Explanation for the choice of comparators

All vaccines evaluated in this trial will be approved for use in the target age group by Australia’s Therapeutic Goods Administration (TGA) (including for emergency use) or an equivalent regulatory agency. However, vaccines need not be recommended by ATAGI for boosting for all age groups or specific populations under study. This trial is operating under a TGA clinical trial notification (CTN).

Vaccines investigated at trial commencement may be superseded by updated vaccine formulations as they become available for use in Australia (e.g. vaccines targeting new SARS-CoV-2 variants). To ensure the contemporary relevance of the trial data, investigational vaccines will be introduced or removed from the platform uniformly across all study sites at the discretion of the trial steering committee (TSC), with oversight provided by the data safety monitoring committee (DSMC).

Intervention description

Participants within each stratum will be randomised to receive a single COVID-19 booster vaccine. Each stratum is defined by primary vaccination schedule (two doses of AZD1222 (Vaxzevria, AstraZeneca), BNT162b2 (Comirnaty, Pfizer), or mRNA-1273 (Spikevax, Moderna) and age cohort (12– < 18, 18– < 50, 50– < 70, or 70 + years of age).

At the time of publication, nine COVID-19 vaccines have been evaluated in the PICOBOO platform. BNT162b2, mRNA-1273, and NVX-CoV2372 (Nuvaxovid, Novavax) were evaluated at trial commencement. BNT162b2 and mRNA-1273 were removed for evaluation on January 4, 2023. Tozinameran/riltozinameran (Comirnaty original/Omicron BA.1, Pfizer) and elasomeran/imelasomeran (Spikevax bivalent Original/Omicron, Moderna) were introduced for evaluation on January 5, 2023, and removed for evaluation on June 4, 2023. Tozinameran/famtozinameran (Comirnaty Original/Omicron BA.4–5, Pfizer) and elasomeran/davesomeran (Spikevax bivalent Original/Omicron BA.4–5, Moderna) were introduced for evaluation on June 5, 2023, and removed for evaluation on January 8, 2024. Raxtozinameran (Comirnaty Omicron XBB.1.5, Pfizer) and andusomeran (SPIKEVAX XBB.1.5, Moderna) were introduced to the platform on January 9, 2024. Dosing and administration information is described in further detail, below:

1.

BNT162b2

This mRNA vaccine encodes the full-length SARS-CoV-2 spike protein. The dose for individuals ≥12 years old is 30 micrograms (μg) in 0.3mL of the diluted vaccine delivered by intramuscular injection. Each multidose vial contains 6 doses.

2.

mRNA-1273

A lipid nanoparticle encapsulated mRNA which encodes the full-length SARS-CoV-2 spike protein modified with 2 proline substitutions within the heptad repeat 1 domain. The booster dose is 50μg (0.25mL) for individuals aged >12 years old delivered as an intramuscular injection. Each multidose vial contains 20 doses.

3.

NVX-CoV2373

A nanoparticle vaccine. It is constructed from the full-length wild-type pre-fusion trimers of SARS-CoV2 spike glycoprotein and is co-formulated with a saponin-based adjuvant, Matrix-M1™. The booster dose is 5μg (0.5mL) for individuals aged >12 years old delivered as an intramuscular injection. Each multidose vial contains 10 doses.

4.

Tozinameran/riltozinameran

This mRNA vaccine comprises tozinameran and riltozinameran, the later encoding the viral spike protein of SARS-CoV-2 Omicron BA.1. The dose for individuals >12 years of age is 15μg tozinameran and 15μg riltozinameran in 0.3mL delivered as an intramuscular injection. Each multidose vial contains 6 doses.

5.

Elasomeran/imelasomen

This vaccine contains mRNA coding for the original mRNA-1273 spike glycoprotein as well as the altered version mRNA-1273.529, based on the original mRNA-1273 vaccine but containing mRNA that encodes for the B.1.1.529-matched S glycoprotein. The dosage of mRNA-1273.214 is 25μg of elasomeran and 25μg of imelasomeran in 0.5mL for individuals >12 years old delivered as an intramuscular injection. Each multidose vial contains 5 doses.

6.

Tozinameran/famtozinameran

This vaccine comprises mRNA including tozinameran and riltozinameran, the later encoding the viral spike (S) protein of SARS-CoV-2 Omicron BA.1. The dose of Comirnaty bivalent Original/Omicron BA.1 for boosting is 15 of tozinameran and 15 of riltozinameran contained in 0.3mL of the diluted vaccine for individuals aged ≥12 years old delivered as an intramuscular injection. Each multidose vial contains 6 doses.

7.

Elasomeran/davesomeran

This vaccine comprises mRNA including elasomeran and of davesomeran, the later encoding the viral spike (S) protein of SARS-CoV-2 (Omicron BA.4-5). The S proteins of the SARS-CoV-2 Omicron variant lineages BA.4 and BA.5 are identical. The dosage of mRNA-1273.222 is 25μg of elasomeran and 25μg of davesomeran in 0.5mL for individuals >12 years old delivered as an intramuscular injection. This formulation will be available as either a multidose vial containing 5 doses, or as a single dose per vial.

8.

Raxtozinameran

This is an mRNA vaccine which encodes the viral spike protein of SARS-CoV-2 Omicron XBB.1.5. One dose (0.3 mL) contains 30μg (≥12 years) or 10μg (5 to <12 years) of raxtozinameran delivered as an intramuscular injection. A single vial contains one dose. The formulation for individuals >12 years of age is available as a multi-dose vial, containing 6 doses. The formulation for use in children 5 to <12 years of age is available in a single dose vial.

9.

Andusomeran

This is an mRNA vaccine which encodes the viral spike protein of SARS-CoV-2 Omicron XBB.1.5. One dose contains 50μg of andusomeran in 0.5mL for individuals >12 years old delivered as an intramuscular injection. A single vial contains one dose.

Criteria for discontinuing or modifying allocated interventions

A maximum of 50 participants per intervention per intervention strategy (booster dose number) per stratum will be recruited. Randomisation to an intervention within an intervention strategy and stratum will be ceased prior to enrolment of 50 participants if required because of external factors (such as updates to ATAGI vaccine recommendations) or if a pre-specified statistical criterion is exceeded at a pre-specified interim analysis. The statistical criterion is based on the precision of the primary estimate for each intervention assessed in the intervention strategy and stratum as detailed in a separate Statistical Appendix [6].

Strategies to improve adherence to interventions

Investigational vaccines are delivered as a single dose on the day of randomisation.

Relevant concomitant care permitted or prohibited during the trial

As detailed in the core Protocol [5], individuals were permitted to receive their regular medications if they participated in the trial in addition to paracetamol if required, after vaccine administration.

Provisions for post-trial care

As detailed in the PICOBOO Core Protocol [5], participants will receive usual supportive care following vaccination, as per standard Australian immunisation practice. Specifically, participants will be observed for a minimum of 15 min, and supportive treatment for the management of acute hypersensitivity reactions (e.g. anaphylaxis) will be administered, if required.

Outcomes

Outcomes reported for all participants enrolled in the booster vaccination substudy will include the log10 concentration of SARS-CoV-2 anti-spike immunoglobulin (IgG) at the time points indicated in Table 1, clinical outcomes, and reactogenicity and safety outcomes, as detailed in the core protocol [5]. Additional pre-specified immunological tests will be performed on a dedicated subset, comprising the first 20 participants per booster dose number per stratum to provide samples within the window period at visit 3 (day 28) [6]. Outcomes and endpoints for participants enrolled in the booster vaccination substudy are detailed in Table 1. The availability of new assays and/or funding constraints may impact on immunological testing as the trial progresses.

Table 1 Outcomes and endpoints for participants in the booster vaccination substudyParticipant timeline

The schedule of events detailing enrolment, the intervention, and study visits are detailed in Table 2.

Table 2 Timeline for enrolment, allocation and post-allocation events and trial termination

For re-randomised participants, study visits 1–5 will be repeated. Any visits remaining from the previous randomisation will not be performed. Collection of participant-reported outcome data will recommence from the point of re-randomisation.

Sample size

The maximum planned recruitment per intervention per stratum for each booster dose is 50 participants. The pre-planned adaptations include ceasing recruitment to a booster dose within a stratum when the precision threshold is met for the primary estimand across all interventions and are detailed in the Statistical Appendix [6].

Recruitment

As detailed in the PICOBOO Core Protocol [5], potential screening avenues to identify eligible participants include during vaccination/healthcare visits and advertising material via community locations, research and consumer networks, and social media and via targeted recruitment via Services Australia Medicare mailouts or short-message services delivered via healthcare providers (e.g. via the SMARTVAX network).