Abstract
Background : The Covid-19 pandemic is characterized by extreme
variability in the outcome distribution and mortality rates across
different countries. Some recent studies suggested an inverse
correlation with BCG vaccination at population level, while others
denied this hypothesis. In order to address this controversial issue, we
performed a strict epidemiological study collecting data available on a
global scale, considering additional variables such as
cultural-political factors and adherence to other vaccination coverages.
Methods : Data on 121 countries, accounting for about 99% of
Covid-19 cases and deaths globally, were from John’s Hopkins Coronavirus
Resource Center, World Bank, International Monetary Fund, United
Nations, Human Freedom Report, BCG Atlas. Statistical models were
Ordinary Least Squares, Tobit and Fractional Probit, implemented on
Stata/MP16 software.
Results : Countries where BCG vaccination is or has been
mandated in the last decades have seen a drastic reduction in Covid-19
diffusion (-80% on average) and mortality (-50% on average), even
controlling for relative wealth of countries and their governmental
health expenditure. A significant contribution to this reduction
(respectively -50% and -13% on average) was also associated to the
outbreak onset during summer, suggesting a possible influence of
seasonality. Other variables turned out to be associated, though to a
lesser extent.
Conclusions : Relying on a very large dataset and a wide array
of control variables, our study confirms a strong and robust association
between Covid-19 diffusion and mortality with BCG vaccination and a set
socio-economic factors, opening new perspectives for clinical
speculations, experimental studies and public health policies.
Keywords BCG vaccination, Covid-19, Probit fractional
regression, Tobit regression, Trained immunity.
Introduction
Since the novel coronavirus SARS-CoV-2 was initially detected in Wuhan,
China, in December 2019 (1) more than two million cases of Covid-19 have
been confirmed worldwide with a death toll about 140,000 by April 2020,
as reported by WHO
(https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200417-sitrep-88-covid-191b6cccd94f8b4f219377bff55719a6ed.pdf?sfvrsn=ebe78315_6).
One of the puzzles associated to the outspread of this pandemic is the
extreme geographic (2) and ethnical (3) variability of its outcomes,
both in terms of contagion and mortality with inevitable economic
implications (4).
We have witnessed an increased variance in fatality rates as more
countries were hit by the virus, generating a clustering of countries in
terms of incidence and mortality rates (MR), both across and within
affected continents. In Europe, for example, the case fatality rate
(CFR) is below or around 3%, such as Portugal, Ireland, Norway and
Finland, respectively with 3.45%, 3.79%, 2.35%, 2.35%, but much
higher with rates hovering around and above 10% in countries such as
Italy, Spain, UK, Sweden, with their respective rates of 13.19%,
10.48%, 13.41%, 10.59% (5).
Especially striking is the contiguity of countries (such as Portugal and
Spain, Ireland and UK, Norway/Finland and Sweden) where low and high
rates are respectively recorded. Moreover, eastern and south-eastern
European countries tend to belong to the first group of countries, those
with low incidence and mortality, and south and continental Europe
countries to the latter.
By and large, low- and middle-income countries in other continents
feature lower fatality and mortality rates, and lower incidence of the
epidemic. East Asian countries are characterized, on average, by lower
incidence and CFR, with an analogous variability in MRs, that results
even higher than the variability in CFR’s (5). It would thus be quite
important to understand the main drivers of that variability.
A controversial issue concerns the possible protective role of the
Bacillus Calmette–Guérin (BCG) vaccination, opening a still unresolved
debate regarding its impact on Covid-19 distribution in countries with
different BCG vaccination policies (6-11).
The protective effect of BCG on viral infections had been already
suggested by experimental trials, clinical reports and epidemiological
studies, and the biological mechanism is supported by different
hypothesis, that basically lie in the enhancement of the innate immune
response thru trained-immunity processes (12, 13).
The aim of this paper is to robustly investigate the role of BCG
vaccination on global incidence, CFRs and MRs of Covid-19 by using
linear and nonlinear statistical methods. In so doing, we account for
demographic, socioeconomic and health policy confounding factors which,
if not properly controlled for, might seriously impair the validity of
results and the implications for the following immunological and
clinical studies.