In a recent medRxiv* preprint research paper, scientists from India analyzed twenty European countries and showed that the prevalence of exposure to Mycobacterium spp. (which includes BCG vaccine) is consistently negatively correlated with coronavirus disease (COVID-19) infections.

Bacteria Mycobacterium tuberculosis, the causative agent of tuberculosis, 3D illustration. Image Credit: Kateryna Kon / Shutterstock

While the COVID-19 cases are still skyrocketing, many countries around the world have started to ease lockdown measures in order to save the ailing economy. However, the threat from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not going away anytime soon.

In the meantime, many different research groups have touted the hypothesis that the implementation of mandatory BCG (Bacillus Calmette-Guérin) vaccination policy by many countries in the past, as well as BCG immunization coverage of different populations, have been associated with the lower COVID-19 cases and mortality rates.

On the other hand, we recently reported a study that showed no significant differences in SARS-CoV-2 infection or COVID-19 mortality rates between BCG obligatory nations and non-BCG obligatory nations on the Diamond Princess cruise ship.

What we can be sure of is that confounding variables among countries (such as the population age distribution, outbreak stage, health infrastructure, testing/screening/management practices, and reporting guidelines) make the comparisons rather tenuous.

What is ‘trained immunity’?

Trained immunity‘ of certain populations as a result of mandatory BCG immunization policy implementation can mediate various beneficial heterologous effects and has been suggested as one of the key factors why COVID-19 infection and mortality rates were dissimilar in different countries.

Important trials are currently underway that aim to evaluate the purported protective role of BCG vaccination in this pandemic. Nonetheless, inadequate clarity on the use of controls concerning ‘trained immunity’ has caused concern and led to even more confusion (as illustrated by some recent trials that failed to find any correlation).

Still, the European countries without mandatory BCG vaccination policy, but comparable mobility, medical infrastructure, exposure to SARS-CoV-2, and other confounding variables offer an excellent opportunity to appraise such assertion. Naturally, they have to be at a similar outbreak stage but encompass differential ‘trained immunity’ status reflected in the percentage of latent tuberculosis infections.

Latent tuberculosis in European countries

This intrigued Dr. Samer Singh from the Institute of Medical Sciences, Banaras Hindu University in Varanasi, and the Department of Microbial Biotechnology of Panjab University in Chandigarh, India, and his co-authors Dr. Rajenda P. Maurya and Dr. Rakesh K. Singh from the Banaras Hindu University in Varanasi, India.

“We reason, if indeed ‘trained immunity’ status could help reduce infections in a population, the estimated prevalence of latent tuberculosis infection of resident populations would more closely correlate with COVID-19 infection and mortality rates”, say study authors.

For the purposes of this study, the researchers included population groups from twenty European countries with a differential prevalence latent tuberculosis infection, primarily by using data published by the Institute for Health Metrics and Evaluation (IHME) of the University of Washington.

Akin to previous studies on vitamin D, three time-points of the ongoing pandemic were selected – April 8, May 12, and May 26, 2020. Furthermore, comparable confounding variables were assessed for any correlation of COVID-19 cases and mortality data, without any exclusion criteria (such as sex, age, or ethnicity).

Correlation with COVID-19 infection

The groundbreaking revelation of this study is the observed significant correlation of the ‘trained immunity’ population prevalence with COVID-19 infections. More specifically, the data analysis reveals a consistently negative covariation of the cases per million with population latent tuberculosis infection at all the time points evaluated – regardless of the pre- or post-infections peak.

Conversely, the negative covariation of deaths per million population observed remained insignificant, as would be expected with individuals and populations without sufficient ‘trained immunity’ being vulnerable to getting infected with SARS-CoV-2.

The authors also emphasize that the correlation analysis consistently showed basically the same association pattern at all three different time points of the epidemic curve that were appraised.

Clinical trials needed for final answers

“In the light of observation presented, it may be suggested that ongoing trials/studies evaluating the effect of BCG vaccination on COVID-19 infections could provide more objective conclusions on inclusions of the estimates about the ‘trained immunity’ of study participants/populations”, study authors accentuate the importance of their findings.

In any case, dedicated studies that will use epidemiological surveys or all available patient records, backed by follow-up clinical trials with adequate controls for the ‘trained immunity’ correlates, are warranted to elucidate the biological significance of the correlation found in this study.

This will result in more steadfast and meaningful conclusions regarding BCG vaccination, conferred ‘trained immunity’, and COVID-19 control. For now, we rely on this type of descriptive studies to generate hypotheses which can only be confirmed by a robust research approach.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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