP-CorV®); Sputnik V (Gam-COVID-Vac®)
Time frame: 28-days post booster vaccination
SARS-CoV-2 Specific IgG Antibodies at Baseline (Pre-booster), 28 Days, 6 Months, 12 Months, 18 Months, and 24 Months Post-booster Vaccination.
Serum samples collected at baseline (pre booster), 28 days, 6 months, 12 months, 18 months, and 24 months post booster vaccination from the study arms will be evaluated for SARS-CoV-2 specific IgG antibodies using the commercial Euroimmun S1 IgG ELISA. Data will be reported as binding antibody units (BAU)/mL and presented as geometric mean concentration (GMC) and 95% confidence intervals (CI).
Time frame: Baseline (pre booster), 28 days, 6 months, 12 months, 18 months, and 24 months post-booster vaccination.
SARS-CoV-2 Specific Neutralising Antibodies at Baseline (Pre-booster), 28 Days, 6 Months, 12 Months, 18 Months, and 24 Months Post-booster Vaccination Measured by Surrogate Virus Neutralisation Test (sVNT).
Serum samples collected at baseline (pre booster), 28 days-, 6- and 12-months post booster vaccination from all groups will be evaluated for SARS-CoV-2 specific neutralising antibodies using the GenScript® cPass surrogate virus neutralization test (sVNT) for both wild-type and Omicron variant. Neutralising antibody response will be reported as percentage (%) inhibition of receptor binding domain-angiotensin-converting enzyme 2 (RBD-ACE2) binding relative to a positive control.
Time frame: Baseline (pre-booster), 28 days, 6 months, 12 months, 18 months, and 24 months post-booster vaccination.
SARS-CoV-2 Specific Neutralising Antibodies at Baseline (Pre Booster), 28 Days-, 6- and 12-months Post Booster Vaccination Measured by SARS-CoV-2 Microneutralisation Assay
A subset of samples (20%) from all four timepoints will be assessed using a SARS-CoV-2 microneutralisation assay to both the wild type (vaccine) strain and for two SARS-CoV-2 Variants of concern. Neutralizing antibody will be reported as endpoint titre.
Time frame: Baseline (pre booster), 28 days-, 6- and 12-months post booster vaccination
Interferon Gamma (IFNγ) Concentrations in International Units (IU)/mL
IFN-γ concentrations (IU/mL) as a measure of cellular immunity will be assessed in a subset of participants. IFN-γ production will be stimulated using QuantiFERON Human IFN-γ SARS-CoV-2 (Qiagen) and quantified by ELISA. Results are summarised as geometric mean concentrations (GMCs) with 95% confidence intervals.
Time frame: Baseline (pre booster), 28 days, 6-, 12 -, 18-, and 24-months post booster vaccination
Number of IFNγ Producing Cells/Million PBMCs
Applicable to the subset participants with additional blood collection. IFNγ producing cells as a measurement of cellular immunity will be assessed on a subset of the participants (40%) from each group. IFN-γ Enzyme-Linked ImmunoSpot (Elispot) assay will be performed on isolated peripheral blood mononuclear cells (PBMCs). Data will be reported as number of IFNγ producing cells/million and presented using means and 95% CI.
Time frame: Baseline (pre-booster), 28 days, 6 and 12 months post booster vaccination
Frequency of Cytokine-expressing T Cells
Frequency of wild-type SARS-CoV-2 spike-specific cytokine-expressing T cells will be assessed in a subset of participants (\~40%) using intracellular cytokine staining (ICS) by flow cytometry on PBMC samples. Results are reported as the frequency (%) of cytokine-expressing CD4 and CD8 memory T cells, summarised as geometric mean concentrations (GMCs) with 95% confidence intervals.
Time frame: Baseline (pre-booster), 28 days, 6 and 12 months post-booster vaccination
Cellular Immunity: Multiplex Cytokine Assays - Reported as Cytokine Concentrations in pg/ml and Presented as GMC and 95% CI
Wild-type SARS-CoV-2 spike-specific cytokine concentrations following PBMC stimulation will be assessed in a predefined subset of participants (approximately 40%) using multiplex cytokine assays. Cytokine concentrations will be reported in pg/mL and summarised as geometric mean concentrations (GMCs) with 95% confidence intervals. IFN-γ ELISpot, intracellular cytokine staining (flow cytometry), and multiplex cytokine assays will be performed on isolated peripheral blood mononuclear cells (PBMCs).
Time frame: Baseline (pre booster), 28 days-, 6 and 12 months post booster vaccination
Incidence of Unsolicited Adverse Events (AE)
All unsolicited AE will be collected for 28 days post booster vaccination. Data will be presented as proportion of participants who report unsolicited AE.
Time frame: 28 days-post booster vaccination
Incidence of Medically Attended Adverse Events
All participants with medically attended AE will be collected for 3 months post booster vaccination. Data will be presented as number of participants who report unsolicited AE.
Time frame: 3 months post booster vaccination
Incidence of Serious Adverse Events (SAE)
SAE will be collected throughout the follow-up period of 24 months post booster vaccination. Data will be presented as a proportion of participants who report unsolicited SAE.
Time frame: 24 months post-booster
Incidence of PCR Confirmed COVID-19 Infection
Confirmed SARS-CoV-2 infections will be documented throughout the follow-up period, by clinical severity.
Time frame: Up to 24 months post booster vaccination
Number of IFNγ Producing Cells/Million PBMCs
Applicable to the subset participants with additional blood collection. IFNγ producing cells as a measurement of cellular immunity will be assessed on a subset of the participants (40%) from each group. IFN-γ Enzyme-Linked ImmunoSpot (Elispot) assay will be performed on isolated peripheral blood mononuclear cells (PBMCs). Data will be reported as number of IFNγ producing cells/million and presented using means and 95% CI.
Time frame: At 18 and 24 months post booster vaccination
Frequency of Cytokine-expressing T Cells
Frequency of wild-type SARS-CoV-2 spike-specific cytokine-expressing T cells will be assessed in a subset of participants (\~40%) using intracellular cytokine staining (ICS) by flow cytometry on PBMC samples. Results are reported as the frequency (%) of cytokine-expressing CD4 and CD8 memory T cells, summarised as geometric mean concentrations (GMCs) with 95% confidence intervals.
Time frame: 18 and 24 months post-booster vaccination
Cellular Immunity: Multiplex Cytokine Assays - Reported as Cytokine Concentrations in pg/ml and Presented as GMC and 95% CI
Wild-type SARS-CoV-2 spike-specific cytokine concentrations following PBMC stimulation will be assessed in a predefined subset of participants (approximately 40%) using multiplex cytokine assays. Cytokine concentrations will be reported in pg/mL and summarised as geometric mean concentrations (GMCs) with 95% confidence intervals. IFN-γ ELISpot, intracellular cytokine staining (flow cytometry), and multiplex cytokine assays will be performed on isolated peripheral blood mononuclear cells (PBMCs).
Time frame: 18 and 24 months post booster vaccination
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