Vaccines 2022, 10, 1006. https://doi.org/10.3390/vaccines10071006 www.mdpi.com/journal/vaccines Review Fiction and Facts about BCG Imparting Trained Immunity against COVID-19 Gurpreet Kaur 1 , Sanpreet Singh 2 , Sidhanta Nanda 1 , Mohammad Adeel Zafar 1 , Jonaid Ahmad Malik 1 , Mohammad Umar Arshi 1 , Taruna Lamba 1 and Javed Naim Agrewala 1, * 1 Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar 140001, India; gurpreet.dipas@gmail.com (G.K.); sidhantananda23@gmail.com (S.N.); shaikhadeel143@gmail.com (M.A.Z.); junaidpsst@gmail.com (J.A.M.); md.umararshi@gmail.com (M.U.A.); lamba2414taruna@gmail.com (T.L.) 2 Immunology Laboratory, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology, Chandigarh 160036, India; sanpreet2488@gmail.com * Correspondence: jagrewala@iitrpr.ac.in Abstract: The Bacille Calmette-Guérin or BCG vaccine, the only vaccine available against Mycobac- terium tuberculosis can induce a marked Th1 polarization of T-cells, characterized by the antigen- specific secretion of IFN-γ and enhanced antiviral response. A number of studies have supported the concept of protection by non-specific boosting of immunity by BCG and other microbes. BCG is a well-known example of a trained immunity inducer since it imparts ‘non-specific heterologous’ immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus respon- sible for the recent pandemic. SARS-CoV-2 continues to inflict an unabated surge in morbidity and mortality around the world. There is an urgent need to devise and develop alternate strategies to bolster host immunity against the coronavirus disease of 2019 (COVID-19) and its continuously emerging variants. Several vaccines have been developed recently against COVID-19, but the data on their protective efficacy remains doubtful. Therefore, urgent strategies are required to enhance system immunity to adequately defend against newly emerging infections. The concept of trained immunity may play a cardinal role in protection against COVID-19. The ability of trained immunity- based vaccines is to promote heterologous immune responses beyond their specific antigens, which may notably help in defending against an emergency situation such as COVID-19 when the protec- tive ability of vaccines is suspicious. A growing body of evidence points towards the beneficial non- specific boosting of immune responses by BCG or other microbes, which may protect against COVID-19. Clinical trials are underway to consider the efficacy of BCG vaccination against SARS- CoV-2 on healthcare workers and the elderly population. In this review, we will discuss the role of BCG in eliciting trained immunity and the possible limitations and challenges in controlling COVID-19 and future pandemics. Keywords: Innate immunity; BCG; SARS-CoV-2; COVID-19; vaccines 1. Introduction Vaccines provide a long-lived pathogen-specific protective immunity. However, some vaccines, viz., influenza, oral polio, MMR (measles, mumps, rubella), smallpox, measles, BCG, etc., can also provide non-specific cross-protection against other patho- gens. The non-specific cross-protection against unrelated diseases has been described for other vaccines such as influenza, oral poliovirus, smallpox, and measles vaccines. These heterologous effects emerge from vaccine-induced immunomodulation. Various studies have shown non-specific protective effects after immunization with an unrelated vaccine or microbial antigens (Table 1). This de facto immunological memory occurs in innate im- Citation: Kaur, G.; Singh, S.; Nanda, S.; Zafar, M.A.; Malik, J.A.; Arshi, M.U.; Lamba, T.; Agrewala, J.N. Fiction and Facts about BCG Imparting Trained Immunity against COVID-19. Vaccines 2022, 10, 1006. https://doi.org/10.3390/ vaccines10071006 Academic Editors: Rafael Blasco, Javier Ortego and Alejandro Marin-Lopez Received:22 May 2022 Accepted:21 June 2022 Published: 23 June 2022 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institu- tional affiliations. Copyright: © 2022 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://cre- ativecommons.org/licenses/by/4.0/).