BCG Vaccine to Reduce Unplanned Absenteeism Due to Illness of Health Care Workers During the COVID-19 Pandemic. A Multi-center Randomised Controlled Trial (BCG-COVID-RCT)
Phase: PHASE4
Conditions: Covid19, Morbidity, Absenteeism
Sponsor: University of Southern Denmark

Cover page 
 
 
Official title of the study:  
BCG to Reduce Absenteeism Among Health Care Workers During the COVID-19 Pandemic 
 
 
NCT number:  
NCT04641858 - https://clinicaltrials.gov/ct2/show/NCT04641858  
 
 
Date of document:  
January 20, 2022 

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BCG vaccine to reduce unplanned absenteeism due to illness of health care 
workers during the COVID-19 pandemic. A multi-center randomised 
controlled trial (BCG-COVID-RCT) 
 
 

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LIST OF ABBREVIATIONS 
 
AEs – Adverse Events 
BCG – Bacille Calmette-Guérin 
CFU – Colony-Forming Units 
CI – Confidence Interval 
COVID-19 – Corona Virus Disease 
DSMB – Data Safety and Management Board 
EDCTP - European & Developing Countries Clinical Trials Partnership  
HCW – Health Care Workers 
HIV – Human Immunodeficiency virus 
ISC – International Steering Committee 
NSC – National Steering Committee 
NSEs – Non-specific effects 
PCR – Polymerase Chain Reaction 
POC – Point Of Care 
PI – Principal Investigator 
RCT – Randomized Controlled Trial 
RR – Relative Risk 
SAEs – Serious Adverse Events 
SARS-CoV2 - Severe Acute Respiratory Syndrome Coronavirus 2 
 
 

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ABSTRACT 
The COVID-19 pandemic challenges available hospital capacity. This is augmented by 
absenteeism of health care workers (HCW). Strategies to protect HCW are desperately needed. 
Bacille Calmette-Guérin (BCG) has protective non-specific effects against other infections; a 
plausible immunological mechanism has been identified in terms of “trained innate immunity”. 
European and North American trials to study if BCG can reduce the incidence and/or severity of 
COVID-19 have now been initiated. African studies are needed. The underlying hypothesis for this 
study is that BCG vaccination of HCW reduces unplanned absenteeism due to illness by 20%. 
The primary objective of the study is to evaluate whether BCG can reduce unplanned absenteeism 
due to illness among HCW during the COVID-19 pandemic. Secondary objectives are to reduce 
the number of HCW that are infected with COVID-19, reduce hospital admissions of HCW during 
the COVID-19 pandemic and to improve the capacity for clinical research in Cape Verde and 
Guinea-Bissau. 
Design: Single-blind, parallel-group placebo-controlled multi-centre block randomized trial 
including a total of 1050 HCW. The study sites will be the Manhiça District Hospital and Mavalane 
Hospital in Mozambique and Hospital Nacional Simão Mendes and other hospitals in the capital 
Bissau in Guinea-Bissau. Population: HCW (nurses/physicians/others) ≥18 years. Exclusion criteria: 
known allergy to (components of) BCG or serious adverse events to prior BCG administration; 
known previous, active or latent infection with Mycobacterium tuberculosis or other mycobacterial 
species, fever (>38 C) within past 24 hours; suspicion of active viral or bacterial infection, severely 
immunocompromised subjects, self-reported HIV infection, self-reported pregnancy; active solid 
or non-solid malignancy or lymphoma within the last two years; any other contraindications for 
live-attenuated vaccine administration fulfilled, not having a mobile phone.   
Intervention: Block randomization 1:1 to intradermal standard dose (0.1 ml) of BCG vaccine or 
placebo (saline). Endpoints: Primary: Days of unplanned absenteeism due to illness. Secondary: 
Days of absenteeism because of documented COVID-19; cumulative incidence of infectious 
disease hospitalizations.  
Baseline data collection: Enrolment data regarding chronic illnesses and treatment, lifestyle (family 
structure, socioeconomic factors, smoking), vaccination history including previous BCG 
vaccination. Blood sample for SARS-CoV-2 serology. Follow-up: mobile phone interviews every 
second week, regarding symptoms, absenteeism and causes, COVID-19 testing (if done) and their 
results. Supplemented by daily workplace presence registry information (where present).  
Statistical analysis: Total number of unplanned days of absenteeism analysed using Bayesian 
negative binomial regression with a fixed effect for BCG, hospital, professional category, 
observation week, number of average workdays per week. Monthly interim analyses. 
Adaptive design with frequent interim analyses will allow results to inform policy-makers during 
the ongoing pandemic. 
Perspectives: If BCG can reduce HCW absenteeism it has global implications. The intervention can 
quickly be scaled up all over the world. 
ADMINISTRATIVE INFORMATION 
Trial registration 
The trial is registered at clinicaltrials.gov. (https://clinicaltrials.gov/ct2/show/NCT04641858) 
 
 

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Data category 
Information 
Primary registry and trial 
identifying number 
https://clinicaltrials.gov/ct2/show/NCT04641858 
Date of registration in 
primary registry 
November 24, 2020 
Secondary identifying 
numbers 
NA 
Source(s) of monetary or 
material support 
EDCTP 
Primary sponsor 
EDCTP 
Secondary sponsor(s) 
Institute of Hygiene and Tropical Medicine, NOVA University Lisbon 
University of Southern Denmark 
Contact for public queries 
Christine Stabell Benn 
Contact for scientific queries 
Christine Stabell Benn 
Public title 
 
Scientific title 
BCG vaccine to reduce unplanned absenteeism due to illness of health care workers 
during the COVID-19 pandemic. A multi-centre randomised controlled trial (BCG-
COVID-RCT) 
Countries of recruitment 
Guinea-Bissau, Mozambique 
Health condition(s) or 
problem(s) studied 
BCG vaccine, absenteeism, COVID-19 
Intervention(s) 
Active comparator: intradermal standard 0.1 ml dose of attenuated Mycobacterium 
bovis BCG (Bacillus Calmette-Guerin), Danish strain 1331, 2-8 × 105 CFU 
Placebo comparator: intradermal standard 0.1 ml saline solution (NaCl 0.9%) 
Key inclusion and exclusion 
criteria 
Population: Health care workers (physicians, nurses, and others), ≥18 years. Exclusion 
if known allergy or previous adverse events to BCG; previous/active infection with M. 
tuberculosis; Fever (>38 C) within past 24 hours; Suspicion of active viral/bacterial/HIV 
infection; Pregnancy; Being immunocompromised; Not having mobile phone.   
Study type 
Single-blind, 
parallel-group 
placebo-controlled 
adaptive 
multi-centre 
block-
randomised trial including a total of 1050 HCW with two arms (BCG arm and placebo 
arm). 
Date of first enrolment 
 
Target sample size 
1050 
Primary outcome(s) 
Days of unplanned absenteeism due to illness 
Key secondary outcomes 
Days of unplanned absenteeism due to documented COVID-19;  
Cumulative incidence of hospitalisations 
 
 
 

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Funding 
EDCTP is funding the run-in costs for the BCG-COVID-RCT, including trials in the respective 
countries and for training and management. The budget of each RCT site covers costs related to 
regulatory and ethical approval, clinical and supervisory personnel, field workers (enrolment of 
study subjects and data collection, including biological samples), costs of communication, cost of 
materials (offices, electricity, vaccines) and costs of communication (follow up will be by 
telephone). 
The collaboration of the tenured staff members of the Cape Verdean, Danish and Portuguese 
Institutions (University of Cape Verde, National Institute of Public Health of Cape Verde, University 
of Southern Denmark, NOVA University Lisbon, Portugal) will be fully supported by their own 
institutions. 
 
 

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TECHNICAL INFORMATION 
Background and rationale 
The COVID-19 pandemic reflects a serious threat to hospital personnel capacity as the number of 
COVID-19 infected patients that require hospital care may well exceed the capacity of hospital 
personnel. Furthermore, healthcare workers (HCW) face an elevated risk of exposure to - and 
infection with - SARS-CoV-2. Even if further mobilisation of hospital personnel is possible to some 
extent, it is imperative to ensure the safety, health and fitness of hospital personnel, not only for 
moral and professional reasons, but also in order to safeguard continuous patient care and to 
prevent health care systems from collapsing. Strategies to prevent COVID-19 infection or to 
mitigate its clinical consequences among HCW are therefore desperately needed. 
To date, treatment therapies for COVID-19 has been of supportive nature, and no curative or 
protective treatment has been identified yet, despite many ongoing trials. Particularly, there are 
no interventions specifically targeting HCW, apart from adequate personal protective equipment 
and sound professional practices. 
Bacillus Calmette-Guérin (BCG) was developed as a vaccine against tuberculosis, but it has been 
shown that it can protect against death from other infections - it has so-called non-specific effects 
(NSEs) (1-3). In clinical studies, BCG vaccination was associated with reduced infant mortality, 
mainly as a result of fewer cases of neonatal sepsis and respiratory infections (4-6). NSEs of BCG 
are not limited to infants (7,8). For instance, an Indonesian trial showed that consecutive BCG 
vaccination for 3 months reduced the incidence of acute upper tract respiratory infections by 80% 
(95%CI=22% to 95%) (8), and in a South African trial among adolescents, the risk of upper 
respiratory tract infections was 2.1% in the BCG revaccination group but 7.9% in the placebo group 
(P<0.001) (9). 
It has recently been demonstrated that the beneficial NSEs of BCG vaccination are due to 
epigenetic and metabolic reprogramming of innate immune cells leading to an increased 
antimicrobial activity, a process termed “trained immunity” (10). Upon stimulation with a 
pathogen, the innate immune system becomes primed and can react faster and more efficiently 
to a secondary (and non-related) stimulus. These effects lasts for at least one year (10). There is 
proof-of-principle that this will affect the course of a viral challenge; in a human experimental 
study randomising adult volunteers to BCG vs. placebo 4 weeks prior to a yellow fever vaccine 
challenge, those who had received BCG had a lower yellow fever viral load, and improved anti-
viral responses (11). 
Boosting with BCG (revaccination) may enhance these beneficial NSEs (12). This has been shown 
for children in an RCT of BCG revaccination (13). Also, the therapeutic effect of BCG for bladder 
cancer is higher for patients that had previously been vaccinated with BCG (14). It was recently 
demonstrated in a pilot study of 40 Guineans above 50 years of age, that BCG revaccination was 
associated with “innate training”, and this was most pronounced in individuals who had a positive 
IGRA test (submitted). In the proposed trial, boosting may be important, as many HCW are 
expected to have been BCG vaccinated previously. 
BCG vaccine in immunocompetent adults is considered safe, also for persons with prior BCG 
vaccination and even in latently infected adults (15). In a randomised controlled trial (RCT) that 
compared revaccination with BCG versus placebo, no vaccine-related serious adverse events were 
observed in the 312 patients in the BCG arm (9). 
Research hypothesis 
The COVID-19 pandemic in Africa challenges available hospital capacity. This is augmented by 
unplanned absenteeism of HCW. Strategies to prevent their absenteeism are needed. BCG has 

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protective NSEs against other infections and a plausible immunological mechanism, “trained 
innate immunity”, has been identified.  
Based on the capacity of BCG to: 1) reduce the incidence of respiratory tract infections and 
mortality in children and perhaps in the elderly; 2) exert antiviral effects and reduce viremia in an 
experimental human model of viral infection, we hypothesize that BCG vaccination may induce 
partial protection against susceptibility to and/or severity of COVID-19 and associated 
complications which might result in a reduction in the number of days of unplanned absenteeism 
from work for HCW. 
Objectives  
Primary: Test the capability of BCG to reduce absenteeism among HCW working at a health care 
facility that treats patients who could suffer from COVID during the COVID-19 pandemic. 
Secondary: reduce number of HCW that develop COVID-19; ii) reduce number of hospital 
admissions due to illness of HCW during the COVID-19 pandemic; iii) improve capacity for clinical 
research in Guinea-Bissau. 
Trial design  
Single-blind, parallel-group placebo-controlled adaptive multi-centre trial, with block-
randomisation 1:1 to intradermal standard 0.1 ml dose of BCG vaccine or placebo (saline) 
including a total of 1050 HCW (BCG arm and placebo arm). 
 
 

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Figure 1 – Trial design and flowchart  
 
Study population 
Health Care Workers defined as a person who delivers care and services to the sick and ailing 
either directly as doctors and nurses or indirectly as aides, helpers, laboratory technicians, or even 
medical waste handlers.  
Inclusion and exclusion criteria for participants 
Participants must provide written, informed consent before any study procedures occur (see ethics 
section).  
Inclusion criteria 
Participants eligible for the trial must comply with all of the following at randomization: 
• 
health care worker (physician, nurse, or other) based at one of the research hospitals. 
• 
age ≥18 years 
Exclusion criteria 
• 
known allergy to (components of) BCG or serious adverse events to prior BCG 
administration; 
 
Recruitment of health care workers with high risk of exposure to SARS-CoV2 
Verification of eligibility criteria 
Not eligible for inclusion 
Eligible for inclusion 
Informed consent procedure 
Informed consent not provided 
Randomization 
BCG vaccination 
2-Weekly telephone follow-up to participants with surveillance of adverse events 
Follow-up duration determined by interim analysis  
Primary endpoint: Days of unplanned 
absenteeism for any reason 
Secondary endpoints: Days of unplanned absenteeism 
because of documented COVID and cumulative incidence of 
hospital admissions due to illness (minus accidents). 
Monthly interim analysis 
assessing superiority and 
futility  
metanalysis with related RCTs elsewhere 
Placebo  

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• 
known previous, active or latent infection with Mycobacterium tuberculosis or other 
mycobacterial species 
• 
fever (>38 C) within past 24 hours;  
• 
suspicion of active viral or bacterial infection  
• 
severely immunocompromised subjects 
• 
self-reported HIV infection or a positive HIV test at inclusion 
• 
self-reported pregnancy;  
• 
active solid or non-solid malignancy or lymphoma within the prior two years; 
• 
contraindications for live attenuated vaccine administration. 
• 
not having a mobile phone.   
Intervention 
The intervention will consist of the administration of an intradermal injection of a standard 0.1 ml 
adult dose of attenuated Mycobacterium bovis BCG (Bacillus Calmette-Guerin), Danish strain 1331, 
2-8 × 105 CFU or the placebo comparator: intradermal standard 0.1 ml saline solution (NaCl 0.9%). 
Both BCG and saline solution will be injected in the skin over the upper deltoid muscle. 
Product name 
Manufacturer 
Details of product 
BCG 
AJ vaccines (first market 
authorization 1993 - 
marketing authorization 
number 14762) 
Attenuated Mycobacterium bovis BCG (Bacillus Calmette-Guerin), 
Danish strain 1331, 2-8 × 105 cfu (Approval for use No 08731) 
http://www.produktresume.dk/AppBuilder/search?utf8=%E2%9C
%93&id=&type=&q=bcg&button=S%C3%B8g  
Saline Solution 
(NaCl 0.9%) 
NA 
NA 
The BCG vaccine has been commercialized since the 1930s and the current stock is sufficient to 
meet the study needs. BCG vaccines from different manufacturers are not identical. The results 
from this clinical trial will therefore be applicable for BCG Vaccine AJV and not necessarily to other 
BCG vaccine strains. 
The expected local reaction after successful vaccination with BCG Vaccine "AJ Vaccines" is injection 
site swelling followed by a local lesion that can form an ulcer after 2-4 weeks and heal after a few 
months, leaving a small flat scar. Redness and tenderness may occur at the injection site. Regional 
swelling of the lymph node <1 cm may also occur. Not common (≥1/1,000 to <1/100) and rare 
(≥1/10,000 to 1/1,000) adverse reactions:  
• 
Blood and lymphatic system - Regional swelling of lymph nodes> 1 cm  
• 
Nervous system disorders - Headache 
• 
Bones, joints, muscles and connective tissue - Osteitis 
• 
Infections and parasitic diseases - Suppurative lymphadenitis, osteomyelitis, BCGitis 
• 
Abscess at the injection site 
We will specifically enquire about adverse events at the biweekly interviews and in the end 
questionnaire.  
Outcomes 
Primary outcome measures 
Difference between the two treatment arms in the numbers of days of unplanned absenteeism 
due to illness.  

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Secondary outcome measures 
Days of unplanned absenteeism because of documented COVID-19 and cumulative incidence of 
hospital admissions due to illness (minus accidents).  
Unplanned absenteeism is defined by being absent from work due to causes other than holidays, 
parental leave, and other planned leaves, family assistance (including mourning leave) and 
quarantine measures. 
Hospital admissions involves staying at a hospital for at least one night or more for medical 
reasons. It includes admissions to hospital wards and overnight stays in emergency departments. 
Sample size 
The sample size was calculated on the basis of the primary hypothesis. A total of 1050 HCW 
randomized with an estimated loss to follow-up of 5%, and a mean number of days off work due 
to illness in the control group of 5 days (SD=5) over a 6-month period will demonstrate a 
reduction among BCG vaccinated of 20% for a mean absence of 4 days (80% power and alpha 
0.05). The estimated loss to follow-up (5%) was based on past telephone-based surveys conducted 
in Mozambique and Bissau. 
Assignment of interventions  
Randomization 
All participants who give consent for participation and who fulfil the inclusion criteria will be 
randomly assigned to either placebo or BCG group with a 1:1 (treatment:placebo) allocation in 
blocks of 4 to 6 within strata defined by gender (male/female) and occupational group (doctors/ 
nurses/other).  
Blinding 
The BCG vaccine will be administered by study physicians/nurses, who are not blinded but also 
not involved in the data collection. Participants, data collectors and data entry clerks will be 
blinded to the treatment allocation. In case of serious adverse events, the participant can be 
unblinded after consultation with the investigator or the vaccinating physician/nurse. 
When the study has ended, all participants will receive information about the intervention that 
they received. 
Data collection 
Data collection instruments include: consent form, inclusion/exclusion criteria form, baseline 
questionnaire, follow-up questionnaire, and end questionnaire. 
 
Variables 
The endpoint variables are described in  
Table 1. 
 
Table 1 – Definition of end-point variables 
Variables 
Definition 
Type 
Scale 
Domain 
Absenteeism  
Refers to the total number 
of days absent from work 
due to illness 
Quantitative 
Numeric 
In days 

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Variables 
Definition 
Type 
Scale 
Domain 
Absenteeism for 
COVID-19 
Refers to the number of 
days absent from work 
due to COVID-19 
Quantitative 
Numeric 
In days 
Absenteeism besides 
COVID-19 
Refers to the number of 
days absent from work 
due to diseases /illness 
besides COVID-19 
Quantitative 
Numeric 
In days 
Absenteeism for 
infections 
Refers to the number of 
days (unplanned) absent 
from work due to 
infections 
Quantitative 
Numeric 
In days 
Absenteeism for 
respiratory infections 
Refers to the number of 
days (unplanned) absent 
from work due to 
respiratory infections 
Quantitative 
Numeric 
In days 
COVID-19 infection 
Describes if the 
participant is positive for 
SARS-CoV2 or has had 
COVID-19 
Qualitative 
Nominal 
No 
Yes 
Death 
Whether the participant 
died during follow-up 
Qualitative 
Nominal 
No 
Yes 
Cumulative 
incidence of 
infectious disease 
episodes 
Cumulative incidence of 
infectious disease 
episodes 
Quantitative 
Numeric 
Episodes 
Cumulative 
incidence of 
respiratory infectious 
disease episodes 
Cumulative incidence of 
respiratory infectious 
disease episodes 
Quantitative 
Numeric 
Episodes 
Cumulative 
incidence of hospital 
admissions 
Cumulative incidence of 
hospital admissions 
Quantitative 
Numeric 
Admissions 
Cumulative 
incidence of 
infectious disease 
hospital admissions 
Cumulative incidence of 
infectious hospital 
admissions 
Quantitative 
Numeric 
Admissions 
Cumulative 
incidence of 
respiratory infectious 
hospital admissions 
Cumulative incidence of 
respiratory infectious 
hospital admissions 
Quantitative 
Numeric 
Admissions 
Cumulative 
incidence of hospital 
admissions due to 
documented COVID-
19 
Cumulative incidence of 
hospital admissions due 
to documented COVID-19 
Quantitative 
Numeric 
Admissions 
Cumulative 
incidence all-cause 
and infectious 
intensive care 
admission 
Cumulative incidence all-
cause and infectious 
intensive care admission 
Quantitative 
Numeric 
Nights 
Cumulative 
incidence of 
intensive care 
admission due to 
Cumulative incidence all-
cause and infectious 
intensive care admission 
Quantitative 
Numeric 
Nights 

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Variables 
Definition 
Type 
Scale 
Domain 
documented COVID-
19 infection 
Statistical methods 
The responsible for statistical analyses in the consortium will be Sebastian Nielsen affiliated with 
the University of Southern Denmark. 
Data analysis: 
Data will be reported quantitatively. All analyses will be performed from the intention-to-treat 
principle. Missing data on background variables will be dealt with by multiple imputation. Final 
data analysis will begin when the last participant in the multicentric RCT has completed the follow-
up period. The primary endpoint, work absenteeism due to illness, will be reported as the total 
number of sick days with standard deviation. Total days of absenteeism will be analysed using a 
Bayesian negative binomial regression with a fixed effect for BCG, hospital, professional category, 
age, enrolment week and number of average workdays per week. The brm function from the R 
package “brms” will be used for fitting the negative binomial model. The effect will be reported 
as a relative risk with 95% confidence interval (CI). Please refer to section interim analysis for type-
1 error control and power. 
Similar regression models will be used for secondary endpoints. Cumulative incidence outcomes 
will primarily be analysed using Cox Proportional Hazard Regression. 
Continuous baseline characteristics will be reported as means with the standard deviation or 
medians with the inter-quartile range, as appropriate. Categorical baseline characteristics will be 
reported as count and percentage. No statistical testing for baseline characteristics will be 
reported. 
Please refer to the Data Analysis Plan for more details.  
Interim analysis 
Every month, an interim analysis will be conducted for each study site and of the combined 
dataset. Interim analyses will start after the 200th participant has been recruited across the two 
sites. The primary endpoint will be analysed as described above. The Bayesian model yields a 
posterior distribution of the relative risk (RR). The posterior probability of the superiority 
hypothesis (RR < 1) will be calculated. If during any of the interim analyses, the posterior 
probability of superiority is > 0.995, a conclusion is reached, and the trial will be stopped.  
Monthly, the following secondary endpoints will be reported from the sites: hospital admissions, 
and deaths. 
IMPLEMENTATION 
Inception 
The study will begin with an inception meeting to be held in Cape Verde or virtually, depending 
on travel and quarantine recommendations at the time. Besides administrative issues, the meeting 
will address: 
a) Strengthening Health Care Workers knowledge on Personal Protective Measures through 
provision of leaflets with detailed information on reasoning the use, the best practices, and the 
common pitfalls to avoid getting infected by COVID-19 or any other transmissible pathogens 
(when dealing with endemic highly transmissible diseases and/or future outbreaks, epidemics or 
pandemics). The leaflets will be developed based on best evidence available by members of 
consortium and will be handed-out to all health care workers working at the inclusion sites. 

13 
 
b) Short course on Fundamentals of Epidemics and Pandemics for Health Care Workers based in 
hospitals with limited resources. The course will cover best available knowledge on 
epidemiological characteristics of epidemics and pandemics and impart abilities/skills and 
attitudes to deal will epidemics and pandemics based on lessons learned from previous epidemics 
and pandemics in last 100 years, including strategies and interventions that are possible to 
implement for adequate containment and mitigation of epidemics and pandemics. We expect to 
develop the curriculum for the training and implement in all study sites. The initial training will be 
for 20 to 25 participants who will be trained in order to themselves be trainers and therefore 
replicate to their fellow colleagues along the time in their own Districts/Regions and elsewhere in 
their respective countries; 
c) Short course on fundamentals of clinical research and RCT management - Training of research 
staff will include obtaining a certification in good clinical practice (GCP) and in the appropriate 
field procedures for all researchers involved in the study. GCP is an international ethical and 
scientific quality standard for designing, conducting, recording and reporting clinical trials, whose 
principles help assure the safety, integrity, and quality of clinical trials. The GCP training aims to 
ensure that the rights, safety, and well-being of human subjects are protected and that clinical 
trials are conducted in accordance with approved plans with rigor, and that data with integrity 
derived from clinical trials is reliable. GCP certification will be done online. Several certified online 
courses are currently available. We will prefer those recommended by the NHI. 
See also study management, monitoring and quality control and Gantt chart. 
Study setting 
The study will be conducted in two different African countries: Guinea-Bissau and Mozambique. 
These countries were selected because they 1) are both Portuguese Speaking; and 2) have a low 
amount of HCW per population ratio which, in the scenario of the COVID-19 pandemic, places 
them in a fragile situation in terms of health care system capacity to respond to the pandemic; 3) 
have long-standing research/academic working relationships, namely with the European partners; 
and 4) belong to EDCTP supported networks of excellence.  
The sites in the two countries were selected because they all provide care for COVID patients and 
have well established research capacity. 
In Guinea-Bissau, the study site will be Hospital Simão Mendes and other hospitals located in the 
capital city. Hospital Simão Mendes is the national hospital of reference and the leading public 
health institution in the provision of care to COVID-19 patients.  
The same criteria apply to Mozambique (Manhiça Hospital) (Table 2).  
Table 2 – Participating hospitals and anticipated number of participants 
Country  
Participating hospitals 
Hospital collaborator 
Anticipated number of 
eligible participants 
Guinea-Bissau 
Hospital Simão Mendes 
Dr. Agostinho Pedro 
Semedo 
1050 
Mozambique 
Hospital Distrital da Manhiça 
Dr. Flezer Tomadote 
100 
Hospital Geral de Mavalane 
Dra. Marlene Tovele 
150 
 

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Recruitment 
Prior to the initiation of the trial, the hospital director will inform the department heads about the 
trial. Each department head will be provided with written material about the trial, its objectives 
and the practicalities. A telephone number will be provided, to which HCW can address potential 
questions. After a week (where presumably all staff has rotated and been informed about the 
upcoming trial), enrolment dates will be arranged with the department heads and communicated 
to staff. Enrolment will take place at a designated room at the hospital. A point-of-care (POC) test 
will be done for antibodies anti-SARS-CoV2. 
BCG will be given by people trained to administer vaccines by the intradermal technique. The 
injection site should be clean and dry. The vaccine should be injected intradermally on the outer 
side of the upper arm, corresponding to the area of the distal insertion of the deltoid muscle 
(about one-third down the upper arm), as follows: 
• 
The skin is stretched between the thumb and index finger. 
• 
The injection needle is held almost parallel to the skin surface and inserted slowly with 
the oblique edge pointing upwards, approx. 2 mm down into the upper skin layer. 
• 
The needle should be visible through the epidermis at insertion. 
• 
Vaccination should be performed slowly. 
• 
The appearance of a pale bladder is evidence of proper injection technique. 
• 
The injection site should be uncovered to promote healing. 
• 
The administration of the saline solution will follow the exact same procedure. 
Follow-up 
Follow-up will last for 6 months (182 days). Every second week, participants will be contacted over 
telephone and interviewed for symptoms and absenteeism from work. By the end of follow-up, 
participants will be invited for another POC test for COVID-19 serology. 
Figure 2 - Flowchart 
 
 
In case of not answering the telephone call and questionnaire for ≥18 days, information on the 
participant will be retrieved from hospital registries for absenteeism and hospital admission 
registries, ICU admission and outcomes. An explicit permission for this procedure will be 
requested from the participant during informed consent procedures at enrolment. 
 
Participant timeline 
 
 
Staff member 
Enrolment  
Follow-up 
End of Follow-up  
Enrolment (day 0)
Inclusion and 
randomization
Baseline questionnaire
POC test
BCG vaccine/ placebo
Follow-up (day 0 to 
day 181)
Weekly mobile phone 
interview about work 
absenteeism, 
symptoms and 
potential side effects
End of follow-up 
(day 182)
POC test
End questionnaire

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(W1) 
(W2 to W25) 
(W26) 
Consent form 
Research assistant 
x 
 
 
Inclusion/exclusion criteria form  
Research assistant 
x 
 
 
POC test for COVID antibodies 
Study nurse 
x 
 
 
Randomization 
Study nurse 
x 
 
 
Administration of intervention  
Study nurse 
x 
 
 
Baseline questionnaire 
Research assistant 
x 
 
 
Follow-up Interview 
Research assistant 
 
x 
 
End questionnaire 
Research assistant 
 
 
x 
 
Data management 
The researchers will archive the published articles and the final peer-reviewed manuscripts in an 
online repository before, if feasible, at the same time as, or after publication in open access mode. 
The researchers will also make their data available according to the Open Research Data Pilot 
(ORD pilot) of the Horizon 2020 program.  
Study management, monitoring and quality control 
The project will be led by an International Steering Committee (ISC) consisting of PIs in each of 
the five countries involved: Amabelia Rodrigues, PI from Guinea-Bissau; Christine Stabell Benn 
(international coordinator), PI from Denmark; Inês Fronteira, PI from Portugal; Isabel Inês Araújo, 
PI from Cape Verde; and Pedro Aide, PI from Mozambique.  
Figure 3 - Organogram of management structures 
 
Overall coordination will be with the Danish partner. The leader has extensive leadership 
experience from heading a Center of Excellence in Denmark and the Bandim Health Project 
research group in Bissau for many years. Bandim Health Project has a history of past collaboration 
with the Portuguese partner.  
The ISC will have telemeetings, at least once a week, with a formal pre-arranged agenda on 
training, enrolment, follow up, losses to follow up, staff turn-over, vaccine logistics, quality control 
of data collection, data entry and database management, interim analysis, communication and 
dissemination activities, other risks. Decisions of each meeting will be recorded by the coordinator. 

16 
 
Co-PIs in each one of the hospitals involved as study sites will constitute a National Steering 
Committee (NSC) coordinated by the country’s PI. Meeting frequency will depend on project 
needs, but the NSC will interact at least once a week before ISC telemeetings. The agenda will be 
of a more operational nature.  
The NSC should provide country PIs with information relevant to the agenda of fortnightly 
telemeeting of ISC and will also address other site relevant issues. Decisions of each meeting will 
be recorded by the country PI.

 
17 
 
Structure 
Membership 
Functions 
Description 
Name 
Affiliation 
Data Safety and 
Monitoring 
Board (DSMB) 
António Pedro de Sá 
NOVA-IHMT 
Member 
Quality management activities include recruitment of a Data Safety and Monitoring 
Board, who are actively involved in the project, approving the quality of the project 
outputs, including deliverables and dissemination, and supporting the consortium 
in key decisions taken within the project, while maintaining their independence. 
Furthermore, each site will recruit an internal monitor, who will conduct at least 
two monitoring visits during the conduct of the trial.  
Mariza Morgado 
Fundação Oswaldo Cruz 
Member 
Poul-Erik Kofoed 
Lillebaelt Hospital 
President 
Jahit Sacarlal 
Eduardo Mondlane Med School 
Member 
Zacarias da Silva 
National Institute of Health, Guinea-Bissau 
Member 
International 
Trial Steering 
Committee 
(ITSC) 
Christine S Benn 
Southern Denmark University 
Presides, Danish PI 
The project will be led by an International Steering Committee (ISC) consisting of 
PIs in each one of the five countries involved. Overall coordination will be with the 
Danish partner. The leader has extensive leadership experience from heading a 
Center of Excellence in Denmark and the Bandim Health Project research group for 
many years. Bandim Health Project has a history of past collaboration with the 
Portuguese partner. 
The ISC will have at least once a week telemeetings  with a formal pre-arranged 
agenda on training, enrolment, follow up, losses to follow up, staff turn-over, 
vaccine logistics, quality control of data collection, data entry and database 
management, interim analysis, communication and dissemination activities, other 
risks. Decisions of each meeting will be recorded by the coordinator. 
Amabélia Rodrigues 
Bandim Health Project 
Guinean-Bissau PI 
Inês Fronteira 
Universidade Nova de Lisboa 
Portuguese PI 
Isabel Araújo 
Universidade de Cabo Verde 
Cape Verdean PI 
Pedro Aide 
Centro de Investigação em Saúde da Manhiça 
Mozambican PI 
Guinea-Bissau 
Trial Steering 
Committee 
(GBTSC) 
Amabélia Rodrigues 
Bandim Health Project 
Guinean-Bissau PI 
Co-PIs in each one of the hospitals involved as study sites will constitute a National 
Steering Committee coordinated by the country’s PI. Meeting frequency 
will depend on project needs, but the NSC will interact at least once a week before 
telemeeting of ISC. The agenda will be of a more operational nature. This should 
provide the country PI with information relevant to the agenda of weekly 
telemeeting of ISC and will also address other site relevant issues. Decisions of 
each meeting will be recorded by the country PI. 
 
Christine Benn 
Sebastian Nielsen 
Frederik Schaltz-
Buchholzer 
Elsi Ca 
Researchers coordinating field work at Hospital 
Nacional Simão Mendes and other participating 
hospitals. 
Members 

 
18 
 
Structure 
Membership 
Functions 
Description 
Name 
Affiliation 
Isaquel da Silva 
Mozambique 
Trial Steering 
Committee 
(MZSC) 
Pedro Aide 
Centro de Investigação em Saúde da Manhiça 
Mozambican PI 

 
19 
 
Critical risks 
The critical risks for implementation are  
• 
Negative effect of the intervention - negative BCG effect on COVID cannot be excluded. 
It is reassuring that other trials are already ongoing and are likely to detect if BCG, against 
all indications, should have a harmful effect in HCW, before we have enrolled a lot of 
participants. Hence, we would limit any harm of participants. BCG has been used for 100 
years, and it is considered a very safe vaccine. We have no reason to believe that it causes 
harm, rather the contrary. 
• 
Lack of clinical research experience is variable among sites and unsatisfactory compliance 
with requirements for data collection – the workplan contemplates: training of researchers 
and data collectors; pre-testing data collection tools, repeat 10% of data collection 
interviews by different interviewer, data entry from early on with ongoing validation. Both 
Mozambique and Guinea-Bissau have well established, experienced cadres of field 
research workers. 
• 
Study sites with insufficient staff to perform all tasks required - Staff will either be hospital-
based or working from home. Quarantine is not likely to affect health workers unless they 
are infected or symptomatic. That is precisely the main outcome we want to study. 
Collaborators doing phone calls for follow-up will be working from home/project offices. 
• 
Hospital staff lacks interest in participating in trial - The participating hospitals anticipate 
having enough eligible participants between them. Should we face a situation where we 
cannot recruit the anticipated 1050 participants, other hospitals expressed interest in 
participating, but were not able to confirm participation before the grant deadline. 
• 
Enrolment is too slow - Good management and monitoring of recruitment and follow-
up.  
• 
Recruitment is too fast and outstrips capacity of data collection team - Good 
management and monitoring of recruitment and follow-up. 
• 
High volumes of data queries and re-queries - Once again good data management and 
monitoring. 
• 
Staff carrying out follow-up leaves the project and needs to be replaced without losing 
efficiency - Both Mozambique and Guinea-Bissau have well established, experienced 
cadres of field research workers.  
• 
Limited capacity for COVID-testing - If point-of-care tests are not available, we may have 
to collect capillary blood samples for later serology. This analysis is not central for the 
main objective of the RCT (absenteeism). 
• 
Ensuring vaccine supply - We will procure vaccines locally, rather than relying on flying in 
vaccines specifically for the trial. This may give variability in vaccine type available (supply 
can be from several UNICEF-pre-qualified producers). However, in the current situation 
with limited shipping possibilities for research, we find this the best, pragmatic solution. 
If producers are different in the different sites, this will be noted, and we will scrutinize 
data for signs of differences in effect by producer. Essentially, this trial will address the 
research question of relevance for Africa now: can we use the BCG available to mitigate 
the pandemic. 
Quality management 
Quality management activities include recruitment of a Data Safety and Monitoring Board 
(DSMB), who are actively involved in the project, approving the quality of the project outputs, 
including deliverables and dissemination, and supporting the consortium in key decisions 
taken within the project, while maintaining their independence. Furthermore, each site will 
recruit an internal monitor, who will conduct at least two monitoring visits during the conduct 
of the trial.

 
20 
 
ETHICS 
The protocol for this study follows standard clinical trials ethical approval procedures for each 
country. In Mozambique, the study protocol was first approved by the CISM Committee for 
Bioethics in Health on the 26th of October 2021, approval number CIBS-CISM/079/2020. Approval 
by the National Committee on Bioethics in Health (Comité Nacional de Bioética para a Saúde), 
was given on March 11 2021 with approval number Ref: 115/CNBS/21. A protocol amendment 
regarding changes in inclusion criteria was approved on June 21, 2021 with approval number Ref: 
347/CNBS/21. In Guinea-Bissau, the study protocol was approved by the Ethics Committee for 
Research (Comité Nacional de Ética na Saúde) on November 3 2020 with approval number 
119/CNES/INASA/2020.  
In Denmark, the study protocol was given consultative approval by the National Ethics Committee 
on November 2, 2020, approval number 2015556. In Portugal and Denmark, no local ethical 
approval is required as long as the study protocol is approved by the Ethics Committees of the 
countries where the study is to be conducted. 
Ethical approval and legal documentation will be kept by the PI of the respective country. 
Recruitment, inclusion and exclusion criteria and informed consent procedures. 
The RCT involves healthy, volunteer human participants able to give informed consent to 
participate in an interventional trial consisting in the intradermal administration of BCG vaccine 
standard dose or placebo (saline). 
The participants of this research will be health care workers defined as nurses, physicians and 
other health workers, including students and auxiliary staff.  
Prior to the initiation of the trial, the hospital director will inform the department heads about the 
trial. Each department head will be provided with written material about the trial, its objectives 
and the practicalities. A telephone number will be provided, to which HCW can address potential 
questions. After a week (where presumably all staff has rotated and been informed about the 
upcoming trial), inclusion dates will be arranged with the department heads and communicated 
to staff. To avoid queuing and to ensure privacy, staff interested in participating will be asked to 
come one-by-one for enrolment. Whenever possible, a separate cabinet will be allocated to the 
study, in each study site to keep the HCW privacy. 
All HCW who are 18 or older that present themselves to inclusion sites will be considered as 
potential participants. Those with known allergy to (components of) BCG or serious adverse events 
to prior BCG administration; known previous, active or latent infection with Mycobacterium 
tuberculosis or other mycobacterial species; fever (>38 C) within the past 24 hours; suspicion of 
active viral or bacterial infection; pregnancy; and severe immunocompromised subjects; active 
solid or non-solid malignancy or lymphoma within the prior two years; or with contraindication 
for live attenuated vaccine administration, will be excluded. 
Participants will be asked about their HIV status and a HIV test will be performed before 
enrolment. Because they are HCW, we believe that most of them are aware of their HIV status, 
especially in high prevalence settings as is the case of Mozambique. Participants who report that 
they are HIV-positive and those that test positive with the point-of-care HIV test will be excluded 
from the study; the latter will be referred for confirmatory testing.  
Eligible participants will be invited to participate in the study after being informed thoroughly 
about the intervention and having been given the opportunity to discuss the main features of the 
study with the research team and having the possibility to ask questions. The discussion will 
include the aims, methods and implications of the research, the nature of the participation, 
potential benefits, risks or discomfort that might ensue as well as the voluntary nature of their 
participation and the right to withdraw from the study.  

 
21 
 
After information of the main features of the study, participants will be asked to sign the 
information sheets, containing all information in writing plus the e-mail and telephonic contacts 
of the research team, procedures to withdraw from the study and informed consent. The informed 
consent will comprise 1) consent to have either BCG or saline water administered by intradermal 
injection; 2) consent to collect personal data as determined in the study protocol; 3) consent to 
do POC testing for SARS-CoV2 antibodies at the beginning and end of the study; and 4) consent 
to be contacted through mobile calls biweekly during follow-up procedures conducted by the 
research team. 
Each participant will be given a copy of the signed informed consent and information sheets and 
a second copy will be kept by the research team in each study site. Informed consent for all study 
sites will be kept by the country research team in a locked room where only  research team 
personnel will have access.  
Risk assessment for intervention  
Based on previous experience and randomized controlled trials in adult and elderly individuals, 
the risks of BCG vaccination are considered low. It is common and not treatment-demanding that, 
following BCG vaccination, redness, swelling and ulceration of the skin where the vaccine is given 
will occur. There may be swollen lymph nodes in the area some weeks after the vaccine is given, 
and in the longer term, a small ~5 mm diameter scar will appear where the vaccine was given. In 
case these appear, we will follow the recommendations of the National Immunization plan. Severe 
but very rare side effects are injection site abscesses, BCG lymphadenitis, disseminated BCG 
diseases, osteitis, osteomyelitis, anaphylaxis, formation of keloid/lupoid and suppurative 
lymphadenitis. In case these adverse events occur, the participant will be provided with medical 
assistance. 
An insurance for the clinical trial participants will be contracted. This insurance provides cover for 
damage to research subjects through injury or death caused by the study. Participants will not be 
compensated for participating in this study. Damage to subjects through injury or death, caused 
by the study or negligence of local study investigators, is not accountable to the principle 
investigator. 
Follow-up 
Follow-up will take place every second week through telephone interview and by checking register 
of attendance at the worksite (where available). 6 months after recruitment, the participant will be 
invited to the study site for a new POC test for SARS-CoV2 antibodies and to answer an end-
questionnaire. The participant will be informed of the result of the test. The participant will also 
be informed of the intervention he/she received. 
The telephone contact information of the participant will be shared only with the research 
assistant responsible for doing the follow-up. 
Protection of personal data  
This research involves data collection and processing of sensitive personal data, tracking of 
participants and further processing of previously collected personal data (data on immunization). 
Because the study comprises follow-up of participants after administration of the intervention, 
data cannot be anonymised. As so, data pertaining to participants will be stored in a locked room 
in the institution responsible for the RCT in each country (ICSM in Mozambique and Bandim 
Health Project in Guinea-Bissau) in one computer not connected to the internet and protected by 
a password. The password will be only known by the PI, Co-PI and the study supervisors.  
Data analysis will be conducted by the IHMT. Personal data include: eligibility criteria, baseline 
characteristics, adverse events of intervention, work absenteeism and reasons, hospitalization. 

 
22 
 
Several investigators across the world have set up trials of BCG vaccination among health care 
workers. Until today, >20 trials are ongoing or in preparation.  
Spearheaded by the Dutch group, a platform is now being established for a meta-analysis to be 
done immediately (i.e. within one week) after the first trial yields a significant result. The meta-
analysis will include all ongoing trials except for the one yielding the significant result. If the meta-
analysis confirms the effect (i.e. statistically significant difference at a two-sided p-value < 0.05) 
the recommendation will be to offer BCG to HCW or to stop trials. If it is not confirmed, the 
recommendation will be to continue all trials. The result of the interim analysis will be made public 
to inform health authorities.  
A Data Transfer Agreement has been established to allow anonymous sharing of our data to 
contribute to this meta-analysis. 
Safety 
Intervention consist of intradermal administration of a standard dose of BCG vaccine or placebo 
(saline). Based on previous experience and randomized controlled trials in adult and elderly 
individuals, the risks of BCG vaccination are considered low. It is common and not treatment-
demanding that, following BCG vaccination, redness, swelling and ulceration of the skin where the 
vaccine is given will occur. There may be swollen lymph nodes in the area some weeks after the 
vaccine is given, and in the longer term, a small ~5 mm diameter scar will appear where the 
vaccine was given.  
Severe but very rare side effects are injection site abscesses, BCG lymphadenitis (simple or 
suppurative, disseminated BCG disease, osteitis, osteomyelitis, anaphylaxis, formation of 
keloid/lupoid. They are so rare that it would be unlikely with cases in the present trial of 1050 
participants, but we will specifically enquire about adverse events at the weekly interviews and in 
the end questionnaire. In the case of adverse events they will be reported to the vaccine producer 
and the patient will be receive treatment. 
Temporary halt for reasons of subject safety: In accordance to section 10, subsection 4, of the 
Medical Research Involving Human Subjects Act (WMO), the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardize subject health or safety. 
The sponsor will notify the EC without undue delay of a temporary halt including the reason for 
such an action. The study will be suspended pending a further positive decision by the EC and the 
DKMA. The investigator will take care that all subjects are kept informed. 
Adverse events (AEs): defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to the investigational product, the placebo or the trial 
procedures, will be biweekly assessed during the mobile phone interviews. All adverse events will 
be reported to the relevant authorities according to existing national notification procedures. 
Serious adverse events (SAEs) is any untoward medical occurrence or effect that results in death, 
is life threatening or requires hospitalization or prolongation of existing inpatients’ hospitalization, 
results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect 
or any other important medical event due to the intervention based upon appropriate judgement 
by the investigator. An elective hospital admission will not be considered as a serious adverse 
event.  
Participants will be asked about the occurrence of SAE’s biweekly in the questionnaire. In case of 
a SAE, dependent on the symptoms of the participant, he/she will be contacted by the investigator 
and if necessary, admitted to the hospital. The condition of the participant will be evaluated by 
the investigator, who can decide to un-blind if deemed necessary.  

 
23 
 
The investigator will notify sponsor and DSMB within 24 hours after first knowledge of any SAEs, 
in order for DSMB and sponsor to assess whether it is a suspected unexpected serious adverse 
reactions (SUSAR).  
Unexpected adverse reactions are SUSARs if the event is serious, if there is a certain degree of 
probability that the event is a harmful and an undesirable reaction to the medicinal product under 
investigation, regardless of the administered dose and it is unexpected, that is to say, the nature 
and severity of the adverse reaction is not in agreement with the product information as recorded 
in the summary product characteristics. 
The investigator and the sponsor will report to the EC and competent national authorities.  
Beneficence  
It is clear that we need better tools against emerging pandemic threats. In the current approach 
we can first act only once we have identified the new pathogen; then we can start to develop new 
vaccines or new forms of treatment. This may take a long time before such measures are approved. 
If this RCT provides us with evidence of protective NSEs against COVID-19, we will not only have 
a tool against COVID-19, but likely also a tool that may help protect against other emerging 
pandemics in the future. 
The current pandemic, COVID-19, seriously challenges the available hospital capacity and this is 
augmented by absenteeism of HCWs. HCWs are at high risk, as they constitute over 20% of all the 
COVID-19 cases in countries with available data. Strategies to prevent absenteeism of HCW are 
therefore desperately needed. This study contributes to that goal.  
Elderly are another vulnerable group of the COVID-19 pandemic. If BCG protects COVID-19 in 
HCW, it will be an obvious next step to expand its use to other population groups. 
Additionally, if BCG proves useful against COVID-19 it would be yet another confirmation that it 
strengthens the immune system against unrelated pathogens. While it is not a given that it will 
work against any kind of pathogen, we have so far seen BCG protects against viruses, bacteria as 
well as parasite infections. 
Hence, there is reason to believe that it works against a large range of pathogens. Our results will 
provide further scientific evidence of these non-specific effects of BCG with relation to our central 
hypothesis that BCG (re)vaccination may induce (partial) protection against susceptibility to 
and/or severity of COVID-19. 
Withdrawal from the study 
Subjects can leave the study at any time for any reason if they wish to do so, without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons.  
COVID-19 diagnosis and treatment 
In case of suspicion of COVID-19, the national guidelines for testing and treatment of patients will 
be followed.  
Public disclosure and publication policy:  
The results of this study will be disclosed unreservedly at the end of the study. Results that are 
important for public health will be notified to the competent authorities as swiftly as possible. The 
trial will be registered in a public trial registry before the first patient is recruited. 
 
 
 

 
24 
 
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