Link between BCG and lower COVID-19 mortality disproved by new analysis

The association between BCG (Bacillus Calmette-Guérin) vaccination and its purported beneficial effect on COVID-19 transmission/mortality rates was challenged in an expert appraisal of Diamond Princess cruise ship data. At the same time, cross-national differences previously reported were shown to be flawed, reports a new medRxiv study.

A global pandemic of coronavirus disease (COVID-19) caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) represents an international public health crisis. Since there is still no vaccine or effective treatment modality, the scientific community explores different options to lessen the infection burden.

Recently, several author groups have proposed the hypothesis that BCG vaccination reduces both the morbidity and mortality of COVID-19. A correlation between national BCG vaccination policies and infection rates arguably supported this hypothesis.

The assumption was that the BCG vaccine is not specifically preventing tuberculosis, influenza, or COVID-19, but actually shows a 'harmonizing effect' that directs the immune system to respond.

But although the hypothesis that BCG vaccination reduces the infection propensity of SARS-CoV-2 and mortality of COVID-19 is intriguing, it is disproved in a recent study authored by Dr. Masakazu Asahara from the Division of Liberal Arts and Sciences of the Aichi Gakuin University in Nisshi, Japan.

Novel Coronavirus SARS-CoV-2 Transmission electron micrograph of a SARS-CoV-2 virus particle, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
Novel Coronavirus SARS-CoV-2 Transmission electron micrograph of a SARS-CoV-2 virus particle, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

Local and international comparisons

To examine the hypothesis in more depth, this paper (available on the preprint server medRxiv) pursued the statistical analysis of the publicly available data by using several different approaches. The first step was to compare the infection and mortality ratios of individuals on the international cruise ship Diamond Princess carrying approximately 3,700 passengers.

A majority of patients on board were infected before they were aware that SARS-CoV-2 was spreading in the ship. This means that cultural specificities of different countries (such as the habit of wearing masks) or national policies (e.g. "cluster buster" policy instituted in Japan) can be excluded, knowing at the same time that the identical viral strain was implicated in the outbreak.

The next step was to compare the number of deaths among nations, as well as to compare the maximum daily increase rate of total deaths in each nation. A general linear model was employed for appraising BCG vaccination effects, as well as the timing of COVID-19 entry to nations and regions.

No correlation with COVID-19

The results have shown no significant differences in infection or mortality rates between Japanese citizens and other nationalities, as well as between BCG obligatory nations and non-BCG obligatory nations on the Diamond Princess cruise ship.

Furthermore, after correcting for SARS-CoV-2 arrival time in different countries, the previously disclosed effect of BCG vaccination on reducing total mortality actually disappeared. This is due to the fact that nations without mandatory BCG vaccination are concentrated in Western Europe, close to the epicenter of COVID-19.

Finally, the maximum daily increase rate in deaths among nations showed no significant difference among BCG vaccination policies. There was indeed a weak correlation for Japan, but this may have been influenced by the sample size, outliers, and sizable regional differences.

The results reveal that the beneficial effect of BCG vaccination if there is any at all, can be masked by a myriad of other factors; hence, the possible effect might be rather small. In fact, in Japan, almost all citizens have been vaccinated, but COVID-19 cases are constantly on the rise.

Such ecological studies are always prone to significant bias due to many confounding factors, cautions the World Health Organization (WHO). This includes differences in the country's demographics and disease burden, the stage of the pandemic in different nations, as well as testing rates.

"There can be many hypotheses explaining the differences of COVID-19 morbidity, mortality, and how those increase among nations", explain Dr. Ashara. "Simple comparisons among nations may address these problems/hypotheses."

A note of caution

Although the link between BCG and COVID-19 was not proven, many media outlets and social networks were reporting the hypothesis, causing people to gradually consider it as a fact (most notably in nations with active BCG vaccination programs).

"The hypothesis that BCG vaccination reduces the infection and mortality of COVID-19 is attractive", says Dr. Ashara in this study. "However, previous international comparative reports may not prove the hypothesis because many other possibilities can explain the observed pattern," he adds.

In any case, ongoing clinical studies will give the final answer to this question. Until then, the research community should be careful when reporting patterns emerging in the statistical data, and also not to cause more harm than good when spreading optimistic conclusions from unproven theories, cautions Dr. Ashara.

In the absence of evidence, the WHO still does not recommend BCG vaccination for preventing COVID-19. Nonetheless, the further progress of research is closely monitored, and neonatal BCG vaccination in countries with a high incidence of tuberculosis is still recommended.

Important Notice

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

Source:

World Health Organization (WHO). (2020). Bacille Calmette-Guérin (BCG) vaccination and COVID-19 [Scientific Brief]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.17.20068601v1

Journal reference:

Asahara, M. (2020). The effect of BCG vaccination on COVID-19 examined by a statistical approach: no positive results from the Diamond Princess and cross-national differences previously reported by world-wide comparisons are flawed in several ways. medRxiv. doi: https://doi.org/10.1101/2020.04.17.20068601

Dr. Tomislav Meštrović

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university - University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.

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Comments

  1. G Georg G Georg Bulgaria says:

    This particular study by Dr. Ashara should be viewed with great caution and the title of your article should be much more moderate. It should be noted that Ashara's work has not been peer reviewed or published in true academic journal.

    First, let us summarize criticisms on using Diamond Princess for such gross estimations:

    - Diamond Princess has 712 confirmed cases. Considering the serious limitations in diagnostics this number should be taken with care as well. However even if considered true it should be kept in min that this is a small sample size and there are numerous confounding factors involved, i.e. the passengers belong to the elderly upper class that is generally well nurtured and had received top quality medical care through life (with BCG or not)

    - It is totally ridiculous to speculate on the arrival date of SARS-CoV-2 in different countries in Europe because: (i) EU is characterized with great people mobility across countries, (ii) most cases are asymptomatic or mild and patients had not visited a doctor, hence virus arrival date is impossible to be determined with any reasonable precision and (iii) actually there is no big time lapse between first diagnosed cases in different countries. Just an example on the last point (source: www.worldometers.info/coronavirus/#countries). BCG- countries: Italy- Feb 15, Spain- Mar 02, France- Feb 10, Netherlands- Feb-27, Belgium-Feb 28. BCG+ countries: Japan- Feb 15, Portugal- Mar 02, Poland- Mar 04, Hungary- Mar 04, Bulgaria- Mar-05, Latvia- Mar 02. The arrival of SARS-CoV-2 is approximately at the same time in both group of countries but the mortality is much different. The constraint measures in the East European countries are far from draconian compared to the implemented in the West. It is even more interesting if you see the Covid-19 mag in West and East Germany.

    Indeed there are multiple confounding factors to be accounted but the Ashara's work is far more questionable compared to the BCG supportive studies.

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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