Modifications following HREC review of amendment · Addition of details around clinicaltrials.gov registration · Increase of planned number of participants to 10,078, including updated information on trial statistics · Addition of sites to enable recruitment of 10,078 participants · Change to timing of flu vaccine: can be given concurrently with BCG OR can have been given a minimum of 72 hours prior to randomisation · Change to Primary Outcome 2: - definition of severe COVID-19 disease: “COVID-19 positive test, AND hospitalised OR non-hospitalised severe disease” · Change to follow-up blood collection from 6m, to 3m & 12m · Change to follow-up surveys: increase from 6m to 12m · Change to outcome measures: “febrile respiratory illness” revised to “fever OR respiratory illness” · Minor changes for clarity and correction of typographical errors Updates to inclusion/exclusion criteria: flu vaccine timeframe changed in IC, BCG adverse reactions added as EC, influenza contraindications added to EC, breastfeeding removed from EC as not required, participation in other COVID-12 prevention trials added as EC.

· Addition of placebo for those randomised to non-BCG arm · Removal of option of receiving influenza vaccine at same time as BCG vaccine. Participants will have obtained their flu vaccine prior to enrolment and randomisation.

· Change to definition of healthcare worker for Australian sites – expand to match definition for European sites · Addition of information about data retention and Gates Foundation requirements · Correction of error in product stability information in protocol, to match product information · Addition of appendix describing stool sample collection, to take place at selected sites only · Updates for clarity

· Trial name updated by removing ‘following Coronavirus exposure’ · Refining of objective language and definitions, as well as removal of secondary objective · Addition of additional blood samples at 6- and 9-month time points · Recruitment window for the BRACE trial extended to 2.5 years · In line with the window for blood samples extended to 42 days, the timeline for participant follow-up has been updated to 13.5 months from randomisation · Clarification of roles of Chief PI, Regional PI and Site PI, as well as addition of Brazil and UK collaborators · Update to the influenza vaccination eligibility criteria · Review of the Recruitment and Consent section to ensure practical application across all BRACE sites · Inclusion of detail pre-randomisation blood sample · Expansion of needle gauge size under Administration of trial drug · Update to the trial timeline and schedule of assessments · Update to the descriptions of procedures · Consolidated procedure discontinuation, withdrawals and losses to follow-up for clarity and include additional detail on processes in Brazil · Safety definitions and information have been consolidated for clarity and a toxicity grading scale has been included · Adjustments made to the data and information management section · Revisions to the description of the BRACE trial Governance structure · Removal of Appendix which outlines division of sponsor responsibilities between Chief PI · Site specific Appendices included

· Update of Regional Principal Investigator for Rio de Janerio, Brazil, · A negative PCR test is not proposed as an inclusion criteria for participants in Brazil. Such a screening test was mooted as possible but has since been found to be logistically impossible. · A respiratory swab will be collected at baseline, following informed consent and randomisation. These swabs are being collected as the Brazilian investigators are keen to conduct a COVID prevalence sub-study. These samples cannot be rapidly analysed due to logistic limitations but will be batch analysed at a later date. Brazilian health authorities will be informed of the results after analysis. Results will be shared with participants approximately 3 months after randomisation. Participants will be specifically told that they won’t be informed of the results for approximately 3 months. · Expansion of needle gauge size under Administration of trial drug to include Preference to use 25G or 26G accepted up to 30G to incorporate BCG administration practice in Europe, · Refinement of SUSAR definition of expectedness to align with WHO information sheet, · Update to Appendix 4 Brazil Specific Requirements; o To clarify safety reporting roles o Adjustment of approach to collection of respiratory swab at baseline with additional detail included outlining the strategy.

AMENDMENT TO OUTCOMES: Administrative correction to the Objective 2 and 4 to ensure minor adjustment to correct language and ensure consistency of wording throughout the protocol. Secondary outcomes 5, 6 and 7 will analyze data over the 6 and 12 months following randomization. Inclusion in exploratory outcome 13 specific reference factors including COVID-19 vaccines that influence adult immune responses, infection and COVID-19 risk. Section 1.3: To reach recruitment target a longer recruitment period will be required. Recruitment will be extended until the end in March 2021. Section 1.4: Section removed. Section 4.1: Inclusion of some specific site details ie. site names in Brazil. Inclusion of electronic messaging as a form of follow-up as preferred by study teams and participants in Brazil. Section 4.3.2: Collaborators in Europe have reported a number of operational challenges in the access and availability of the influenza vaccine for healthcare workers in 2020. Influenza vaccination levels in Spain are significantly lower than other sites. After discussion and review of the impact on recruitment and the trial, proposing the adjustment of the inclusion criteria related to influenza vaccination will be relevant for Australian sites only. Section 4.3.3: Add exclusion criteria to ensure exclusion of people receiving antibiotics as a preventative treatment against TB, add detail on the definition of previous SARSCoV- 2 to include positive PCR and approved antigen testing and clarification on alternative site. Section 5.8: timeline for participants not taking part in any other COVID-19 preventative intervention clinical trial is revised to 6 months. Section 7.3: Inclusion of electronic messaging in Brazil. Added detail on questionnaires sent. Blood samples at 9 and 12 months collect for subset of participants. Adjust DBS timepoint. Section 8.5: Itch added to the toxicity grading scale in line with updated BRACE SAE/AE SOP. Section 11.3: Add sub group

Section 4.3.3: Due to the rapid roll-out of COVID-19-specific vaccines in the United Kingdom, additional exclusion criteria proposed - Have previously received a COVID-19-specific vaccine Section 7.3: Proposal to retain ad hoc blood sample collection due to the changeable context and enable additional sample collection if required. Appendix 4: Adjustment to language around COVID-19 testing in Campo Grande and Rio.

Appendix 8: With the availability of COVID-19-specific vaccines, healthcare workers are being prioritized to receive COVID-19-specific vaccines due to their high risk of SARS-CoV-2 exposure. As healthcare workers, participants in the BRACE trial will be prioritized to receive a COVID-19- specific vaccine.There is evidence that BCG can improve the immune responses to other vaccines, so it is possible that this will also apply to COVID-19-specific vaccines as well. The inclusion on Appendix 8 Optional sub-study: a collection of blood samples to measure immune responses to COVID 19-specific vaccines will enable us to determine if BCG vaccination can improve immunity to COVID-19- specific vaccines have important implications for the potential of BCG-vaccination to increase efficacy of COVID-19- specific vaccines, and may also impact our interpretation of the outcomes of the BRACE Trial. This is particularly important for the COVID-19-specific vaccines that have a lower efficacy (e.g. less than 90% efficacy). The changes in protocol v10.2 will only apply to sites that agree to Appendix 8. Site will need to submit protocol v10.2 and the site-specific PICF to their HREC/Governance for approval. Local COVID-19 safe plans will be utilized to ensure researcher/participant safety in relation to COVID-19

Appendix 4: For Visit 1 – Blood can be collected up to 14 days before participant receive the first dose of a COVID-19 specific vaccine. In specific sites, an earlier time-point (<7 days) will enable the exploration of the initial gene expression responses to vaccination. For Visit 2 – Blood can be collected up to 28 days instead of 28 days only after the participant have received the first dose of COVID-19 specific vaccine. The changes implemented is to allow flexibility in collecting blood sample. For visit 2 with the increase of the number of days it has provided the study with an opportunity to explore the initial gene expression to vaccination but this will be site specific only.

Section 4.1: Added Fundação de Medicina Tropical and Health State Office as the principal site for Manaus, Amazonas, Brazil. Section 10.1.2 and 11.1: Update information on interim analysis Section 11.4: The interim analysis will consider severe episodes of COVID-19 by 6 months now only in Stage 2 of the trial this is because Stage 1 includes only Australia, which has had negligible COVID-19. For the primary outcome of severe COVID-19, the strategy has been changed to split the alpha. The DSMB had recommended unbinding and dissemination of the interim analysis results if they determined they were of clinical or public health importance. A larger alpha spend on the interim analysis will provide the best chance of the interim analysis providing results that the DSMB can recommend be unblinded. Appendix 8: A larger number of participants will be recruited to the BCOS sub-study in Brazil to enable the identification of biomarkers predictive of vaccine efficacy against variants. This analysis is in line with exploratory outcome No 13. Manaus will provide more participants in a region with a high prevalence of the P.1 variant.

Section 3.1.3: Addition of Planned Exploratory Analyses 14 (Brazil Specific) to identify biomarkers for diagnosing TB infection. Appendix 4: Updates to include the additional volume of blood to be collected for Planned Exploratory Analyses.

Appendix 9: Addition of Appendix 9 (Brazil Specific) to examine the interplay between SARS-CoV-2 variants and the immune system (for example the immune responses to SARS-CoV-2 and vaccines). This is for testing the respiratory swabs previously collected for further analysis, or access variant results. No additional clinic visits or samples required from participants. An additional PICF will be provided to participants to optionally consent to this sub-study, to test the respirator

All revisions made to the protocol are minor/administrative in nature and do not impact the safety or scientific value of the clinical study. Revision have also been done to align with the Statistical Analysis Plan. - “Symptomatic” word has been added to distinguish COVID 19 from Severe COVID19 - To specific RAT is the antigen test - “Number of participants with” is removed as the outcome is what Sponsor will be collecting from participant. For instance, “symptomatic COVID19 over 6 months” is collected from participants, whereas “Number of participants with symptomatic COVID-19” is what Sponsor’s will analyse/compare between the groups. - Clarify the case definitions for asymptomatic COVID-19 is (e.g. ensure matching format for the outcomes) - Assessing of death registry will not be performed - Clarify the definition of what is severe fever or respiratory illness - Clarification of secondary outcomes related to febrile or respiratory illness - To clarify at which timepoints will objective be assessed and to match with information in objective 8 outcomes - To clarify that BRACE will look at the number of days of unplanned absenteeism due to acute illness or hospitalisation instead of any reason which can include carer’ leave or annual leave. - Data linkage will not be conducted for the study - As Stage 1 recruitment is done in Australia for Victoria and Western Australia sites, where there is negligible COVID-19 exposure risk, there is a high probability that positive SARS-CoV-2 serology results are false positive. As a result Stage 1 data will not be included in Meta- Analysis. This update have been done to also align with the Statical Analysis Plan.