If the United States had mandatory tuberculosis vaccination in place several decades prior, the total number of coronavirus-related deaths might not have reached triple digits by late March.
In fact, according to a new University of Michigan report, the U.S. would have suffered an estimated 94 deaths, which would have been only 4% of the actual death toll of 2,467 in this country on March 29.
The report – titled “Mandated Bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19″ – is an analysis of daily reports of COVID-19 cases and related deaths in more than 50 countries.
Researchers say countries that have a current policy mandating BCG vaccination, a TB vaccine, have significantly slower growth of both cases and deaths, as compared to all other countries.
The preprint article, which is currently under review, builds on prior evidence that the BCG vaccination – typically given at birth or during childhood – offers a long-lasting protective effect not only against tuberculosis but also against various other infectious diseases.
BCG may be effective when a substantial proportion of the population is made resistant to a virus.
That is to say, the spread of the virus may be slowed only when there is “herd immunity” that prevents the virus from spreading easily across the population, said Martha Berg, the study’s lead author and a U-M psychology graduate student.
Berg and colleagues analyzed daily reports of confirmed cases and deaths during a 30-day period, modeling differences between growth curves in countries that have mandated BCG policies at least until very recently (such as Brazil, Ireland, France and India) and countries that do not (such as the U.S., Italy and Lebanon).
While the new report contributes to research involving TB vaccinations, it also noted some limitations; for example, some countries may have better quality data regarding the number of coronavirus cases and deaths than others.
In addition, since BCG is given early in life, it’s unclear whether the vaccination might be effective when given to adults nor how long it might provide immunity to COVID-19.
“Moreover, it is uncertain whether BCG might have any adverse effects when given to those already infected with COVID-19,” Berg said.
“There is an urgent need for randomized clinical trials.”
The study further observed that vaccination may be seen as a prosocial act. People who are not vaccinated can be protected as long as enough other people are, especially in the U.S., which does not mandate BCG.
“Cultural norms emphasizing prosocial interdependent orientations may prove to be crucial for the success of BCG in preventing future outbreaks of COVID-19,” Berg said.
The study’s co-authors are U-M psychology graduate students Qinggang Yu, Cristina Salvador and Irene Melani, and psychology professor Shinobu Kitayama.
In January, World Health Organization (WHO) Director General Tedros Adhanom Ghebreyesus said his “greatest concern” was COVID-19 spreading in countries with fragile health systems.
Although countries like India, Philippines, Sri Lanka, Cambodia, Thailand, Vietnam and Nepal have reported their first confirmed cases of the SARS-CoV-2 virus in January, widespread examples of community spread have not been reported.
In fact, contrary to such justified expectations/predictions, on March 13 2020, WHO declared that “Europe has now become the epicenter of the pandemic, with more reported cases and deaths than the rest of the world combined”.
Even though we are still in the midst of this novel coronavirus pandemic and the situation might drastically change in coming days, the disproportionately smaller number of cases reported from disadvantaged/low income countries remains puzzling.
We hypothesize that general BCG vaccination policies adopted by different countries might have impacted the transmission patterns and/or COVID-19 associated morbidity and mortality.
Ordinarily, a vaccine provides protection from a particular pathogen, by inducing effector mechanisms directed to that pathogen. However, certain live attenuated vaccines like the Bacillus Calmette–Guerin (BCG), an attenuated strain of Mycobacterium bovis, provide protection not only to a specific pathogen, but also against unrelated pathogens, some of which cause acute respiratory tract infections., , , , , , 
The underlying mechanism for the BCG vaccination-induced non-specific protection is thought to be mediated via the induction of innate immune memory, or “trained immunity, as was first proposed by Netea and collaborators.
Trained-immunity inducing agents reprogramme bone marrow hematopietic stem cells and multipotent progenitors through epigenetic and metabolic changes, resulting in a more robust response in differentiated innate immune cells, following encounter with a pathogen., 
Of interest, in a randomized placebo-controlled human study, BCG vaccination was demonstrated to induce epigenetic reprograming in monocytes, conferring protection against experimental infection with an attenuated yellow fever virus vaccine strain.
Based on these observations, we hypothesized that countries who continue BCG immunization programs would contain the spread of this new coronavirus better than those that did not have or have ceased their national BCG vaccination programs.
To check the validity of this hypothesis, we compared the number of cases and deaths per million people from 40 countries with at least 500 cases according to their BCG vaccination status (Figure 1 and Table 1 ).
Case numbers per million people in countries with a national BCG vaccination programme were statistically significantly lower than those that did not have or have ceased their national BCG vaccination programs (P<0.0001).
Since case numbers are dependent on SARS-CoV-2 testing capability of each country and might not be representative of the true extent of the regional epidemic, we also compared the number of deaths per million.
Results showed that COVID-19 associated deaths relative to the size of the population were statistically significantly lower in countries with a national BCG vaccination programme than those that did not have or have ceased their national BCG vaccination programs (P<0.0058).
The most affected country with the highest death toll was Italy, which historically never had a national BCG vaccination policy for all. Consistently, Italy also reports higher mortality rates compared to other countries.
|Countries with National BCG Immunization Coverage||Countries with no National BCG Immunization Coverage|
|Country||TotalCases||TotalDeaths||TotalCases/1M pop||Total Deaths/1M pop||Population||Country||TotalCases||TotalDeaths||TotalCases/1M pop||Total Deaths/1M pop||Population|
If BCG vaccination has a general non-specific protective effect against spread of SARS-CoV-2 or COVID-19-associated morbidity and mortality, then would BCG re-vaccination of populations offer a viable alternative of partial protection until a specific vaccine is available?
If this strategy is worthwhile, then there is the question of which BCG vaccine strain to chose. The BCG vaccine strains that are employed in the immunization programmes of different countries vary widely.
BCG vaccine was first introduced in 1921 and the initial seeds were distributed to various countries. During their serial passage, BCG strains accumulated genomic alterations, including deletions, single-nucleotide polymorphisms and duplications of genomic regions, leading to the emergence of several substrains.
Based on their tandem duplication variants (DU-2), BCG vaccines fall into 4 groups (Figure 2 ). The DU2-I and II group consists of geneologically “early” BCG vaccine strains, including, BCG Japan, BCG Russia and BCG Moreau/Brazil, whereas DU2-III-IV are considered as geneologically more distant “late” vaccines strains (like Pasteur, Denmark , Connaught strains).
The vaccine strains differ in terms of their growth characteristics, biochemistry, immunogenicity, and virulence. In contrast to early strains, the late BCG strains are defective in the production of cell wall methoxymycolic acids and possess only the alpha- and ketomycolic acids.
Consistent with this difference, early BCG strains persisted up to 6 months in the mesenteric lymph nodes of vaccinated children, whereas no live bacteria could be detected in late strain vacinees.
Similarly, methoxymycolate producing early strains were more potent immunostimulating agents than the late strains.
Mycolic acids can condition macrophages to produce higher levels of IFN-γ, myeloperoxidase and TNF-α upon renewed exposure to innate triggers.
Accordingly, mycolic acids constitute an important group of ligands capable of inducing trained immunity. In this respect, methoxymycolic acids were found to be inflammatory and to activate macrophages, whereas, keto mycolic acids promote anti-inflammatory, alternatively activated macrophages.
Therefore, since the persistence and immunostimulatory properties of BCG strains differ, their potential to induce trained immunity in vaccinated individuals could also hypothetically vary.
When we analyzed available data on BCG vaccine strains used in different countries (Figure 3 , modified from references 17 and 18), Iran and China, emerged as local producers of their own vaccines.
Although the vaccine strains used in these countries are not entirely clear, evidence suggests that the BCG vaccine strain in Iran is BCG-Pasteur 1173p2 and the one in China is a strain derived from Glaxo 1077, representing the most modified and highly attenuated strains deficient of methoxymycolic acids when compared to the Japan and Russia strains., 
It is conceivable that the trained immunity induced by the Iran and China BCG vaccine strains are short-lived compared to those conferred by the widely utilized older strains.
Herein, we hypothesize that, the lower than expected number of cases detected in countries in Asia and Africa with extensive travel and trade links with China might stem from the BCG immunization-induced heterologous protective activity of the vaccine.
The only way to test the validity of the hypothesis is to compare the epidemiological data from BCG vaccinated and unvaccinated populations throughout the course of this pandemic. Should this hypothesis hold its ground, then there would be important repercussions that could save lives.
Since BCG vaccination was previously demonstrated to prevent acute respiratory tract infections even in the elderly (5), until a specific vaccine is developed, SARS-CoV-2 vulnerable populations could be immunized with BCG vaccines. Such a strategy would also be suitable for frontline health personnel.
University of Michigan
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