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.