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

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

Coalition for Epidemic Preparedness Innovations, The Peter Doherty Institute for Infection and Immunity

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 participants who have received two doses of either Sinopharm, AstraZeneca or Sputnik vaccine as their primary vaccine will be randomised into one of two groups. The two groups consist of a standard or fractional dose of Pfizer vaccine.

The participants and those evaluating reactogenicity will be blinded to the vaccine allocation for the first 28 days following vaccination. After that, both clinical investigators and participants will be aware of their investigational product allocation. Laboratory staff will remain blinded to the investigational product allocation during the immunology testing.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

All unsolicited AE will be collected for 28 days post booster vaccination. Data will be presented as proportion of participants who report unsolicited AE.

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.

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.

Confirmed COVID-19 infections will be documented throughout the follow-up period, by clinical severity.

Inclusion Criteria: Have completed two doses of Sinopharm, AstraZeneca or Sputnik vaccines with the recommended schedule 6 months prior to the date of enrolment Willing and able to give written informed consent Aged 18 years or above Willing to complete the follow-up requirements of the study Exclusion Criteria: Received 3 doses of COVID-19 vaccine Received 2 doses of COVID-19 less than 6 months prior to the start of the trial Currently on immunosuppressive medication or anti-cancer chemotherapy HIV infection Congenital immune deficiency syndrome Has received immunoglobulin or other blood products in the 3 months prior to vaccination Study staff and their relatives Have a history of a severe allergic reaction to any COVID-19 vaccines or have a medical exception to receiving further COVID-19 vaccines

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.

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.

https://www.reuters.com/business/healthcare-pharmaceuticals/indonesia-reports-record-number-doctor-deaths-covid-19-july-2021-07-18/.

US Food and Drug Administration (FDA). Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 2007

https://www.health.gov.au/resources/publications/atagi-recommendations-on-the-use-of-a-booster-dose-of-covid-19-vaccine

Australian Technical Advisory Group on Immunisation (ATAGI). ATAGI recommendations on the use of a booster dose of COVID-19 vaccine 2021