Evaluation of Full Versus Fractional Dose of COVID-19 Vaccine Given as a Booster for the Prevention of COVID-19 in Adults in Mongolia.

A Randomised Controlled Trial to Assess the Immunogenicity, Safety and Reactogenicity of Standard Dose Versus Fractional Doses of COVID-19 Vaccine (Pfizer-BioNTech) Given as a Booster Dose After Priming With Sinopharm, AstraZeneca or Sputnik in Healthy Adults in Mongolia

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.

Study Overview

• Status: Active, not recruiting
• Conditions: COVID-19
• Intervention / Treatment: Biological: Tozinameran - Standard Dose; Biological: Tozinameran - Fractional Dose

Detailed Description

As per brief summary

• Study Type: Interventional
• Enrollment (Actual): 601
• Phase: Phase 3

Contacts and Locations

Study Locations

• Mongolia
  • Ulaanbaatar, Mongolia
    • District Health Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Have completed two doses of Sinopharm, AstraZeneca or Sputnik vaccines with the recommended schedule 6 months prior to the date of enrolment
2. Willing and able to give written informed consent
3. Aged 18 years or above
4. Willing to complete the follow-up requirements of the study

Exclusion Criteria:

1. Received 3 doses of COVID-19 vaccine
2. Received 2 doses of COVID-19 less than 6 months prior to the start of the trial
3. Currently on immunosuppressive medication or anti-cancer chemotherapy
4. HIV infection
5. Congenital immune deficiency syndrome
6. Has received immunoglobulin or other blood products in the 3 months prior to vaccination
7. Study staff and their relatives
8. Have a history of a severe allergic reaction to any COVID-19 vaccines or have a medical exception to receiving further COVID-19 vaccines

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: AstraZeneca (ChAdOx1-S, or Vaxzevria®) - Standard Pfizer-BioNTech booster group; Previously received two doses of AstraZeneca as primary COVID-19 vaccine	Biological: Tozinameran - Standard 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 - 30 µg in 0.3 ml. Liquid for injection. Single dose.; Other Names: BNT162b2; Comirnaty; Pfizer Covid-19 vaccine
Experimental: AstraZeneca (ChAdOx1-S, or Vaxzevria®) - Fractional Pfizer-BioNTech booster group; Previously received two doses of AstraZeneca as primary COVID-19 vaccine .	Biological: Tozinameran - Fractional 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.; Other Names: BNT162b2; Comirnaty; Pfizer Covid-19 vaccine
Active Comparator: Sinopharm (BBIBP-CorV®)- Standard Pfizer-BioNTech booster group; Previously received two doses of Sinopharm as primary COVID-19 vaccine	Biological: Tozinameran - Standard 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 - 30 µg in 0.3 ml. Liquid for injection. Single dose.; Other Names: BNT162b2; Comirnaty; Pfizer Covid-19 vaccine
Experimental: Sinopharm (BBIBP-CorV®)- Fractional Pfizer-BioNTech booster group; Previously received two doses of Sinopharm as primary COVID-19 vaccine	Biological: Tozinameran - Fractional 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.; Other Names: BNT162b2; Comirnaty; Pfizer Covid-19 vaccine
Active Comparator: Sputnik V (Gam-COVID-Vac®)- Standard Pfizer-BioNTech booster group; Previously received two doses of Sputnik as primary COVID-19 vaccine	Biological: Tozinameran - Standard 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 - 30 µg in 0.3 ml. Liquid for injection. Single dose.; Other Names: BNT162b2; Comirnaty; Pfizer Covid-19 vaccine
Experimental: Sputnik V (Gam-COVID-Vac®)- Fractional Pfizer-BioNTech booster group; Previously received two doses of Sputnik as primary COVID-19 vaccine	Biological: Tozinameran - Fractional 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.; Other Names: BNT162b2; Comirnaty; Pfizer Covid-19 vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SARS-CoV-2 specific Immunoglobulin (Ig)G antibodies at 28-days post booster vaccination	Serum samples collected at 28-days post booster vaccination from all groups will be evaluated for SARS-CoV-2 specific IgG antibodies using IgG CMIA. 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.	28-days post booster vaccination
Total incidence of solicited reactions (systemic and local)	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.	7 days post booster vaccination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	28 days-post booster vaccination
Incidence of serious adverse events (SAE)	SAE will be collected throughout the follow-up period of 12 months post booster vaccination. Data will be presented as a proportion of participants who report unsolicited SAE.	12 months post booster vaccination
SARS-CoV-2 specific IgG antibodies at baseline (pre booster), 28- days, 6- and 12-months post booster vaccination.	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 IgG antibodies using IgG CMIA. Data will be reported as binding antibody units (BAU)/mL and presented as geometric mean concentration (GMC) and 95% confidence intervals (CI).	Baseline (pre booster), 28 days, 6- and 12-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 surrogate virus neutralization 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.	Baseline (pre booster), 28 days-, 6- and 12-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.	Baseline (pre booster), 28 days-, 6- and 12-months post booster vaccination
Interferon gamma (IFNγ) concentrations in International Units (IU)/mL	Applicable to the subset participants with additional blood collection. Interferon gamma (IFNγ) concentrations as a measurement of cellular immunity will be assessed on a subset of the participants from each group. QuantiFERON Human IFN-γ SARS-CoV-2 (Qiagen) will be used to stimulate IFN-γ production in peripheral blood mononuclear cells (PBMCs) and then IFN-γ production will be measured using ELISA (enzyme-linked immunosorbent assay). Data will be presented as GMC and 95% CI.	Baseline (pre booster), 28 days-, 6- and 12-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.	Baseline (pre booster), 28 days-, 6- and 12-months post booster vaccination
Frequency of cytokine-expressing T cells	Frequency of cytokine-expressing T cells will be assessed on a subset of participants (40%) using flow cytometry (intracellular staining) on PBMCs samples. Data will be reported as frequency (%) of cytokine-expressing T cells presented as means and 95% CI.	Assessed at 4 time-points (baseline, 28 days, 6 months, and 12 months)
Cellular immunity: Multiplex cytokine assays - reported as cytokine concentrations in pg/ml and presented as GMC and 95% CI	Cytokine concentrations following PBMCs stimulation will be assessed on a subset of participants (40%) using multiplex cytokine assays.Data will be reported as cytokine concentrations in pg/ml and presented as GMC and 95% CI.IFN-γ Elispot, intracellular cytokine assays (flow cytometry) and multiplex cytokine assays will be performed on isolated PBMCs.	Baseline (pre booster), 28 days-, 6- and 12-months 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 proportion of participants who report unsolicited AE.	3 months post booster vaccination
Incidence of PCR confirmed COVID-19 infection	Confirmed COVID-19 infections will be documented throughout the follow-up period, by clinical severity.	Up to 12 months post booster vaccination

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute
• Collaborators: Coalition for Epidemic Preparedness Innovations; The Peter Doherty Institute for Infection and Immunity
• Investigators: Principal Investigator: Kim Mulholland, MD/Prof, Murdoch Childrens Research Institute; Principal Investigator: Tsetsegsaikhan Batmunkh, MD, Ministry of Health, Mongolia

Publications and helpful links

General Publications

• Munro APS, Janani L, Cornelius V, Aley PK, Babbage G, Baxter D, Bula M, Cathie K, Chatterjee K, Dodd K, Enever Y, Gokani K, Goodman AL, Green CA, Harndahl L, Haughney J, Hicks A, van der Klaauw AA, Kwok J, Lambe T, Libri V, Llewelyn MJ, McGregor AC, Minassian AM, Moore P, Mughal M, Mujadidi YF, Murira J, Osanlou O, Osanlou R, Owens DR, Pacurar M, Palfreeman A, Pan D, Rampling T, Regan K, Saich S, Salkeld J, Saralaya D, Sharma S, Sheridan R, Sturdy A, Thomson EC, Todd S, Twelves C, Read RC, Charlton S, Hallis B, Ramsay M, Andrews N, Nguyen-Van-Tam JS, Snape MD, Liu X, Faust SN; COV-BOOST study group. Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. Lancet. 2021 Dec 18;398(10318):2258-2276. doi: 10.1016/S0140-6736(21)02717-3. Epub 2021 Dec 2. Erratum In: Lancet. 2021 Dec 18;398(10318):2246.

Helpful Links

• US Food and Drug Administration (FDA). Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 2007
• Coalition for Epidemic Preparedness Innovations (CEPI). Priority List of Adverse Events of Special Interest
• Indonesia reports record number of doctor deaths from COVID-19 in July
• Quarter-dose of Moderna COVID vaccine still rouses a big immune response
• US Food and Drug Administration (FDA). Moderna COVID-19 Vaccine
• Australian Technical Advisory Group on Immunisation (ATAGI). ATAGI recommendations on the use of a booster dose of COVID-19 vaccine 2021

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2022
• Primary Completion (Actual): September 30, 2022
• Study Completion (Anticipated): September 30, 2023

Study Registration Dates

• First Submitted: March 1, 2022
• First Submitted That Met QC Criteria: March 1, 2022
• First Posted (Actual): March 3, 2022

Study Record Updates

• Last Update Posted (Actual): November 18, 2022
• Last Update Submitted That Met QC Criteria: November 16, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: mRNA vaccine; COVID-19 vaccination; fractional and standard doses; Pfizer; Booster dose
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: 81800

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will share de-identified data to ethically approved studies in cases where participants have indicated on the consent form that they consent to the use of their data and where consistent with terms of collaboration agreements.
• IPD Sharing Time Frame: Individual participant data (IPD) sharing plans in development
• IPD Sharing Access Criteria: IPD sharing plans in development
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes