With the continuing global devastation caused by the Covid-19 pandemic, researchers worldwide are reviewing all available data to identify key trends that could play a role in combating Covid-19.

The extent of Covid-19’s impact in different countries remains widely varied, with some countries being heavily impacted despite imposing high-level mitigation strategies and stringent containment measures. A group of researchers have suggested that the severity of Covid-19’s impact is greater in countries that do not have a history of Bacillus Calmette–Guerin (BCG) vaccination programmes, including Italy and the US.

BCG vaccines have been available since the early twentieth century, and are mandatory in several countries such as Japan and South Korea and many more for protection against tuberculosis (TB) infection. BCG vaccines are not mandated in several other countries, including Italy, the US, and other developed countries. BCG vaccines contain a live attenuated strain of Mycobacterium bovis, the causative agent of TB. The BCG vaccination has been suggested to induce heterologous immunity against non-mycobacterial pathogens. The vaccine is thought to engineer metabolic and epigenetic alterations, resulting in the promotion and production of pro-inflammatory cytokines following exposure to a stimulus. Preliminary reports from epidemiological studies suggest that counties with universal BCG vaccination programs have been impacted less by Covid-19, leading researchers to theorise that BCG vaccination may offer some level of heterologous immunity against COVID-19.

On 12 April, the World Health Organization (WHO) stated in a press briefing that there is currently no data-based evidence that the BCG vaccination provides protection against Covid-19. There are multitudes of confounding variables that prevent any firm correlations from being drawn. However, due to continuously evolving Covid-19 data, the WHO has not ruled out the fact that the vaccine may exhibit positive effects. Consequently, the WHO is closely monitoring the progression of two clinical trials.

These studies are the Phase III BRACE clinical trial, an Australian study sponsored by the Murdoch Children’s Research Institute in collaboration with The Royal Children’s Hospital, and the Phase III BCG-CORONA trial, a Dutch study sponsored by the University Medical Center Uterecht in collaboration with Radbound University. These trials are investigating the effect of BCG vaccination in healthcare workers to determine if this vaccine is able to offer a level of innate immunity against Covid-19.

Both are placebo-controlled trials that are administering the BCG vaccine to one cohort and a placebo control to the other. The Australian study is significantly larger, with a planned trial population of 4,170 participants, while the Dutch study aims to recruit 1,500 participants. The patient population of the two studies differ slightly, as the BRACE study is administering the vaccine to all healthcare workers whereas the BCG-CORONA trial is only administering the vaccine to health personnel who are taking care of patients with a Covid-19 infection. It is therefore probable that the participants of the BCG-CORONA trial will have a higher level of exposure to coronavirus, and the study should be able to provide a better indicator of the BCG vaccine’s potential protective effects. The two studies are both measuring the levels of absenteeism over six months to determine whether there is a significant difference in the level of incidence of Covid-19 between the experimental and placebo cohorts.

Both studies have detailed exclusion criteria, including individuals who have received a vaccine in the last four weeks to limit the number of confounding variables. However, the Australian study has adopted more stringent guidelines, stating that individuals who have received a BCG vaccination in the last year are excluded from the study. This reduces the likelihood of individuals who may be benefiting from the vaccination’s
protective effects from being placed in the placebo group and potentially distorting the results. Both these studies are in non-Covid-19 infected subjects. Although they may provide information on the endpoints outlined in the studies, it may not provide data on a direct correlation on protection from Covid-19, especially if the subjects are naturally resistant to Covid-19. It is important to note that several Covid-19-positive subjects are non-symptomatic, potentially due to inherent immunity.

Baylor College of Medicine and Ain Shams University are both conducting similar trials  in which the patient population consists of health workers, and the trials are under Phase IV and Phase III level of development, respectively. The study populations are split into two cohorts consisting of an experimental arm receiving the BCG vaccination and a placebo comparator arm. The primary outcome of both of these studies is focused on the incidence of Covid-19 rather than the abseentism. The Ain Shams study measures the incidence of Covid-19 over nine months, while the Baylor study measures the primary outcome through a six-month period. The Baylor study has Harvard University, Radboud University Medical Centre, and University of Texas MD Anderson Cancer Center all listed as collaborators. This trial is also notable because it is the first to exhibit international collaboration in BCG trials targeted against Covid-19.

Two more trials have recently been registered, offering additional data to investigate potential correlations between Covid-19 and BCG vaccines. A Phase IV study in the Netherlands sponsored by the Radboud University Medical Centre aims to tests the effectiveness of the BCG vaccine against Covid-19 in an elder patient cohort, where participants are ages 60 years or older. This study utilises a similar placebo-controlled design and aims to enroll 1,600 participants with a primary duration of six months. The primary outcome is based upon the number of Covid-19 related admissions and aims to evaluate if the administration of the BCG vaccine reduces the rate of hospital admissions in elderly patients.

The latest study, a Phase II trial located in Egypt sponsored by Assiut University, takes a different approach. This trial assesses the severity of Covid-19-positive patients ages 12–80 years who have previously been vaccinated with a BCG vaccine. Subjects are grouped into two cohorts: those with a positive tuberculin test and those with a negative tuberculin test. This study will be very useful in assessing if the BCG vaccination decreases the impact of the disease as opposed to whether the vaccine offers immunity. This study has the shortest trial duration of 2.2 months, which may be attributed to the trial participants not requiring vaccine administration, therefore any potential immunoprotective effects will be evident from the offset of the trial. However as the participants would have been vaccinated at different time intervals, the degree of immunoprotective effects offered by the vaccine may be largely variable in the patient cohort and may have an effect on the results. Furthermore, the smaller planned participant size of 100 subjects decreases the power of the trial.

Taken together, the results of all the listed trials could provide essential data in determining whether the BCG vaccine provides a level of immunity or protection against Covid-19. A positive correlation could prove to be key in combating
Covid-19, as the BCG vaccine has a well-documented safety profile. Furthermore, the vaccine already has well-established production routes that would enable quick delivery to all those who require it.