The Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO) booster vaccination substudy protocol

The Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO) booster vaccination substudy protocol | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO) booster vaccination substudy protocol Charlie McLeod, Michael Dymock, Katie L Flanagan, Magdalena Plebanski, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4357872/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Nov, 2024 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background : Coronavirus-2019 (COVID-19) vaccination in Australia commenced in February 2021. The first vaccines recommended for use were AZD1222 and BNT162b2, both delivered as a two-dose primary schedule. In the absence of sustained immunity following immunisation, recommendations for booster vaccination have followed. It is likely that periodic boosting will be necessary for at least some Australians, but it is unknown what the optimal booster vaccines and schedules are, or for whom vaccination should be recommended. Methods : The P latform Trial I n CO VID-19 priming and BOO sting (PICOBOO) is a multi-site, multi-arm, randomised, Bayesian adaptive platform trial evaluating different booster vaccine interventions in immunocompetent children and adults, stratified by their primary vaccination schedule and age. Participants are randomised to receive one of three licensed COVID-19 booster vaccines available for use in Australia. PICOBOO aims to generate evidence about the immunogenicity, reactogenicity and cross-protection of different booster vaccine strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants/subvariants. The protocol structure specifying PICOBOO is modular and hierarchical. We have previously published the PICOBOO core (master) protocol. Here we detail the substudy protocol which outlines the study processes which are specific to PICOBOO participants enrolled in the booster vaccination substudy. Discussion : PICOBOO is an adaptive platform trial evaluating different COVID-19 booster vaccination strategies to generate evidence to inform immunisation practice and policy. The modular and flexible protocol structure is intended to enable investigators to respond with agility to new research questions as they arise, such as immunogenicity targeting emergent virus variants, and the immunogenicity and reactogenicity of new vaccines as they become available for use. Trial registration : Australian and New Zealand Clinical Trials Register ACTRN12622000238774; registered on 10/02/2022. Protocol V8.0_23112023. COVID-19 booster vaccination vaccination immunisation adaptive platform trial policy pandemic. Figures Figure 1 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} The P latform Trial I n CO VID-19 Vaccine priming and BOO sting (PICOBOO) booster vaccination substudy protocol. Trial registration {2a and 2b}. Australian and New Zealand Clinical Trials Register ACTRN12622000238774; registered on 10/02/2022. Protocol version {3} V8.0_231132023 Funding {4} Funding is provided by the Snow Foundation and the Medical Research Future Fund (MRFF 2014690 and 2016473). Funding bodies were not involved in the design of the study, nor the collection, analysis or interpretation of data or the preparation of manuscripts for publication. Author details {5a} 1 Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, Australia 2 Infectious Diseases Department, Perth Children’s Hospital, Nedlands, Australia 3 School of Medicine, University of Western Australia, Crawley, Australia 4 Tasmanian Vaccine Trial Centre, Clifford Craig Foundation, Launceston General Hospital, Tasmania, Australia 5 School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia 6 Women’s and Children’s Health Network, North Adelaide, Australia 7 Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Australia 8 Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Australia 9 Centre for Child Health Research, The University of Western Australia, Crawley, Australia 10 Department of Immunology and Infectious Diseases, Sydney Children’s Hospital Network, Australia 1 1 School of Women and Children’s Health, UNSW, Australia 1 2 Division of Paediatrics, School of Medicine, University of Western Australia, Crawley, Australia 1 3 WHO Collaborating Centre for reference and research on Influenza, University of Melbourne, Parkville, Victoria 1 4 Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia 1 5 Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia 1 6 Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia 1 7 National Institute of Health Research Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom 18 Faculty of Medicine and Institute for Life Sciences, University of Southampton, United Kingdom 19 General Paediatrics and Immunology Departments, Perth Children’s Hospital, Nedlands, Australia Name and contact information for the trial sponsor {5b} Trial Sponsor: Telethon Kids Institute (TKI), Northern Entrance, Perth Children’s Hospital, 15 Hospital Avenue, Nedlands, Australia Research Governance Office P: +61 8 6319 1327 Role of sponsor {5c} TKI is the Sponsor and assumes ultimate responsibility for the initiation, conduct, management, and financing of PICOBOO, and the quality and integrity of study data. TKI delegates its Sponsor study-related duties to the PICOBOO Trial Steering Committee (TSC). TKI is providing clinical trial indemnity, and sites are providing site-specific indemnity for study personnel and equipment. Introduction Background and rationale {6a} Primary COVID-19 vaccination in Australia commenced in February 2021 and recommendations for booster vaccination have followed in select populations. Vaccines recommended for primary vaccination in Australia included AZD1222 and mRNA vaccines (BNT162b2 or mRNA-1273) as a two-dose primary schedule in immunocompetent individuals. The need for periodic boosting, including across age groups and in vulnerable sub-populations, is the subject of ongoing debate globally (1). The durability of protection offered by vaccination is likely to be influenced by the host, including exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the circulating strains of the virus (1, 2), the vaccine dose, dosing interval and type of vaccine administered, and the differential impacts of homologous versus heterologous schedules on immune responses (antibodies, B cells, CD4+ and CD8+ T-cells) (3, 4). The P latform Trial I n CO VID-19 priming and BOO sting (PICOBOO) is a randomised, Bayesian adaptive platform trial that is generating evidence of the immunogenicity, reactogenicity and cross-protection of different booster vaccination strategies against SARS-CoV-2 and its variants/subvariants in immunocompetent adolescents and adults. This trial will also evaluate how these immune responses correlate with protection from infection and disease, and how this is impacted by natural infection. PICOBOO has been designed in consultation with the National Community Advisory Group for COVID-19 research and members of national COVID-19 policymaking bodies and is intended to inform practice and policy in Australia. The documentation specifying PICOBOO is modular and hierarchical ( Figure 1 ). The Core Protocol describes study procedures that apply to all participants and aspects of the trial and is presented elsewhere (5). Here we present the booster vaccination substudy protocol (SSP), which details the outcomes, endpoints and study processes that relate specifically to participants enrolled in the booster vaccination substudy. Figure 1 PICOBOO Booster vaccination substudy protocol in relation to other study documents Objectives {7} The primary objective of the PICOBOO booster vaccination substudy is to generate high-quality evidence about the immunogenicity of different COVID-19 boostervaccination strategies against SARS-CoV-2 and its variants/subvariants in immunocompetent hosts, stratified by the primary vaccination history and age group. Trial design {8} The PICOBOO booster vaccination substudy is a randomised, Bayesian adaptive platform trial. It will allow the introduction of new vaccines/schedules for evaluation in this platform and/or to remove vaccines in response to the emergence of external data or changes in immunisation policy in Australia, while preserving the integrity of the trial. Methods: Participants, interventions, and outcomes Study setting {9} This study is currently recruiting at three sites across Australia; these include Telethon Kids Institute (Western Australia), the Women’s and Children’s Hospital (South Australia), and Launceston General Hospital (Tasmania). Eligibility criteria {10} To be eligible a person must: 1. Meet eligibility criteria for the PICOBOO platform trial as outlined in the PICOBOO core protocol (5). 2. Be > 12 years old. 3. Have undergone primary COVID-19 vaccination with: (i) two doses of AZD1222 and be 50 years or over OR (ii) two doses of BNT162b2 and be less than 70 years OR (iii) two doses of mRNA-1273 and be aged between 12 and 18 years old. A person is not eligible if they: 1. Have received a COVID-19 booster vaccine in the preceding 3 months*. 2. Are contraindicated to receive any of the COVID-19 study vaccines, e.g., have a history of anaphylaxis to a vaccine component. *If the Australian Technical Advisory Group on Immunisation (ATAGI) advises an alternative window for COVID-19 boosting vaccinations for eligible participants, this criterion will be reviewed. Participants already enrolled in the PICOBOO adaptive platform trial may be eligible for re-randomisation to receive additional COVID-19 booster vaccine doses, providing the eligibility criteria detailed in the PICOBOO core protocol (5) and the PICOBOO booster vaccination substudy protocol are met. Who will take informed consent? {26a} Informed consent will be obtained by means of written or electronic signature which will be dated and countersigned by the research staff member who obtained it. Additional details regarding the consent process are detailed in in the PICOBOO Core Protocol (5). Additional consent provisions for collection and use of participant data and biological specimens {26b} As detailed in the PICOBOO Core Protocol (5), participants and/or their legal guardians provided consent for blood and saliva samples to be tested and stored for COVID-19 research (including genetic studies) at participating laboratories. Participants have additionally provided consent for de-identified data and samples to be used for future research by participating institutions and third-party organisation(s). Interventions Explanation for the choice of comparators {6b} 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 {11a} 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 Jan 4, 2023. Tozinameran/riltozinameran (Comirnaty original/Omicron BA.1, Pfizer) and elasomeran/imelasomeran (Spikevax bivalent Original/Omicron, Moderna) were introduced for evaluation on Jan 5, 2023, and removed for evaluation on Jun 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 Jun 5, 2023, and removed for evaluation on Jan 8, 2024. Raxtozinameran (Comirnaty Omicron XBB.1.5, Pfizer) and andusomeran (SPIKEVAX XBB.1.5, Moderna) were introduced to the platform on Jan 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 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 {11b} 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 (7). Strategies to improve adherence to interventions {11c} Investigational vaccines are delivered as a single dose on the day of randomisation. Relevant concomitant care permitted or prohibited during the trial {11d} 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 {30} 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 {12} Outcomes reported for all participants enrolled in the booster vaccination substudy will include the log 10 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) (7). 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 substudy OUTCOMES/ENDPOINTS * IMMUNOLOGICAL Concentration of anti-spike Immunoglobulin G (IgG antibody) against SARS-CoV-2 Day 7, 24, 84/180 ** , 365 Concentration of neutralising SARS-CoV-2 antibodies against SARS-CoV-2 *** Day 24, 84/180**, 365 The percentage inhibition of SARS-CoV-2 *** Day 28, 84/180**, 365 The number of IFN-𝛾 b spot forming cells per 10 6 /L peripheral blood mononuclear cells, following in vitro stimulation with SARS-CoV-2 spike overlapping pools of lyophilized peptides, consisting mainly of 15-mer sequences with 11 amino acids overlap *** Day 7, 84/180**, 365 Mucosal salivary IgA c and IgG d Day 28, 84/180**, 365 Presence of anti-nucleocapsid antibodies Day 7, 28, 84/180 ** , 365 REACTOGENICITY/SAFETY Participant or carer-reported local and systemic reactions assessed daily up to Day 7 graded as no reaction, mild, moderate, severe, or life-threatening Days 1-7 Any participant or carer-reported solicited and unsolicited AE e up to ~28 days Day 28 Hospitalisation resulting from AEFI f up to ~28 days Day 28 Any SAR g thought to be causally related to the study Intervention Variable CLINICAL Any PCR h -confirmed SARS-CoV-2 OR RAT i positive result for SARS-CoV-2 up to Day 720 Variable Any PCR h -confirmed SARS-CoV-2 infection up to Day 720 Variable Any PCR h -confirmed wild-type or predominant circulating variant SARS-CoV-2 infection up to Day 720 Variable Any hospitalisation (days) for management of PCR h -confirmed or RAT i -positive SARS-CoV-2 infection up to Day 720 Variable Any participant or carer-reported days off work, study, or usual activities (days) due to PCR h -confirmed or RAT i -positive SARS-CoV-2 infection up to Day 720 Variable * Relative to randomisation ** For adolescent participants and adult participants receiving a 3rd or subsequent (5th dose) booster, visit 4 (Day 84) will be substituted for Day 180 *** This will be performed separately for ancestral SARS-CoV-2 and the predominant circulating variant a Primary endpoint; b IFN- 𝛾: interferon-𝛾; c IgA: Immunoglobulin A; d IgG: Immunoglobulin G; e AE: Adverse event; f AEFI: Adverse event following immunisation; g SAR: Serious adverse reaction; h PCR: Polymerase chain reaction; i RAT: Rapid antigen test. Participant timeline {13} 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 {14} 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 (7). Recruitment {15} As detailed in the PICOBOO Core Protocol (5), potential screening avenues to identify eligible participants include during vaccination/healthcare visits, advertising material via community locations, research and consumer networks, 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). Assignment of interventions: allocation Sequence generation {16a} A sequence of intervention assignments will be generated by an un-blinded trial statistician using random permuted blocks for each booster dose within each stratum using computer software with a validated random number generator and equal allocation for all booster interventions. Concealment mechanism {16b} As detailed in the PICOBOO Core Protocol (5), an un-blinded research nurse will obtain the next contiguous stratum allocation (i.e. the lowest available randomisation number) from the study REDCap database on the day of randomisation. Implementation {16c} As detailed in the PICOBOO Core Protocol (5), at vaccination, two unblinded members of the research team will check and dispense the study vaccine for administration. Pre-filled syringes containing one of the COVID-19 booster vaccines approved for use will be covered with opaque tape and concealed until ready for administration. Prior to opening the box, the participant will be asked to look away. The vaccine intervention will be administered in accordance with routine immunisation practices stipulated per Australian guidelines. Assignment of interventions: Blinding Who will be blinded {17a} Participants will be blinded to the specific COVID-19 vaccination received, at least until after the primary estimand data are collected. Further details are provided in the PICOBOO Core Protocol (5), At this time, details regarding vaccination will be uploaded to the Australian Immunisation Register, where it will be possible for participants to access their individual vaccination history, if desired. Procedure for unblinding if needed {17b} The corresponding site principal investigator will provide authorisation for unblinding if compelling reasons arise. Further details are provided in the PICOBOO Core Protocol (5). Data collection and management Plans for assessment and collection of outcomes {18a} As detailed in the PICOBOO Core Protocol (5), data will be collected on hard or electronic case report forms (eCRF), including (i) demographic data, (ii) COVID-19 vaccination history, (iii) previous medical history, (iv) anthropometric data (including height and weight), (v) laboratory data and (vi) participant/carer-reported outcomes. Plans to promote participant retention and complete follow-up {18b} Participants will be contacted and reminded to attend for their follow-up visits. We will use all available data on any patients who are lost to follow-up. If a participant withdraws, we will use all data collected up until the time of withdrawal unless they explicitly request their data to be removed. Data management {19} Data will be collected into a secure REDCap database, hosted by the sponsor. Further details regarding data management and security are provided in the PICOBOO Core Protocol (5), Confidentiality {27} Robust measures will be taken to ensure confidentially for participants enrolled in the trial, as detailed in the PICOBOO Core Protocol (5). Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} As detailed in Table 2 , blood and saliva samples will be collected at pre-specified time points. Blood will be separated into the sera, plasma, and peripheral blood mononuclear cells (PBMCs) at local sites prior to transportation to reference laboratories for processing. Granulocytes collected from baseline blood samples during gradient centrifugation will be used for deoxyribonucleic acid (DNA) extraction for human leucocytic antigen (HLA) I and II typing. This will be performed to evaluate susceptibility to and protection from SARS-CoV-2 infection and disease. Genomic DNA will be extracted using commercial kits, harmonised across sites. DNA will be aliquoted and stored as per standard operating procedures (SOPs). Statistical methods Statistical methods for primary and secondary outcomes {20a} A Bayesian three-level hierarchical linear model will be used for the primary analysis as it is anticipated that immune responses may be mutually informative across COVID-19 vaccination dose, age groups and potentially across messenger ribonucleic acid (mRNA) vaccine interventions (7). The model estimates the posterior distribution of the mean log10 anti-spike SARS-CoV-2 IgG antibody against Ancestral SARSCoV-2 measured ~ 28 days after receipt of the assigned booster COVID-19 vaccine for each intervention and vaccination strategy in each stratum, denoted by vaccine history group and age group. Further detail can be found in the Statistical Appendix (7). Interim analyses {21b} Interim analyses were pre-specified. The first analysis was performed after participants had completed 300 vaccination events and 21-31 days follow-up post-randomisation. Further details regarding interim analyses detailed in the Statistical Appendix (7). Methods for additional analyses (e.g. subgroup analyses) {20b} Any analyses not specified in the Statistical Appendix (7) will be designated as exploratory. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Immune responses and reactogenicity to COVID-19 vaccines will be assessed using a treatment policy strategy. Further detail regarding the analytical approach to handling intercurrent events is detailed in the Statistical Appendix (7). Plans to give access to the full protocol, participant level-data and statistical code {31c} Current versions of the PICOBOO core protocol (8), the Statistical Appendix (7), the PICOBOO substudy protocol, and the Laboratory Appendix will be accessible on the trial website ( https://picoboo.com.au/ ). Decisions regarding the sharing of de-identified data and/or statistical code will be assessed by the PICOBOO TSC and will be conditional upon any necessary institutional and ethics approvals. Oversight and monitoring. Composition of the coordinating centre and trial steering committee {5d} The PICOBOO administrative structure detailed in the PICOBOO core protocol applies to all nested platform substudies (5). Composition of the data monitoring committee, its role and reporting structure {21a} As detailed in the PICOBOO Core Protocol (5), A Data and Safety Monitoring Committee (DSMC) will be appointed to provide safety oversight. The DSMC will have an advisory role as outlined in the DSMC Charter. Adverse event reporting and harms {22} All serious adverse events (SAEs), adverse events of special interest (AESI), medically attended AEs (MAAEs) and adverse events (AEs) resulting in withdrawal occurring from day 0 to day 28 after randomisation will be recorded. From day 29 to day 720 after randomisation, all SAEs, AESIs, MAAEs, and AEs resulting in withdrawal that are found to be related to the study vaccine or study procedures will be reported. The processes for assessing and reporting safety are detailed in the PICOBOO Core Protocol (5). Frequency and plans for auditing trial conduct {23} Monitoring will be conducted according to a risk-stratified approach as detailed in the PICOBOO Core Protocol (5). Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Any substantial amendments to the PICOBOO protocol will require prior approval by the relevant ethics and governance regulatory bodies (5). Dissemination plans {31a} The National COVID-19 CRG will provide guidance on the best methods for dissemination of information to participants and the broader community. The TSC will, as far as possible, make the protocol(s), laboratory appendix, statistical analysis plans, and non-identifying patient-level data available, to allow independent scientific scrutiny and validation of any published results. Discussion We present the protocol for a randomised, Bayesian adaptive trial nested within the PICOBOO study platform; the trial aims to generate high quality evidence regarding the immunogenicity, reactogenicity, and cross protection offered by different COVID-19 booster vaccination strategies against SARS-CoV-2 and its variants/subvariants. The PICOBOO booster vaccination substudy is unique in terms of evaluating the impacts of multiple alternative COVID-19 vaccination strategies concurrently and sequentially, across different age groups, including in children. It is expected to generate evidence to shape immunisation practice and policy while also contributing to the growing body of evidence informing vaccination policy globally. COVID-19 vaccines have led to substantial reductions in severe disease, hospitalisation, and death, with an estimated 19.8 million deaths averted in 2021 alone ( 9 ). While periodic booster vaccination is likely to remain a core strategy for achieving protection against disease in at least some risk groups, there are limited data to inform the best ongoing strategies for vaccination. Specifically, it is unknown whether some vaccines are better than others, and if so, which homologous and/or heterologous vaccine strategies are best and in whom, and what the optimal intervals between booster doses are. We aim to provide a detailed profile of the immunological and safety outcomes of different vaccines available for use in Australia to add to the available published literature to aid decision-making. We expect that the trial’s Bayesian adaptive design will have three main benefits over conventional trial methods ( 10 ). First, the flexibility to introduce new vaccines or schedules for evaluation as they become available, or to remove vaccines in response to changes to vaccine policy in Australia or the emergence of external data, while preserving the overall integrity of the trial. Second, the decision rules are designed to avoid over-recruitment to a stratum based on pre-specified precision criteria, facilitating timely decision-making. This is possible owing to improved statistical efficiency resulting from data sharing that is expected with the use of hierarchical Bayesian statistical models. Third, the trial structure will facilitate nesting of additional studies in the future, which is likely to be more efficient and cost-effective than conducting multiple trials independently. While serum anti-spike immunoglobin G concentrations and anti-SARS-CoV-2 neutralising antibody titres have emerged as correlates of vaccine protection against symptomatic COVID-19 disease ( 11 , 12 ), more data are required to delineate specific threshold titres that correlate with protection ( 13 ), including against variants of concern. Further, additional work is required to elucidate correlates of protection based on other immunologic functions, such as effector memory and T-cell function, which may play a role in controlling infection once established ( 11 ). It is intended that the data generated from this trial will be combined with other data available internationally to further inform correlates of protection against COVID-19 infection and disease. One issue that has garnered attention throughout the pandemic has been the timely dissemination of data and how this is impacted by the need for rigorous peer-review, ideally prior to the release of results ( 14 ). The Bayesian statistical model used in this trial will be periodically updated as data accrue, even after recruitment to a particular booster intervention (e.g., third dose, fourth dose boosters) ceases within a stratum. Statistical reports detailing pre-specified analyses will be made available within the public domain on the trial website as soon as practicable following review by the trial statistical analysis team, the trial steering committee, and the DSMC. Results will also be disseminated periodically via peer-reviewed publications. To facilitate knowledge transfer, modification and re-purposing, all trial processes, governance arrangements, and digital infrastructure have been developed in partnership with relevant stakeholders and based on FAIR data principles (findable, accessible, interoperable, reusable) ( 15 ). The need for robust evidence to inform practice and policy in the face of a rapidly evolving pandemic has outstripped efforts to generate it quickly; consequently, decision-making has largely occurred ahead of the science. Moving forward, important vaccine policy questions must be addressed with agility to ensure that the recommended vaccination schedules will enhance population-level immunity while protecting vulnerable sub-populations. The PICOBOO booster vaccination substudy will fill critical knowledge gaps to optimize immunisation policy in Australia and elsewhere. Initial results were generated in the first quarter of 2023. Trial status Current PICOBOO Core Protocol Version 15.0_28112023. Substudy Protocol: Booster vaccination V8.0_28112023. Recruitment commencement date: 29th of March 2022. Recruitment is expected to be completed by 7 Feb, 2025. Abbreviations ATAGI Australian Technical Advisory Group on Immunisation COVID-19 Coronavirus 2019 DSMC Data Safety Monitoring Committee mRNA messenger ribonucleic acid PICOBOO Platform trial In COVID-19 BOOsting SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus-2 TKI Telethon Kids Institute TGA Therapeutic Goods Administration TSC Trial Steering Committee. Declarations Acknowledgements We are grateful to multiple individuals and groups for supporting this work. To the Child and Adolescent Health Service Human Research Ethics Committee (CAHS HREC), for reviewing the PICOBOO ethics submission (and subsequent amendments) to allow this trial to progress. To the participants and families who chose to contribute to this study. To the National Consumer Advisory Group for COVID-19 research, who have informed all stages of this research project. To Jess Ramsay and George Salama, who led the project management for this trial. We acknowledge members of the Data Safety Monitoring Committee including Professor Margie Danchin (Chair), Professor Nigel Crawford, A/Professor Christopher Oldmeadow, Dr Daniel Barker, A/Professor Trisha Peel, Professor David Nolan, and Dr Tony Korman for their commitment to monitoring the safety of participants and the scientific integrity of this trial. We also thank the research and laboratory staff involved in this project who have worked tirelessly to recruit participants and process biospecimens for this trial. CM is supported by a Raine Fellowship. TS is supported by an MRFF Investigator Award (MRF1195153). MD is supported by a NHMRC Postgraduate Research Award (APP2022557). CCB is supported by a NHMRC Investigator Award (APP1173163). Support for the design of PICOBOO was provided by Snow Medical Foundation. Authors’ contributions {31b} TS and PR conceived the study. CM, JR, ME, TS, JM, and MD led the protocol development. PR, CM, MP, KF, HM, KS, UW, SN, PW, RT, CT, JR, ME, JM, MD, and TS contributed to the study design. CM produced the first draft of this manuscript. All authors read and approved the final manuscript. Funding {4} Funding for this trial was provided by the Snow Foundation and the Medical Research Future Fund #2014690 and #2016473. RT is supported by a mid-career researcher fellowship generously awarded by the Passe and Williams Foundation. SNF is a UK NIHR Senior Investigator. Availability of data and materials {29} Access to data will be granted to study Investigators and authorised representatives from the Sponsor and the regulatory authorities to allow trial-related monitoring, audits, and inspections to occur. PICOBOO will also comply with relevant jurisdictional and academic requirements relating to access to data, as apply at the time that the data are generated. Ethics approval and consent to participate {24} Ethics approval for the conduct of this study has been provided by the Child and Adolescent Health Service Human Research Ethics Committee (RGS 9722). Informed consent to participate will be obtained from all participants in either written or electronic form. Consent for publication {32} Individual consent for publication will not be required from participants. The final decision to publish will lie with the PICOBOO TSC. Competing interests {28} KF and TS are members of the Australian Technical Advisory Group on Immunisation (ATAGI) which advises the government on vaccine policy; their involvement as investigators on this trial has been declared to ATAGI. MP is involved in an ovarian cancer clinical trial that received funding from AstraZeneca. MP was involved in performing immunological assays on biological specimens obtained from participants in this trial, but was not involved in participant recruitment, data collection or the analysis of results. SNF leads the UK National Institute for Health and Care Research funded trial of third and fourth dose COVID-19 boosters. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust, UK as an Investigator and/or providing consultative advice on clinical trials and studies of vaccines funded or sponsored by vaccine manufacturers including Moderna, Sanofi, Janssen, BNT162b2izer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Medimmune, Merck and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. The other authors declare that they have no competing interests. References Krause PR, Fleming TR, Peto R, Longini IM, Figueroa JP, Sterne JAC, et al. Considerations in boosting COVID-19 vaccine immune responses. Lancet (British edition). 2021;398(10308):1377–80. Juno JA, Wheatley AK. Boosting immunity to COVID-19 vaccines. Nat Med. 2021;27(11):1874–5. Atmar RL, Lyke KE, Deming ME, Jackson LA, Branche AR, El Sahly HM, et al. Homologous and Heterologous Covid-19 Booster Vaccinations. N Engl J Med. 2022;386(11):1046–57. Au W, Cheung P. Effectiveness of heterologous and homologous covid-19 vaccine regimens: living systematic review with network meta-analysis. BMJ. 2022;377:e069989. J. R CM, KL. F M, P HM. M. D, Core Protocol for the adaptive Platform Trial in COVID-19 vaccine priming and BOOsting (PICOBOO). Trials. 2023;24(202). Thomas SJ Jr., EDM, Kitchin. N AJ, Gurtman A, Lockhart S et al. Six month safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. medRxiv. 2021. Dymock M, McLeod C, Richmond P, Snelling T, Marsh J. Statistical considerations for the Platform Trial in COVID-19 vaccine priming and boosting. Preprint (version 1) available at Research Square 2024. McLeod C, Ramsay J, Flanagan KL, Plebanski M, Marshall H, Dymock M, et al. Core protocol for the adaptive Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO). Curr controlled trials Cardiovasc Med. 2023;24(1):202. Organisation WH. Global Covid-19 Vaccination Strategy in a Changing World: Ju;y 2022 update. World Health Organisation; 2022. Saville BR, Berry SM. Efficiencies of platform clinical trials: A vision of the future. Clin Trials. 2016;13(3):358–66. Gilbert PB, Donis RO, Koup RA, Fong Y, Plotkin SA, Follmann D. A Covid-19 Milestone Attained — A Correlate of Protection for Vaccines. N Engl J Med. 2022;387(24):2203–6. Feng S, Phillips DJ, White T, Sayal H, Aley PK, Bibi S, et al. Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection. Nat Med. 2021;27(11):2032–40. Krammer F. Correlates of protection from SARS-CoV-2 infection. Lancet (British edition). 2021;397(10283):1421–3. Watson C. Rise of the preprint: how rapid data sharing during COVID-19 has changed science forever. Nat Med. 2022;28(1):2–5. Boeckhout M, Zielhuis GA, Bredenoord AL. The FAIR guiding principles for data stewardship: fair enough? Eur J Hum genetics: EJHG. 2018;26(7):931–6. Table 2 Table 2 is available in the Supplementary Files section. Supplementary Files Table2.xlsx Table 2 Timeline for enrolment, allocation and post-allocation events and trial termination Cite Share Download PDF Status: Published Journal Publication published 01 Nov, 2024 Read the published version in Trials → Version 1 posted Editorial decision: Accept 04 Sep, 2024 Reviewers agreed at journal 04 Sep, 2024 Reviewers invited by journal 04 Sep, 2024 Editor assigned by journal 08 May, 2024 First submitted to journal 05 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4357872","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":349433729,"identity":"3a137b4e-1047-4132-9c7a-c163dc3214ca","order_by":0,"name":"Charlie 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Sydney","correspondingAuthor":false,"prefix":"","firstName":"Tom","middleName":"L","lastName":"Snelling","suffix":""},{"id":349433746,"identity":"e3d9199a-7c21-4313-9b33-589b29178dfc","order_by":17,"name":"Peter Richmond","email":"","orcid":"","institution":"Telethon Kids Institute","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Richmond","suffix":""}],"badges":[],"createdAt":"2024-05-02 08:48:51","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4357872/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4357872/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-024-08456-4","type":"published","date":"2024-11-01T16:20:25+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":67112679,"identity":"16de1f8d-e080-4010-b2fb-0598ddfe2522","added_by":"auto","created_at":"2024-10-21 09:54:35","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":161140,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePICOBOO Booster vaccination substudy protocol in relation to other study documents\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4357872/v1/496ce33381bfd68452755c53.jpg"},{"id":68207300,"identity":"62225e8d-b9c1-4dc3-91a2-54adcd9cd3ed","added_by":"auto","created_at":"2024-11-04 16:36:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1163544,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4357872/v1/792db925-6c27-4979-bae7-46021db696ad.pdf"},{"id":67112724,"identity":"d2ae72ab-9593-4ec1-ace1-99064170ad19","added_by":"auto","created_at":"2024-10-21 09:54:39","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10813,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eTable 2 Timeline for enrolment, allocation and post-allocation events and trial termination\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4357872/v1/54585217baa470338d23499b.xlsx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eThe Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO) booster vaccination substudy protocol\u003c/p\u003e","fulltext":[{"header":"Administrative information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eThe\u0026nbsp;\u003cu\u003eP\u003c/u\u003elatform Trial \u003cu\u003eI\u003c/u\u003en\u0026nbsp;\u003cu\u003eCO\u003c/u\u003eVID-19 Vaccine priming and\u0026nbsp;\u003cu\u003eBOO\u003c/u\u003esting (PICOBOO) booster vaccination substudy protocol.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eAustralian and New Zealand Clinical Trials Register\u0026nbsp;ACTRN12622000238774; registered on 10/02/2022.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eV8.0_231132023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eFunding is provided by the Snow Foundation and the Medical Research Future Fund (MRFF\u0026nbsp;2014690\u0026nbsp;and 2016473). Funding bodies were not involved in the\u0026nbsp;design of the study, nor the collection, analysis or interpretation of data or the preparation of manuscripts for publication.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003eWesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e2\u003c/sup\u003eInfectious Diseases Department, Perth Children\u0026rsquo;s Hospital, Nedlands, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e3\u003c/sup\u003eSchool of Medicine, University of Western Australia, Crawley, Australia\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e4\u003c/sup\u003eTasmanian Vaccine Trial Centre, Clifford Craig Foundation, Launceston General Hospital, Tasmania, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e5\u003c/sup\u003eSchool of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e6\u003c/sup\u003eWomen\u0026rsquo;s and Children\u0026rsquo;s Health Network,\u0026nbsp;North Adelaide, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e7\u003c/sup\u003eRobinson Research Institute and Adelaide Medical School, The University of Adelaide, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e8\u003c/sup\u003eSydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e9\u003c/sup\u003eCentre for Child Health Research, The University of Western Australia, Crawley, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e10\u003c/sup\u003eDepartment of Immunology and Infectious Diseases, Sydney Children\u0026rsquo;s Hospital Network, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e1\u003c/sup\u003eSchool of Women and Children\u0026rsquo;s Health, UNSW, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003eDivision of Paediatrics, School of Medicine, University of Western Australia, Crawley, Australia\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003eWHO Collaborating Centre for reference and research on Influenza, University of Melbourne, Parkville, Victoria\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003eDepartment of Microbiology and Immunology, University of Melbourne\u0026nbsp;at the\u0026nbsp;Peter Doherty Institute for Infection and Immunity, Melbourne,\u0026nbsp;Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003eVictorian Infectious Diseases Reference\u0026nbsp;Laboratory,\u0026nbsp;The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity,\u0026nbsp;Melbourne, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003eDepartment of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity,\u0026nbsp;Melbourne, Australia\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e7\u003c/sup\u003eNational Institute of Health Research Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e18\u003c/sup\u003eFaculty of Medicine and Institute for Life Sciences, University of Southampton, United Kingdom\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e19\u003c/sup\u003eGeneral Paediatrics and Immunology Departments, Perth Children\u0026rsquo;s Hospital, Nedlands, Australia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eTrial Sponsor: Telethon Kids Institute (TKI), Northern Entrance, Perth Children\u0026rsquo;s Hospital, 15 Hospital Avenue, Nedlands, Australia\u003c/p\u003e\n \u003cp\u003eResearch Governance Office\u003c/p\u003e\n \u003cp\u003eP: +61 8 6319 1327\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eTKI is the Sponsor and assumes ultimate responsibility for the initiation, conduct, management, and financing of PICOBOO, and the quality and integrity of study data.\u0026nbsp;TKI delegates its Sponsor study-related duties to the PICOBOO Trial Steering Committee (TSC). TKI is providing clinical trial indemnity, and sites are providing site-specific indemnity for study personnel and equipment.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\u003cp\u003e\u003cstrong\u003eBackground and rationale {6a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary COVID-19 vaccination in Australia commenced in February 2021 and recommendations for booster vaccination have followed in select populations. Vaccines recommended for primary vaccination in Australia included AZD1222 and mRNA vaccines (BNT162b2 or\u0026nbsp;mRNA-1273)\u0026nbsp;as a two-dose primary schedule in immunocompetent individuals.\u0026nbsp;The need for periodic boosting, including across age groups and in vulnerable sub-populations, is the subject of ongoing debate globally\u0026nbsp;(1). The durability of protection offered by vaccination is likely to be influenced by the host, including exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the circulating strains of the virus\u0026nbsp;(1, 2), the vaccine dose, dosing interval and type of vaccine administered, and the differential impacts of homologous versus heterologous schedules on immune responses (antibodies, B cells, CD4+ and CD8+ T-cells)\u0026nbsp;(3, 4). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe \u003cu\u003eP\u003c/u\u003elatform Trial \u003cu\u003eI\u003c/u\u003en \u003cu\u003eCO\u003c/u\u003eVID-19 priming and \u003cu\u003eBOO\u003c/u\u003esting (PICOBOO) is a randomised, Bayesian adaptive platform trial that is generating evidence of the immunogenicity, reactogenicity and cross-protection of different booster vaccination strategies against SARS-CoV-2 and its variants/subvariants in immunocompetent adolescents and adults. This trial will also evaluate how these immune responses correlate with protection from infection and disease, and how this is impacted by natural infection.\u0026nbsp;PICOBOO has been\u0026nbsp;designed in consultation with the National Community Advisory Group for COVID-19 research and members of national COVID-19 policymaking bodies and is intended to inform practice and policy in Australia.\u003c/p\u003e\n\u003cp\u003eThe documentation specifying PICOBOO is modular and hierarchical (\u003cem\u003eFigure 1\u003c/em\u003e). The Core Protocol describes study procedures that apply to all participants and aspects of the trial and is presented elsewhere\u0026nbsp;(5). Here we present the booster vaccination substudy protocol (SSP), which details the outcomes, endpoints and study processes that relate specifically to participants enrolled in the booster vaccination substudy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFigure 1\u0026nbsp;PICOBOO Booster vaccination substudy protocol in relation to other study documents\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary objective of the PICOBOO booster vaccination substudy is to\u0026nbsp;generate high-quality evidence about the immunogenicity of different COVID-19 boostervaccination strategies against SARS-CoV-2 and its variants/subvariants in immunocompetent hosts, stratified by the primary vaccination history and age group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe PICOBOO booster vaccination substudy is a randomised, Bayesian adaptive platform trial. It will allow the introduction of new vaccines/schedules for evaluation in this platform and/or to remove vaccines in response to the emergence of external data or changes in immunisation policy in Australia, while preserving the integrity of the trial.\u003c/p\u003e"},{"header":"Methods: Participants, interventions, and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is currently recruiting at three sites across Australia; these include Telethon Kids Institute (Western Australia), the Women\u0026rsquo;s and Children\u0026rsquo;s Hospital (South Australia), and Launceston General Hospital (Tasmania).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo be eligible a person must:\u003c/p\u003e\n\u003cp\u003e1. \u0026nbsp; Meet eligibility criteria for the PICOBOO platform trial as outlined in the PICOBOO core protocol (5).\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; Be \u003cu\u003e\u0026gt;\u003c/u\u003e12 years old.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. \u0026nbsp; Have undergone primary COVID-19 vaccination with:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(i) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;two doses of AZD1222 and be 50 years or over OR\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(ii) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; two doses of BNT162b2 and be less than 70 years OR\u003c/p\u003e\n\u003cp\u003e(iii) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;two doses of mRNA-1273 and be aged between 12 and 18 years old.\u003c/p\u003e\n\u003cp\u003eA person is \u003cu\u003enot\u003c/u\u003e eligible if they:\u003c/p\u003e\n\u003cp\u003e1. \u0026nbsp; \u0026nbsp; Have received a COVID-19 booster vaccine in the preceding 3 months*.\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; \u0026nbsp; Are contraindicated to receive any of the COVID-19 study vaccines, e.g., have a history of anaphylaxis to a vaccine component.\u003c/p\u003e\n\u003cp\u003e*If the Australian Technical Advisory Group on Immunisation (ATAGI) advises an alternative window for COVID-19 boosting vaccinations for eligible participants, this criterion will be reviewed. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants already enrolled in the PICOBOO adaptive platform trial may be eligible for re-randomisation to receive additional COVID-19 booster vaccine doses, providing the eligibility criteria detailed in the PICOBOO core protocol\u0026nbsp;(5)\u0026nbsp;and the PICOBOO booster vaccination substudy protocol are met.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent will be obtained by means of written or electronic signature which will be dated and countersigned by the research staff member who obtained it. Additional details regarding the consent process are detailed in\u0026nbsp;in the PICOBOO Core Protocol\u0026nbsp;(5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs detailed in the PICOBOO Core Protocol\u0026nbsp;(5), participants and/or their legal guardians provided consent\u0026nbsp;for blood and saliva samples to be tested and stored for COVID-19 research (including genetic studies) at participating laboratories. Participants have additionally provided consent for de-identified data and samples to be used for future research by participating institutions and third-party organisation(s).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll vaccines evaluated in this trial will be approved for use in the target age group by Australia\u0026rsquo;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).\u003c/p\u003e\n\u003cp\u003eVaccines 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).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants 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-\u0026lt;18, 18-\u0026lt;50, 50-\u0026lt;70 or 70+ years of age).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt the time of publication, nine COVID-19 vaccines have been evaluated in the PICOBOO platform. BNT162b2, mRNA-1273 and NVX-CoV2372 (Nuvaxovid, Novavax)\u0026nbsp;were evaluated at trial commencement. BNT162b2 and mRNA-1273 were removed for evaluation\u0026nbsp;on Jan 4, 2023. Tozinameran/riltozinameran (Comirnaty original/Omicron BA.1, Pfizer) and elasomeran/imelasomeran (Spikevax bivalent Original/Omicron, Moderna)\u0026nbsp;were introduced for evaluation on Jan 5, 2023, and removed for evaluation on Jun 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 Jun 5, 2023, and removed for evaluation on Jan 8, 2024.\u0026nbsp;Raxtozinameran (Comirnaty Omicron XBB.1.5, Pfizer) and\u0026nbsp;andusomeran (SPIKEVAX XBB.1.5, Moderna) were introduced to the platform on Jan 9, 2024.\u0026nbsp;Dosing and administration information is described in further detail, below:\u003c/p\u003e\n\u003cp\u003e1. \u0026nbsp; \u0026nbsp; BNT162b2\u003c/p\u003e\n\u003cp\u003eThis mRNA vaccine\u0026nbsp;encodes the full-length SARS-CoV-2 spike protein. The dose for individuals \u0026ge;12 years old is 30 micrograms (\u0026mu;g) in 0.3mL of the diluted vaccine delivered by intramuscular injection. Each multidose vial contains 6 doses.\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; \u0026nbsp; mRNA-1273\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA 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 50\u0026mu;g (0.25mL) for individuals aged \u003cu\u003e\u0026gt;\u003c/u\u003e12 years old delivered as an intramuscular injection. Each multidose vial contains 20 doses.\u003c/p\u003e\n\u003cp\u003e3. \u0026nbsp; \u0026nbsp; NVX-CoV2373\u003c/p\u003e\n\u003cp\u003eA 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\u0026trade;. The booster dose is 5\u0026mu;g (0.5mL) for individuals aged \u003cu\u003e\u0026gt;\u003c/u\u003e12 years old delivered as an intramuscular injection. Each multidose vial contains 10 doses.\u003c/p\u003e\n\u003cp\u003e4. \u0026nbsp; \u0026nbsp; Tozinameran/riltozinameran\u003c/p\u003e\n\u003cp\u003eThis mRNA vaccine comprises tozinameran and riltozinameran, the later encoding the viral spike protein of SARS-CoV-2 Omicron BA.1. The dose for individuals \u0026gt;12 years of age is 15\u0026mu;g tozinameran and 15\u0026mu;g\u0026nbsp;riltozinameran\u0026nbsp;in 0.3mL delivered as an intramuscular injection. Each multidose vial contains 6 doses.\u003c/p\u003e\n\u003cp\u003e5. \u0026nbsp; \u0026nbsp; Elasomeran/imelasomen\u003c/p\u003e\n\u003cp\u003eThis 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 25\u0026mu;g of elasomeran and 25\u0026mu;g of imelasomeran in 0.5mL for individuals \u003cu\u003e\u0026gt;\u003c/u\u003e12 years old delivered as an intramuscular injection. Each multidose vial contains 5 doses.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6. \u0026nbsp; \u0026nbsp; Tozinameran/famtozinameran\u003c/p\u003e\n\u003cp\u003eThis 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 \u0026nbsp;of tozinameran and 15 \u0026nbsp;of riltozinameran contained in 0.3mL of the diluted vaccine for individuals aged \u0026ge;12 years old delivered as an intramuscular injection. Each multidose vial contains 6 doses.\u003c/p\u003e\n\u003cp\u003e7. \u0026nbsp; \u0026nbsp; Elasomeran/davesomeran\u003c/p\u003e\n\u003cp\u003eThis 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 25\u0026mu;g of elasomeran and 25\u0026mu;g of davesomeran in 0.5mL for individuals \u003cu\u003e\u0026gt;\u003c/u\u003e12 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. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e8. \u0026nbsp; \u0026nbsp; Raxtozinameran\u003c/p\u003e\n\u003cp\u003eThis is an mRNA vaccine which encodes the viral spike protein of SARS-CoV-2 Omicron XBB.1.5. One dose (0.3 mL) contains 30\u0026mu;g (\u0026ge;12 years) or 10\u0026mu;g (5 to \u0026lt;12 years) of raxtozinameran delivered as an intramuscular injection. A single vial contains one dose. The formulation for individuals \u003cu\u003e\u0026gt;\u003c/u\u003e12 years of age is available as a multi-dose vial, containing 6 doses. The formulation for use in children 5 to \u0026lt;12 years of age is available in a single dose vial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e9. \u0026nbsp; \u0026nbsp; Andusomeran\u003c/p\u003e\n\u003cp\u003eThis is an mRNA vaccine which encodes the viral spike protein of SARS-CoV-2 Omicron XBB.1.5. One dose contains 50\u0026mu;g of andusomeran in 0.5mL for individuals \u003cu\u003e\u0026gt;\u003c/u\u003e12 years old delivered as an intramuscular injection. A single vial contains one dose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 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 (7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInvestigational vaccines are delivered as a single dose on the day of randomisation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs detailed in the core Protocol\u0026nbsp;(5),\u0026nbsp;individuals were permitted to receive their regular medications if they participated in the trial in addition to paracetamol if required, after vaccine administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs detailed in the PICOBOO Core Protocol\u0026nbsp;(5),\u0026nbsp;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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOutcomes reported for all participants enrolled in the booster vaccination substudy will include\u0026nbsp;the\u0026nbsp;log\u003csub\u003e10\u003c/sub\u003e concentration of SARS-CoV-2 anti-spike immunoglobulin (IgG) at the time points indicated in \u003cem\u003eTable 1\u003c/em\u003e, 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) (7). Outcomes and endpoints for participants enrolled in the booster vaccination substudy are detailed in \u003cem\u003eTable 1.\u003c/em\u003e The availability of new assays and/or funding constraints may impact on immunological testing as the trial progresses.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTable 1 Outcomes and endpoints for participants in the booster vaccination substudy\u003c/em\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOUTCOMES/ENDPOINTS\u003csup\u003e*\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eIMMUNOLOGICAL\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eConcentration of anti-spike Immunoglobulin G (IgG antibody) against SARS-CoV-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDay 7, 24, 84/180\u003csup\u003e**\u003c/sup\u003e, 365\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eConcentration of neutralising SARS-CoV-2 antibodies against SARS-CoV-2\u003csup\u003e***\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDay 24, 84/180**, 365\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eThe percentage inhibition of SARS-CoV-2\u003csup\u003e***\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDay 28, 84/180**, 365\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eThe number of IFN-𝛾\u003csup\u003eb\u003c/sup\u003e spot forming cells per 10\u003csup\u003e6\u003c/sup\u003e/L peripheral blood mononuclear cells, following \u003cem\u003ein vitro\u003c/em\u003e stimulation with SARS-CoV-2 spike overlapping pools of lyophilized peptides, consisting mainly of 15-mer sequences with 11 amino acids overlap\u003csup\u003e***\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDay 7, 84/180**, 365\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMucosal salivary IgA\u003csup\u003ec\u0026nbsp;\u003c/sup\u003eand IgG\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDay 28, 84/180**, 365\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePresence of anti-nucleocapsid antibodies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDay 7, 28, 84/180\u003csup\u003e**\u003c/sup\u003e, 365\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eREACTOGENICITY/SAFETY\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eParticipant or carer-reported local and systemic reactions assessed daily up to Day 7 graded as no reaction, mild, moderate, severe, or life-threatening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDays 1-7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny participant or carer-reported solicited and unsolicited AE\u003csup\u003ee\u003c/sup\u003e up to ~28 days\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHospitalisation resulting from AEFI\u003csup\u003ef\u003c/sup\u003e up to ~28 days\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny SAR\u003csup\u003eg\u003c/sup\u003e thought to be causally related to the study Intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCLINICAL\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny PCR\u003csup\u003eh\u003c/sup\u003e-confirmed SARS-CoV-2 OR RAT\u003csup\u003ei\u003c/sup\u003e positive result for SARS-CoV-2 up to Day 720\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny PCR\u003csup\u003eh\u003c/sup\u003e-confirmed SARS-CoV-2 infection up to Day 720\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny PCR\u003csup\u003eh\u003c/sup\u003e-confirmed wild-type or predominant circulating variant SARS-CoV-2 infection up to Day 720\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny hospitalisation (days) for management of PCR\u003csup\u003eh\u003c/sup\u003e-confirmed or RAT\u003csup\u003ei\u003c/sup\u003e-positive SARS-CoV-2 infection up to Day 720\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAny participant or carer-reported days off work, study, or usual activities (days) due to PCR\u003csup\u003eh\u003c/sup\u003e-confirmed or RAT\u003csup\u003ei\u003c/sup\u003e-positive SARS-CoV-2 infection up to Day 720\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003csup\u003e*\u003c/sup\u003eRelative to randomisation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003csup\u003e**\u003c/sup\u003eFor adolescent participants and adult participants receiving a 3rd or subsequent (5th dose) booster, visit 4 (Day 84) will be substituted for Day 180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003csup\u003e***\u003c/sup\u003eThis will be performed separately for ancestral SARS-CoV-2 and the predominant circulating variant\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003ePrimary endpoint; \u003csup\u003eb\u003c/sup\u003eIFN- 𝛾: interferon-𝛾; \u003csup\u003ec\u003c/sup\u003eIgA: Immunoglobulin A; \u003csup\u003ed\u003c/sup\u003eIgG: Immunoglobulin G; \u003csup\u003ee\u003c/sup\u003eAE: Adverse event; \u003csup\u003ef\u003c/sup\u003eAEFI: Adverse event following immunisation; \u003csup\u003eg\u003c/sup\u003eSAR: Serious adverse reaction; \u003csup\u003eh\u003c/sup\u003ePCR: Polymerase chain reaction; \u003csup\u003ei\u003c/sup\u003eRAT: Rapid antigen test.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe schedule of events detailing enrolment, the Intervention, and study visits are detailed in \u003cem\u003eTable 2\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTable 2 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Timeline for enrolment, allocation and post-allocation events and trial termination\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFor re-randomised participants, study visits 1 \u0026ndash; 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 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 (7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs detailed in the PICOBOO Core Protocol (5), potential screening avenues to identify eligible participants include during vaccination/healthcare visits, advertising material via community locations, research and consumer networks, 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).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA sequence of intervention assignments will be generated by an un-blinded trial statistician using random permuted blocks for each booster dose within each stratum using computer software with a validated random number generator and equal allocation for all booster interventions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs detailed in the PICOBOO Core Protocol (5), an un-blinded research nurse will obtain the next contiguous stratum allocation (i.e. the lowest available randomisation number) from the study REDCap database on the day of randomisation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs detailed in the PICOBOO Core Protocol\u0026nbsp;(5),\u0026nbsp;at vaccination, two unblinded members of the research team will check and dispense the study vaccine for administration. Pre-filled syringes containing one of the COVID-19 booster vaccines approved for use will be covered with opaque tape and concealed until ready for administration. Prior to opening the box, the participant will be asked to look away. The vaccine intervention will be administered in accordance with routine immunisation practices stipulated per Australian guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will be blinded {17a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be blinded to the specific COVID-19 vaccination received, at least until after the primary estimand data are collected. Further details are provided in the \u0026nbsp;PICOBOO Core Protocol (5), At this time, details regarding vaccination will be uploaded to the Australian Immunisation Register, where it will be possible for participants to access their individual vaccination history, if desired.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Procedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe corresponding site principal investigator will provide authorisation for unblinding if compelling reasons arise. Further details are provided\u0026nbsp;in the PICOBOO Core Protocol\u0026nbsp;(5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes {18a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs detailed in the PICOBOO Core Protocol\u0026nbsp;(5),\u0026nbsp;data will be collected on hard or electronic case report forms (eCRF), including (i) demographic data, (ii) COVID-19 vaccination history, (iii) previous medical history, (iv) anthropometric data (including height and weight), (v) laboratory data and (vi) participant/carer-reported outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be contacted and reminded to attend for their follow-up visits. We will use all available data on any patients who are lost to follow-up. If a participant withdraws, we will use all data collected up until the time of withdrawal unless they explicitly request their data to be removed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be collected into a secure REDCap database, hosted by the sponsor. Further details regarding data management and security are provided in the\u0026nbsp;PICOBOO Core Protocol\u0026nbsp;(5),\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRobust measures will be taken to ensure confidentially for participants enrolled in the trial, as detailed in the PICOBOO Core Protocol\u0026nbsp;(5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs detailed in \u003cem\u003eTable 2\u003c/em\u003e, blood and saliva samples will be collected at pre-specified time points. Blood will be separated into the sera, plasma, and peripheral blood mononuclear cells (PBMCs) at local sites prior to transportation to reference laboratories for processing. Granulocytes collected from baseline blood samples during gradient centrifugation will be used for deoxyribonucleic acid (DNA) extraction for human leucocytic antigen (HLA) I and II typing. This will be performed to evaluate susceptibility to and protection from SARS-CoV-2 infection and disease. Genomic DNA will be extracted using commercial kits, harmonised across sites. DNA will be aliquoted and stored as per standard operating procedures (SOPs).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA Bayesian three-level hierarchical linear model will be used for the primary analysis as it is anticipated that immune responses may be mutually informative across COVID-19 vaccination dose, age groups and potentially across messenger ribonucleic acid (mRNA) vaccine interventions (7). The model estimates the posterior distribution of the mean log10 anti-spike SARS-CoV-2 IgG antibody against Ancestral SARSCoV-2 measured ~ 28 days after receipt of the assigned booster COVID-19 vaccine for each intervention and vaccination strategy in each stratum, denoted by vaccine history group and age group. Further detail can be found in the Statistical Appendix (7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInterim analyses were pre-specified. The first analysis was performed after participants had completed 300 vaccination events and 21-31 days follow-up post-randomisation. Further details regarding interim analyses detailed in the Statistical Appendix (7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAny analyses not specified in the Statistical Appendix\u0026nbsp;(7)\u0026nbsp;will be designated as exploratory.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eImmune responses and reactogenicity to COVID-19 vaccines will be assessed using a treatment policy strategy. Further detail regarding the analytical approach to handling intercurrent events is detailed in the Statistical Appendix (7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCurrent versions of the PICOBOO core protocol\u0026nbsp;(8), the Statistical Appendix\u0026nbsp;(7), the PICOBOO substudy protocol, and the Laboratory Appendix will be accessible on the trial website (\u003ca href=\"https://picoboo.com.au/\"\u003ehttps://picoboo.com.au/\u003c/a\u003e). Decisions regarding the sharing of de-identified data and/or statistical code will be assessed by the PICOBOO TSC and will be conditional upon any necessary institutional and ethics approvals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe PICOBOO administrative structure detailed in the PICOBOO core protocol applies to all nested platform\u0026nbsp;substudies\u0026nbsp;(5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs\u0026nbsp;detailed in the PICOBOO Core Protocol\u0026nbsp;(5),\u0026nbsp;A Data and Safety Monitoring Committee (DSMC) will be appointed to provide safety oversight. The DSMC will have an advisory role as outlined in the DSMC Charter.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll serious adverse events (SAEs), adverse events of special interest (AESI), medically attended AEs (MAAEs) and adverse events (AEs) resulting in withdrawal occurring from day 0 to day 28 after randomisation will be recorded. From day 29 to day 720 after randomisation, all SAEs, AESIs, MAAEs, and AEs resulting in withdrawal that are found to be related to the study vaccine or study procedures will be reported.\u0026nbsp;The processes for assessing and reporting safety are detailed in the PICOBOO Core Protocol\u0026nbsp;(5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMonitoring will be conducted according to a risk-stratified approach as detailed in the PICOBOO Core Protocol\u0026nbsp;(5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAny substantial amendments to the PICOBOO protocol will require prior approval by the relevant ethics and governance regulatory bodies (5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe National COVID-19 CRG will provide guidance on the best methods for dissemination of information to participants and the broader community. The TSC will, as far as possible, make the protocol(s), laboratory appendix, statistical analysis plans, and non-identifying patient-level data available, to allow independent scientific scrutiny and validation of any published results.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe present the protocol for a randomised, Bayesian adaptive trial nested within the PICOBOO study platform; the trial aims to generate high quality evidence regarding the immunogenicity, reactogenicity, and cross protection offered by different COVID-19 booster vaccination strategies against SARS-CoV-2 and its variants/subvariants. The PICOBOO booster vaccination substudy is unique in terms of evaluating the impacts of multiple alternative COVID-19 vaccination strategies concurrently and sequentially, across different age groups, including in children. It is expected to generate evidence to shape immunisation practice and policy while also contributing to the growing body of evidence informing vaccination policy globally.\u003c/p\u003e \u003cp\u003eCOVID-19 vaccines have led to substantial reductions in severe disease, hospitalisation, and death, with an estimated 19.8\u0026nbsp;million deaths averted in 2021 alone (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). While periodic booster vaccination is likely to remain a core strategy for achieving protection against disease in at least some risk groups, there are limited data to inform the best ongoing strategies for vaccination. Specifically, it is unknown whether some vaccines are better than others, and if so, which homologous and/or heterologous vaccine strategies are best and in whom, and what the optimal intervals between booster doses are. We aim to provide a detailed profile of the immunological and safety outcomes of different vaccines available for use in Australia to add to the available published literature to aid decision-making.\u003c/p\u003e \u003cp\u003eWe expect that the trial\u0026rsquo;s Bayesian adaptive design will have three main benefits over conventional trial methods (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). First, the flexibility to introduce new vaccines or schedules for evaluation as they become available, or to remove vaccines in response to changes to vaccine policy in Australia or the emergence of external data, while preserving the overall integrity of the trial. Second, the decision rules are designed to avoid over-recruitment to a stratum based on pre-specified precision criteria, facilitating timely decision-making. This is possible owing to improved statistical efficiency resulting from data sharing that is expected with the use of hierarchical Bayesian statistical models. Third, the trial structure will facilitate nesting of additional studies in the future, which is likely to be more efficient and cost-effective than conducting multiple trials independently.\u003c/p\u003e \u003cp\u003eWhile serum anti-spike immunoglobin G concentrations and anti-SARS-CoV-2 neutralising antibody titres have emerged as correlates of vaccine protection against symptomatic COVID-19 disease (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), more data are required to delineate specific threshold titres that correlate with protection (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), including against variants of concern. Further, additional work is required to elucidate correlates of protection based on other immunologic functions, such as effector memory and T-cell function, which may play a role in controlling infection once established (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). It is intended that the data generated from this trial will be combined with other data available internationally to further inform correlates of protection against COVID-19 infection and disease.\u003c/p\u003e \u003cp\u003eOne issue that has garnered attention throughout the pandemic has been the timely dissemination of data and how this is impacted by the need for rigorous peer-review, ideally prior to the release of results (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The Bayesian statistical model used in this trial will be periodically updated as data accrue, even after recruitment to a particular booster intervention (e.g., third dose, fourth dose boosters) ceases within a stratum. Statistical reports detailing pre-specified analyses will be made available within the public domain on the trial website as soon as practicable following review by the trial statistical analysis team, the trial steering committee, and the DSMC. Results will also be disseminated periodically via peer-reviewed publications. To facilitate knowledge transfer, modification and re-purposing, all trial processes, governance arrangements, and digital infrastructure have been developed in partnership with relevant stakeholders and based on FAIR data principles (findable, accessible, interoperable, reusable) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe need for robust evidence to inform practice and policy in the face of a rapidly evolving pandemic has outstripped efforts to generate it quickly; consequently, decision-making has largely occurred ahead of the science. Moving forward, important vaccine policy questions must be addressed with agility to ensure that the recommended vaccination schedules will enhance population-level immunity while protecting vulnerable sub-populations. The PICOBOO booster vaccination substudy will fill critical knowledge gaps to optimize immunisation policy in Australia and elsewhere. Initial results were generated in the first quarter of 2023.\u003c/p\u003e"},{"header":"Trial status","content":"\u003cp\u003eCurrent PICOBOO Core Protocol Version 15.0_28112023. Substudy Protocol: Booster vaccination V8.0_28112023. Recruitment commencement date: 29th of March 2022. Recruitment is expected to be completed by 7 Feb, 2025.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eATAGI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAustralian Technical Advisory Group on Immunisation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOVID-19\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCoronavirus 2019\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSMC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eData Safety Monitoring Committee\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emRNA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emessenger ribonucleic acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePICOBOO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePlatform trial In COVID-19 BOOsting\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSARS-CoV-2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSevere Acute Respiratory Syndrome Coronavirus-2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTKI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTelethon Kids Institute\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTGA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTherapeutic Goods Administration\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTrial Steering Committee.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to multiple individuals and groups for supporting this work. To the Child and Adolescent Health Service Human Research Ethics Committee (CAHS HREC), for reviewing the PICOBOO ethics submission (and subsequent amendments) to allow this trial to progress. \u0026nbsp;To the participants and families who chose to contribute to this study. To the National Consumer Advisory Group for COVID-19 research, who have informed all stages of this research project. To Jess Ramsay and George Salama, who led the project management for this trial. We acknowledge members of the Data Safety Monitoring Committee including Professor Margie Danchin (Chair), Professor Nigel Crawford, A/Professor Christopher Oldmeadow, Dr Daniel Barker, A/Professor Trisha Peel, Professor David Nolan, and Dr Tony Korman for their commitment to monitoring the safety of participants and the scientific integrity of this trial. We also thank the research and laboratory staff involved in this project who have worked tirelessly to recruit participants and process biospecimens for this trial. CM is supported by a Raine Fellowship. TS is supported by an MRFF Investigator Award (MRF1195153). MD is supported by a NHMRC Postgraduate Research Award\u0026nbsp;(APP2022557).\u0026nbsp;\u0026nbsp;CCB is supported by a NHMRC Investigator Award (APP1173163).\u0026nbsp;Support for the design of PICOBOO was provided by Snow Medical Foundation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTS and PR conceived the study. CM, JR, ME, TS, JM, and MD led the protocol development. PR, CM, MP, KF, HM, KS, UW, SN, PW, RT, CT, JR, ME, JM, MD, and TS contributed to the study design. CM produced the first draft of this manuscript. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding for this trial was provided by the Snow Foundation and the Medical Research Future Fund\u0026nbsp;#2014690 and #2016473.\u0026nbsp;RT is supported by a mid-career researcher fellowship generously awarded by the Passe and Williams Foundation.\u0026nbsp;SNF is a UK NIHR Senior Investigator.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccess to data will be granted to study Investigators and authorised representatives from the Sponsor and the regulatory authorities to allow trial-related monitoring, audits, and inspections to occur. PICOBOO will also comply with relevant jurisdictional and academic requirements relating to access to data, as apply at the time that the data are generated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval for the conduct of this study has been provided by the Child and Adolescent Health Service Human Research Ethics Committee (RGS 9722). Informed consent to participate will be obtained from all participants in either written or electronic form.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIndividual consent for publication will not be required from participants. The final decision to publish will lie with the PICOBOO TSC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKF and TS are members of the Australian Technical Advisory Group on Immunisation (ATAGI) which advises the government on vaccine policy; their involvement as investigators on this trial has been declared to ATAGI. MP is involved in an ovarian cancer clinical trial that received funding from AstraZeneca. MP was involved in performing immunological assays on biological specimens obtained from participants in this trial, but was not involved in participant recruitment, data collection or the analysis of results. SNF leads the UK National Institute for Health and Care Research funded trial of third and fourth dose COVID-19 boosters. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust, UK as an Investigator and/or providing consultative advice on clinical trials and studies of vaccines funded or sponsored by vaccine manufacturers including Moderna, Sanofi, Janssen, BNT162b2izer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Medimmune, Merck and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. \u0026nbsp; The other authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKrause PR, Fleming TR, Peto R, Longini IM, Figueroa JP, Sterne JAC, et al. Considerations in boosting COVID-19 vaccine immune responses. Lancet (British edition). 2021;398(10308):1377\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJuno JA, Wheatley AK. Boosting immunity to COVID-19 vaccines. Nat Med. 2021;27(11):1874\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtmar RL, Lyke KE, Deming ME, Jackson LA, Branche AR, El Sahly HM, et al. Homologous and Heterologous Covid-19 Booster Vaccinations. N Engl J Med. 2022;386(11):1046\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAu W, Cheung P. Effectiveness of heterologous and homologous covid-19 vaccine regimens: living systematic review with network meta-analysis. BMJ. 2022;377:e069989.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ. R CM, KL. F M, P HM. M. D, Core Protocol for the adaptive Platform Trial in COVID-19 vaccine priming and BOOsting (PICOBOO). Trials. 2023;24(202).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomas SJ Jr., EDM, Kitchin. N AJ, Gurtman A, Lockhart S et al. Six month safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. medRxiv. 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDymock M, McLeod C, Richmond P, Snelling T, Marsh J. Statistical considerations for the Platform Trial in COVID-19 vaccine priming and boosting. Preprint (version 1) available at Research Square 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcLeod C, Ramsay J, Flanagan KL, Plebanski M, Marshall H, Dymock M, et al. Core protocol for the adaptive Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO). Curr controlled trials Cardiovasc Med. 2023;24(1):202.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrganisation WH. Global Covid-19 Vaccination Strategy in a Changing World: Ju;y 2022 update. World Health Organisation; 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaville BR, Berry SM. Efficiencies of platform clinical trials: A vision of the future. Clin Trials. 2016;13(3):358\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGilbert PB, Donis RO, Koup RA, Fong Y, Plotkin SA, Follmann D. A Covid-19 Milestone Attained \u0026mdash; A Correlate of Protection for Vaccines. N Engl J Med. 2022;387(24):2203\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeng S, Phillips DJ, White T, Sayal H, Aley PK, Bibi S, et al. Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection. Nat Med. 2021;27(11):2032\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKrammer F. Correlates of protection from SARS-CoV-2 infection. Lancet (British edition). 2021;397(10283):1421\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatson C. Rise of the preprint: how rapid data sharing during COVID-19 has changed science forever. Nat Med. 2022;28(1):2\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoeckhout M, Zielhuis GA, Bredenoord AL. The FAIR guiding principles for data stewardship: fair enough? Eur J Hum genetics: EJHG. 2018;26(7):931\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 2","content":"\u003cp\u003eTable 2 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, booster vaccination, vaccination, immunisation, adaptive platform trial, policy, pandemic.","lastPublishedDoi":"10.21203/rs.3.rs-4357872/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4357872/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Coronavirus-2019 (COVID-19) vaccination in Australia commenced in February 2021. The first vaccines recommended for use were AZD1222 and BNT162b2, both delivered as a two-dose primary schedule. In the absence of sustained immunity following immunisation, recommendations for booster vaccination have followed. It is likely that periodic boosting will be necessary for at least some Australians, but it is unknown what the optimal booster vaccines and schedules are, or for whom vaccination should be recommended.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: The \u003cu\u003eP\u003c/u\u003elatform Trial \u003cu\u003eI\u003c/u\u003en \u003cu\u003eCO\u003c/u\u003eVID-19 priming and \u003cu\u003eBOO\u003c/u\u003esting (PICOBOO) is a multi-site, multi-arm, randomised, Bayesian adaptive platform trial evaluating different booster vaccine interventions in immunocompetent children and adults, stratified by their primary vaccination schedule and age. Participants are randomised to receive one of three licensed COVID-19 booster vaccines available for use in Australia. PICOBOO aims to generate evidence about the immunogenicity, reactogenicity and cross-protection of different booster vaccine strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants/subvariants. The protocol structure specifying PICOBOO is modular and hierarchical. We have previously published the PICOBOO core (master) protocol. Here we detail the substudy protocol which outlines the study processes which are specific to PICOBOO participants enrolled in the booster vaccination substudy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e: PICOBOO is an adaptive platform trial evaluating different COVID-19 booster vaccination strategies to generate evidence to inform immunisation practice and policy. The modular and flexible protocol structure is intended to enable investigators to respond with agility to new research questions as they arise, such as immunogenicity targeting emergent virus variants, and the immunogenicity and reactogenicity of new vaccines as they become available for use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e: Australian and New Zealand Clinical Trials Register ACTRN12622000238774; registered on 10/02/2022. Protocol V8.0_23112023.\u003c/p\u003e","manuscriptTitle":"The Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO) booster vaccination substudy protocol","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-21 09:53:46","doi":"10.21203/rs.3.rs-4357872/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2024-09-04T16:44:05+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-09-04T11:49:10+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-04T10:37:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-08T11:44:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-05-05T23:48:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"25208678-2a70-418f-869a-ffbeec02e0d3","owner":[],"postedDate":"October 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-04T16:27:39+00:00","versionOfRecord":{"articleIdentity":"rs-4357872","link":"https://doi.org/10.1186/s13063-024-08456-4","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2024-11-01 16:20:25","publishedOnDateReadable":"November 1st, 2024"},"versionCreatedAt":"2024-10-21 09:53:46","video":"","vorDoi":"10.1186/s13063-024-08456-4","vorDoiUrl":"https://doi.org/10.1186/s13063-024-08456-4","workflowStages":[]},"version":"v1","identity":"rs-4357872","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4357872","identity":"rs-4357872","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}