key: cord-270675-37kus7mz authors: Aziz, Asma Binte; Dembinski, Jennifer L.; Jahan, Yasmin title: Debate on Bacille Calmette-Guérin vaccination against COVID-19: Is it worth performing clinical trials? date: 2020-07-09 journal: Biosaf Health DOI: 10.1016/j.bsheal.2020.07.001 sha: doc_id: 270675 cord_uid: 37kus7mz The non-specific beneficial effects of Bacille Calmette-Guérin (BCG) vaccination suggest that this vaccine might play a role in protecting individuals against severe coronavirus disease (COVID-19).Several studies propose that BCG vaccination may increase the body's immunity, thereby preventing respiratory infections caused by other respiratory pathogens. As the number of deaths due to COVID-19 is increasing rapidly and there is no specific treatment available to date, scientists are evaluating the effectiveness of already approved drugs as therapies against COVID-19, and the results were found to vary widely: from no significant effect being observed to a reduction in the time taken for clinical improvement. This study thus aims to evaluate whether it is worth performing clinical trials to examine the effects of the BCG vaccine on COVID-19. We herein emphasize the need to conduct phase III randomized controlled trials with an adequate sample size and quality to investigate the effects of the BCG vaccine on COVID-19. In the event that BCG vaccination provides non-specific protection against COVID-19, administering it could be helpful in controlling the transmission of COVID-19 and other infectious diseases during future pandemics. J o u r n a l P r e -p r o o f vaccination [4] . Therefore, these non-specific beneficial effects of BCG vaccination suggest that the vaccine could play a role in protecting individuals against severe coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [5] . In March 2020, the World Health Organization declared COVID-19 a pandemic as it had spread to more than 210 countries and territories. The existing healthcare systems of even some of the most developed countries failed to control the disease. Although the SARS-CoV-2 virus mostly causes fever and cough in affected individuals, it can lead to fatal respiratory symptoms in severe cases. Further, no approved treatment for COVID-19 is available to date. The number of deaths from COVID-19 continues to increase rapidly, prompting scientists to discover an easy curative or preventive intervention that can have an instant global impact by saving thousands of lives. Evaluating the effectiveness of already approved drugs as therapies against COVID-19 is one of the strategies currently employed in this regard. The results published vary widely and range from no significant effects being observed to results indicating a reduction in time for clinical improvement [6] . Therefore, this manuscript aims to evaluate whether performing clinical trials to examine the efficacy of BCG vaccination against COVID-19 is worthwhile. Once researchers observed higher frequencies of cases of and mortalities from COVID-19 in certain countries than in others [7] , a debate on the efficacy of the BCG vaccine sparked. Scientists then compared data from countries with and without mandatory BCG vaccination policies in their routine immunization programs in an attempt to account for this difference. In a paper published in JAMA, Hamiel et al. analyzed data from Israel, where BCG vaccination was part of routine immunization until 1982. The results of the analysis did not support the theory that BCG vaccination in childhood had a protective effect against COVID-19 in adulthood. However, the investigators of the study did not reach any conclusion about the association between BCG vaccination status and the severity of COVID-19 due to few number of severe cases [8] . Moreover, researchers also noticed a trend of slower transmission of the virus in countries with a national vaccination policy that requires BCG vaccination [9] . Another study found that the incidence and mortality rates were significantly lower among residents of countries with current universal BCG vaccination policies than in residents of countries without or with discontinued BCG vaccination policies [10] . Nevertheless, it is unclear whether BCG vaccination can decrease COVID-19 incidence. Additionally, although these results show interesting trends, they are J o u r n a l P r e -p r o o f prone to significant bias because of the presence of confounders such as unknown vaccination status [8] and inconsistences in testing rates and reporting between countries [11] . Therefore, it is difficult to draw any conclusion about the efficacy of the BCG vaccine against COVID-19 without conducting further controlled clinical trials. A controlled study to evaluate the efficacy of BCG vaccination in protecting against COVID-19 is warranted for several reasons, the most important of which is the non-specific b. BCG vaccination has been found to decrease the risk of pneumonia in people aged >65 years who have comorbidities, and it was also found to significantly prevent acute upper respiratory tract infections [13] ; c. BCG vaccination shows enhanced immunogenicity in response to the A(H1N1) strain of the 2009 pandemic trivalent influenza vaccine but not to the A(H3N2) and A(H7N9) vaccine strains, for unknown reasons [14] d. BCG vaccination has reduced viremia following yellow fever infection, which is correlated with IL-1b production [15] . These findings suggest that as the BCG vaccine exerts non-specific effects on cytokine responses following infection by some unrelated viral pathogens, it may be able to increase the body's immunity, resulting in the prevention of respiratory infections caused by other pathogens. Finally, in addition to the Phase III trials that are currently underway, more RCTs with adequate sample size and quality could be conducted to investigate the effects of BCG vaccination against COVID-19. Given the limited production of the BCG vaccine, scientists could also consider initiating studies using new TB vaccine candidates that are in Phase II of clinical trials and have been shown to confer an immunity similar to that conferred by the traditional BCG vaccine [16] . In the event that any of those vaccines provide non-specific protection, they may be used to bridge the gap before a COVID-19-specific vaccine is developed, which could be a significant means to control the transmission of COVID-19 and similar infectious diseases during future pandemics. History of BCG Vaccine Trained Immunity-Based Vaccines: A New Paradigm for the Development of Broad-Spectrum Anti-infectious Formulations Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity Considering BCG vaccination to reduce the impact of COVID-19. The Lancet Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults. JAMA, e208189. Advance online publication Covid-19: what treatments are being investigated Exercising caution in correlating COVID-19 incidence and mortality rates with BCG vaccination policies due to variable rates of SARS CoV-2 testing Is BCG vaccination causally related to reduced COVID-19 mortality? Non-specific effects of BCG vaccine on viral infections. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of New live attenuated tuberculosis vaccine MTBVAC Journal Pre-proof J o u r n a l P r e -p r o o f None The authors declare that there are no conflicts of interest.