key: cord-0784941-uei9zw6q
authors: Gursel, Mayda; Gursel, Ihsan
title: Is Global BCG Vaccination Coverage Relevant To The Progression Of SARS-CoV-2 Pandemic?
date: 2020-04-06
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.109707
sha: 71086ed3550e091de785138cbe73a343bd0f9dc4
doc_id: 784941
cord_uid: uei9zw6q

The lower than expected number of SARS-CoV-2 cases in countries with fragile health systems is puzzling. Herein, we hypothesize that BCG vaccination policies adopted by different countries might influence the SARS-CoV-2 transmission patterns and/or COVID-19 associated morbidity and mortality through the vaccine’s capacity to confer heterologous protection. We also postulate that until a specific vaccine is developed, SARS-CoV-2 vulnerable populations could be immunized with BCG vaccines to attain heterologous nonspecific protection from the new coronavirus.

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. [1] [2] [3] [4] [5] [6] [7] 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. 8 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. [8] [9] 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. 10 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. 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 revaccination 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. 11 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). 11 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. 12 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. 13 Similarly, methoxymycolate producing early strains were more potent immunostimulating agents than the late strains. 14 Mycolic acids can condition macrophages to produce higher levels of IFN-γ, myeloperoxidase and TNF-α upon renewed exposure to innate triggers. 15 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. 16 Therefore, since the persistence and immunostimulatory properties of BCG strains differ, their potential to induce trained immunity in vaccinated individuals could also hypothetically vary. representing the most modified and highly attenuated strains deficient of methoxymycolic acids when compared to the Japan and Russia strains. [19] [20] 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. 

Nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges

BCG vaccination scar associated with better childhood survival in Guinea-Bissau

Acute lower respiratory infection among

Bacille Calmette-Guérin (BCG)-vaccinated children

Nonspecific (Heterologous) Protection of Neonatal BCG Vaccination Against Hospitalization Due to Respiratory Infection and Sepsis

The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly

Systematic review of the non-specific effects of BCG, DTP and measles containing vaccines

Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomizedcontrolled trial

Trained immunity: a memory for innate host defense

Non-specific effects of BCG vaccine on viral infections

BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

Genome plasticity of BCG and impact on vaccine efficacy

A point mutation in the mma3 gene is responsible for impaired methoxymycolic acid production in Mycobacterium bovis BCG strains obtained after 1927

Sur la vitalite´ du BCG dans l'organisme vaccine´

Comparable studies of immunostimulating activities in vitro among Mycobacterium bovis bacillus Calmette-Guérin (BCG) substrains

The Mycobacterium tuberculosis cell wall component mycolic acid elicits pathogen-associated host innate immune responses

Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern

Mapping the global use of different BCG vaccine strains. Tuberculosis (Edinb)

The BCG World Atlas: a database of global BCG vaccination policies and practices

Bacillus Calmette-Guerin (BCG) vaccine in

An Overview of Coverage of BCG Vaccination and Its Determinants Based on Data from the Coverage Survey in Zhejiang Province

We thank Dr. Ihsan Cihan Ayanoglu for performing statistical analysis of the data.

Conflicts of Interest: The Authors declare no conflicts of interest