Short summary

Based on the capacity of BCG to reduce the incidence of morbidity and mortality due to infectious diseases and exert antiviral effects in experimental models, we hypothesize that BCG vaccination may induce (partial) protection against susceptibility to and/or severity of COVID-19. The study will evaluate the efficacy of BCG to improve the clinical course of COVID-19 and to prevent absenteeism among health care workers during the COVID-19 pandemic.

Rationale

On 30th December 2019, a novel enveloped RNA beta-coronavirus was detected from a patient with pneumonia of unknown etiology in Wuhan, the capital city of Hubei province, China. The pathogen was named the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [1,2]. Since beginning of 2020, SARS-CoV-2 spread rapidly throughout China and the rest of the world, with the first detected case in Denmark on 27 February 2020.

The estimated basic reproduction number (R0) of SARS-CoV-2 is 2.2, i.e. on average, each infected person spreads the infection to an additional two persons. SARS-CoV-2 is being transmitted via droplets during close unprotected contact between people [1]. According to the WHO, as of 8 April 2020, 1,435,091 laboratory-confirmed SARS-CoV-2 cases were established. Health-care workers face an elevated risk of exposure to - and infection with - SARS-CoV-2. This reflects a serious threat to hospital personnel capacity in Denmark as the number of COVID-19 patients that require hospital care may well exceed the capacity of hospital personnel. Even if further mobilization of hospital personnel is possible to some extent, it is imperative to ensure the safety, health and fitness of hospital personnel in order to safeguard continuous patient care. Strategies to prevent SARS-CoV-2 infection or to mitigate its clinical consequences are therefore urgently needed. To date, no curative or protective treatments have been identified yet despite ongoing trials.

BCG vaccine: Bacillus Calmette-Guérin (BCG) was developed as a vaccine against tuberculosis, but our group has shown that it can protect against death from other infections, it has what we have called non-specific effects (NSEs) [3]. In clinical studies, BCG vaccination was associated with less child mortality, mainly as a result of reduced neonatal sepsis and respiratory infections [4-6].

In a WHO-commissioned meta-analysis, BCG was associated with 42% (95%CI: 24-55%) lower child mortality [7]. Non-specific effects (NSEs): NSEs of BCG are not limited to children. An Indonesian trial with 34 subjects has shown that consecutive BCG vaccination for 3 months reduced the incidence of acute upper tract respiratory infections by 80% (95%CI=22-95%) [8]. It has been recently demonstrated that the non-specific beneficial effects of BCG vaccination are due to epigenetic and metabolic reprogramming of innate immune cells such as myeloid cells and NK cells, leading to an increased antimicrobial activity, a process termed 'trained immunity' [9]. Upon stimulation with a pathogen, the innate immune system becomes primed and is able to react faster and more efficiently to a secondary (and non-related) stimulus. In experimental studies, BCG has been shown to protect against not only bacterial and fungal infections, but against viral infections such as influenza as well [10]. Furthermore, among humans receiving yellow fever vaccine virus, those who had received BCG had - compared to placebo treated subjects - lower viral load, and improved anti-viral responses (Figure 1) [11].

The observed effects are proposed to be due to modulation of the human innate immune system through 'trained immunity' and are lasting for at least one year [9]. Based on the capacity of BCG to 1) reduce the incidence of morbidity and mortality due to infectious diseases in children and perhaps in the elderly; 2) exert antiviral effects in experimental models; and 3) 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.

This study will evaluate the efficacy of BCG to improve the clinical course of COVID-19 and to prevent absenteeism.

A randomized controlled trial provides the highest validity for this research question. Given the immediate threat of the COVID-19 epidemic the trial has been designed as a pragmatic study with a highly feasible primary endpoint, that can be continuously measured. This allows for the most rapid identification of a beneficial outcome that would allow other HCW to benefit from the intervention if it is demonstrated to be effective. We have therefore chosen unplanned absenteeism from work as primary outcome, in line with an ongoing clinical trial of BCG in the Netherlands.

Objectives:

Primary objective: To reduce absenteeism among HCW during the COVID-19 epidemic.

Secondary objective: To reduce the number of HCW that are infected with SARS-CoV-2 during the COVID-19 epidemic and to reduce the number of hospital admissions amongst HCW during the COVID-19 epidemic.

Hypothesis: BCG vaccination of HCW will reduce absenteeism by 20% over a period of 6 months.

Description of the cohort

1500 health care workers from 9 Danish hospitals.

Data and biological material

Questionnaire data and blood samples.

Collaborating researchers and departments

Department of Clinical Research, Universyty of Southern Denmark and Bandim Health Project

• Christine Stabell Benn (MD, DMSc)
• Peter Aaby (DMSc)
• Frederik Schaltz-Buchholzer (MD, PhD student)

Radboud Medical Centre, Nijmegen, The Netherlands

• Mihai Netea (MD, DMSc)

Statens Serum Institut

• Tyra Groove Krause (MD, PhD)

Publications associated with the project

Madsen AMR, Schaltz-Buchholzer F, Benfield T et al.Using BCG vaccine to enhance non-specific protection of health care workers during the COVID-19 pandemic: A structured summary of a study protocol for a randomised controlled trial in Denmark. Trials. 2020 Sep 17;21(1):799.