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Objectives: PICOBOO is a randomised, adaptive trial evaluating the immunogenicity, reactogenicity, and safety of COVID-19 booster strategies. Here, we present data for second boosters among individuals aged 18-<50 and 50-<70 years old primed with BNT162b2 until Day (D) 84., Methods: Immunocompetent adults who had received two doses of BNT162b2 and any licensed COVID-19 booster at least three months prior were eligible. Participants were randomly allocated to BNT162b2, mRNA-1273 or NVX-CoV2373 1:1:1. The log 10 concentration of anti-spike Ig Total was summarised as the geometric mean concentration (GMC). Reactogenicity and safety outcomes were captured., Results: Between Mar 2022 and Aug 2023, 743 participants were recruited to the trial and had D28 samples available. Of these, 120 and 103 belonged to the 18-<50 y and 50-<70 y strata, respectively. The mean adjusted GMCs (95% credible intervals) peaked at D28; these were 41 262 (31 611, 51 105), 45 585 (34 194, 57 441) and 25 281 (20 021, 31 234) U/mL in the 18-<50 y stratum and 30 753 (25 071, 36 704), 35 132 (27 523, 42 239) and 17 322 (13 983, 20 641) U/mL in the 50-<70 y stratum following BNT162b2, mRNA-1273 and NVX-CoV2373, respectively. Limited neutralisation against Omicron subvariants was found following boosting with all vaccines. There were 4 possibly or probably-related adverse events in the 18-<50 y stratum and 5 events in the 50-<70 y stratum, and severe reactogenicity events were <10% and <11% in these strata, respectively., Conclusions: Vaccines targeting Ancestral virus elicited boosted antibody responses to Ancestral virus but minimal neutralising antibody against Omicron variants., Competing Interests: Declaration of Competing Interest 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, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Medimmune, Merck and Valneva vaccines and antimicrobials. PR also reports acting on behalf of University of Western Australia, 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, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Merck and Clover Biopharmaceutical vaccines. HSM is an investigator on clinical vaccine trials funded by Industry. Her institution receives funding for investigator led research from Sanofi, Pfizer, Seqirus, and Moderna. UW is an Investigator for industry sponsored clinical vaccine trials. They receive no personal financial payment for this work. The other authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: PICOBOO is a randomised, adaptive trial evaluating the immunogenicity, reactogenicity, and safety of COVID-19 booster strategies. We report data for second boosters among individuals 50-<70 years old primed with AZD1222 (50-<70y-AZD1222) until Day 84., Methods: Immunocompetent adults who received any first booster ≥three months prior were eligible. Participants were randomly allocated to BNT162b2, mRNA-1273 or NVX-CoV2373 1:1:1. The concentrations of ancestral anti-spike immunoglobulin were summarised as the geometric mean concentrations (GMC). Reactogenicity and safety outcomes were captured. Additional analyses including neutralising antibodies were performed on a subset. ACTRN12622000238774., Results: Between Mar 2022 and Aug 2023, 743 participants were recruited and had D28 samples; 155 belonged to the 50-<70y-AZD1222 stratum. The mean adjusted GMCs (95% credible intervals) were 20,690 (17 555-23 883), 23,867 (20 144-27 604) and 8654 (7267-9962) U/mL at D28 following boosting with BNT162b2, mRNA-1273 and NVX-CoV2372, respectively, and 10,976 (8826-13 196), 15,779 (12 512-19 070) and 6559 (5220-7937) U/mL by D84. IgG against Omicron BA.5 was 2.7-2.9 times lower than the ancestral strain. Limited neutralisation against Omicron subvariants was found following all vaccines. Severe reactogenicity events were <4%., Conclusions: All vaccines were immunogenic with more rapid waning after mRNA vaccines. These data support boosting with vaccines with greater specificity for circulating Omicron subvariants., Competing Interests: Declaration of Competing Interest 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, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Medimmune, Merck and Valneva vaccines and antimicrobials. UW is an investigator on clinical trials of vaccines funded or sponsored by vaccine manufactures including Moderna, Sanofi, Pfizer, Merck and GlaxoSmithKline. PR also reports acting on behalf of University of Western Australia, 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, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Merck and Clover Biopharmaceutical vaccines. They receive no personal financial payment for this work. The other authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 Platform Trial In COVID-19 priming and BOOsting (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&#95;23112023., (© 2024. Crown.)

Objectives: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19., Design: Phase III double-blind randomised controlled trial., Setting: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic., Participants: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG., Intervention: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989)., Main Outcome Measures: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion)., Results: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group., Conclusions: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19., Trial Registration: ClinicalTrials.gov NCT04327206., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The trial is financially supported by the Foundations listed in the Funding section. Authors disclose funding support over the past 36 months: National Health and Medical Research Council (NHMRC) Ideas Grant (NM), NHMRC Investigator Grant (NC), Melbourne Children’s Clinician-Scientist Fellowship Grant (KPP). Outside of the submitted work, JCr has received grants or contracts from Sanofi, MSD & CEPI; payment or honoraria for presentations from Pfizer and participates on Latin American data safety monitoring/advisory boards for mRNA-1273 (Modern/Zodiac), RSV maternal vaccine (Pfizer), Qdenga vaccine (Takeda) and Nirmatrelvir/Ritonavir-Paxlovid (Pfizer). KG is a member of the Royal Children’s Hospital (RCH) Human Research Ethics Committee (the primary ethics committee providing approval for the BRACE trial) and Director of Research Operations at RCH; she abstained from all discussion, voting, approval and review related to the BRACE trial. All other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Following reduction of public health and social measures concurrent with SARS-CoV-2 Omicron emergence in late 2021 in Australia, COVID-19 case notification rates rose rapidly. As rates of direct viral testing and reporting dropped, true infection rates were most likely to be underestimated., Objective: To better understand infection rates and immunity in this population, we aimed to estimate SARS-CoV-2 seroprevalence in Australians aged 0-19 years., Methods: We conducted a national cross sectional serosurvey from June 1, 2022, to August 31, 2022, in children aged 0-19 years undergoing an anesthetic procedure at eight tertiary pediatric hospitals. Participant questionnaires were administered, and blood samples tested using the Roche Elecsys Anti-SARS-CoV-2 total spike and nucleocapsid antibody assays. Spike and nucleocapsid seroprevalence adjusted for geographic and socioeconomic imbalances in the participant sample compared to the Australian population was estimated using multilevel regression and poststratification within a Bayesian framework., Results: Blood was collected from 2,046 participants (median age: 6.6 years). The overall adjusted seroprevalence of spike-antibody was 92.1% (95% credible interval (CrI) 91.0-93.3%) and nucleocapsid-antibody was 67.0% (95% CrI 64.6-69.3). In unvaccinated children spike and nucleocapsid antibody seroprevalences were 84.2% (95% CrI 81.9-86.5) and 67.1% (95%CrI 64.0-69.8), respectively. Seroprevalence was similar across geographic remoteness index and socioeconomic quintiles. Nucleocapsid antibody seroprevalence increased with age while the point seroprevalence of the spike antibody seroprevalence decreased in the first year of life and then increased to 97.8 (95% Crl 96.1-99.2) by 12-15 years of age., Conclusion: Most Australian children and adolescents aged 0-19 years, across all jurisdictions were infected with SARS-CoV-2 by August 2022, suggesting rapid and uniform spread across the population in a very short time period. High seropositivity in unvaccinated children informed COVID-19 vaccine recommendations in Australia., Competing Interests: All authors have no financial interests/personal relationships that may be considered as potential competing interests with this study. Some authors have received institutional research grants and travel funding from the Australian Government, non-government or private organisations for other bodies of work. Dr Archana Koirala, Professor Kristine Macartney and Professor Nicholas Wood declare funding support from the Australian Government Department of Health and Aged Care (DoHAC) to the institution National Centre for Immunisation Research and Surveillance (NCIRS). Dr Archana Koirala has received a travel and accommodation grant to present and attend the World Society of Paediatric Infectious Diseases scientific meeting in 2023. Professor Kristine Macartney received payment as an expert witness for Australian Health Departments against proceedings against COVID-19 health regulations in 2021-2022. Professor Kristine Macartney declares institutional directed funding support from the WHO and GAVI the Vaccine Alliance, Welcome Trust and the Australian NHMR, to NCIRS and the University of Sydney; payment as an expert witness for Australian health departments against proceedings against COVID-19 health regulations in 2021-2022, payment less than USD $5,000 for international travel for expert speaking engagements, non-pharmaceutical company sources. Professor Nicholas Wood, Professor Britta S von Ungern-Sternberg and Dr Brendan McMullan declare funding from the National Health and Medical Research Council (NHMRC) grants. Professor Britta S von Ungern-Sternberg declared funding support from Stan Perron Charitable Foundation. Professor Helen S Marshall declares a research grant from Pfizer to Women’s and Children’s Health Network (WCHN), no personal remuneration, for meningococcal research. Professor Peter Richmond declares research grants from Merck Sharpe & Dohme, GlaxoSmithKline (GSK) directed at the Telethon Kids Institute (TKI), no personal remuneration, on RSV, pneumococcal disease, varicella, meningococcal research and a COVID-19 vaccine study to assess immunogenicity and safety of homologous or heterologous vaccine schedules. Professor Peter Richmond, Professor Helen S Marshall and Professor Nicholas Wood declare a research grant from the Australian Government Department of Health and Aged Care to WCHN, TKI and University of Sydney for a COVID-19 DNA vaccine clinical trial Ms Alissa McMinn declares funding support from Pfizer provided support for flights/accommodation to attend the Public Health Association Australia Communicable Diseases & Immunisation Conference in 2023. Dr Ushma Wadia declares funding from Pfizer for flights and accommodation to attend Meningococcal Disease Vaccine Education in 2023. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Koirala et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)