Performance Evaluation of BCG Vaccination in Healthcare Personnel to Reduce the Severity of COVID-19 Infection.

Problem Statement

To date, Colombia has more than 2,800 infected cases and a hundred deaths as a result of
COVID-19, with Antioquia being the third department with the highest number of cases (1).
Official records indicate that, in Colombia, the first case was diagnosed on March 6, 2020,
corresponding to a patient from Italy. However, in conversations with several infectologists
and intensivists from Medellín, it was agreed that clinical cases similar to the clinical
presentation that is now recognized as COVID-19 had arisen since the end of 2019 when it was
still unknown to everyone. The previous suggests that the virus was already circulating in
the country since before March 6, 2020. But at that moment, there were no tools to make a
clinical identification, nor to diagnose it from the laboratory's point of view. This theory
has been gathering momentum in other latitudes, demonstrating how the asymptomatic infected
individuals are responsible for spreading the infection .

Considering as real the hypothesis that the infection has been circulating in the country
since before the first official diagnosis, the question arises: Why does not the country
still has the same healthcare and humanitarian chaos that countries such as Italy and Spain
are suffering at this time? To answer this question, an extensive literature search of
factors that differentiate Europeans from Latin Americans was carried out. Finding, in
addition to genetic factors specific to race, differences in the number of ACEI receptors
(binding site of the coronavirus to the alveolus), and differences in vaccination rates with
BCG (Bacille Calmette-Guérin or tuberculosis vaccine), which is significantly higher in Latin
America compared to those in Europe (3). This last finding could explain to some extent the
situation in the country, since previous studies have shown the influence that this vaccine
can have on the immune response against various other pathogens, including viruses (4,5).

Among the population at risk of infection, health-care workers due to their permanent contact
with patients are the population group with the highest risk of contracting SARS-Cov-2 and
developing COVID-19 in any of its clinical manifestations.

Currently, there are no vaccines or proven preventive interventions available to protect
health-care workers. However, researchers from Germany, the Netherlands, Australia, and
France are working on a clinical trial with an unorthodox approach to combat this new virus.
This research study aims to demonstrate whether the centennial vaccine against tuberculosis
(BCG), a bacterial disease, can activate the human immune system in a broad way, allowing it
to better combat the coronavirus that causes COVID-19 and, perhaps, prevents the
complications that lead the patient to the intensive care unit and death. Initially, studies
in these four countries will be carried out on doctors and nurses, since they are the ones
with a higher risk of becoming infected compared to the general population.

Currently, the available evidence supports the hypothesis that BCG vaccination has beneficial
heterologous effects against viral, bacterial, and fungal infections. The basis of these
effects has been little explored in humans; however, this knowledge opens the door to future
research to explore the effect of "trained immunity" associated with this vaccine, both for
diseases in hosts with immunological disorders, and for autoinflammatory diseases, in which
there is an inappropriate activation of inflammation (21). All of the findings described have
considerable potential to aid in the design of new therapeutic strategies, such as the use of
old and new vaccines that combine classical immune memory, and the activation of innate
immunity by "trained immunity," for prevention and treatment of infections, and modulation of
exaggerated inflammation in autoinflammatory diseases.

A multicenter, double-blind, randomized, phase III clinical trial will be carried out. 1000
healthy healthcare workers (doctors, nurses, and nursing assistants) with a negative test for
COVID-19 and asymptomatic for the disease will be randomly assigned to receive one dose of
BGC vaccine or placebo (saline solution). Volunteers will be followed for one year.

Hypothesis Healthcare workers who have negative SARS-Cov-2 serology and who receive the BCG
vaccine, have a better clinical outcome if they become infected with COVID-19, in terms of
not getting sick, requiring hospitalization or dying, than those who do not receive the
vaccine.

Objectives

Overall Objective

Evaluate the performance of BCG vaccination in reducing the severity of SARS-COV-2 infection
compared to the placebo, in healthcare personnel from Medellín, Colombia.

. Specific Objectives

- Determine if there are differences in the clinical outcome in terms of not getting sick,
requiring hospitalization, or dying in both treatment groups.

- Estimate previous exposure of healthcare personnel to SARS-Cov-2 by conducting rapid
tests that measure IgG and IgM immunity.

- Assess the safety (frequency, seriousness, and severity of adverse events) of BCG
vaccination in an adult population.

- Estimate SARS-Cov-2 infection in healthcare personnel at the end of the study, by
performing rapid tests that measure IgG and IgM immunity.