Wenping Gong
Huiru An
Jie Wang
Peng Cheng
Yong Qi- 1Tuberculosis Prevention and Control Key Laboratory, Senior Department of Tuberculosis, The 8th Medical Center of People's Liberation Army (PLA) General Hospital, Beijing, China
- 2Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8th Medical Center of People’s Liberation Army (PLA) General Hospital, Beijing, China
- 3Huadong Research Institute for Medicine and Biotechniques, Nanjing, China
Introduction
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has inflicted an unprecedented and significant toll on global public health and the economy. During the fight against the pandemic, the century-old tuberculosis (TB) vaccine Bacille Calmette Guérin (BCG), which has been reported to protect against infections of various respiratory pathogens other than Mycobacterium tuberculosis by inducing non-specific immune responses, was found to play an essential role against COVID-19 in various ecological, analytical, and animal studies (1, 2). However, its effectiveness remains controversial due to the limited number of published clinical trials (2). The effect of BCG vaccines appears to be quite non-specific or speculative. Currently there is no clear or strong evidence to support the notion that BCG vaccination confer protection to COVID-19. In the absence of evidence, the World Health Organization (WHO) issued a Scientific Brief on April 12, 2020, against BCG vaccination to prevent COVID-19, and this recommendation has remained unchanged to date (3).
Non-Specific Immune Response Induced by the BCG
Our previous studies have reported that BCG vaccination could induce a non-specific immune response to fight against unrelated pathogens (2, 4–7). The non-specific immune response induced by BCG vaccination may be due to three potential mechanisms: trained immunity, heterologous immunity, and anti-inflammatory effect (2). Of the three possible mechanisms, trained immunity has received the most attention. Trained immunity is derived from immune memory in innate immune cells such as monocytes and macrophages. The primary immunization of BCG can activate innate immune cells to produce IL-1β, TNF-α, and IL-6, generating trained monocytes/macrophages with an “infection memory.” These trained monocytes/macrophages will respond rapidly by releasing higher levels of cytokines to combat the second unrelated pathogens’ invasion (8). The trained immunity induced by BCG has been demonstrated in both animal experiments and human clinical trials, and it may be beneficial for the prevention and treatment of SARS-CoV-2 infection (2, 4–7, 9–11).
Early Evidence on BCG Prevention of COVID-19
Early in the COVID-19 outbreak, the hypothesis that BCG could prevent COVID-19 infection was raised. Isabel N. Kantor was the first to publicly discuss whether BCG has preventive and protective effects against COVID-19 and how strong the association is between the “more BCG vaccination” and the “ less COVID-19 infection” (12). Then, the lead investigator of the BRACE trial (NCT04327206) and the BCG-CORONA trial (NCT04328441) as well as the Director General of WHO discussed this hypothesis, and they suggested that BCG might reduce viremia following SARS-COV-2 exposure, thereby reducing the severity of COVID-19 and recovering faster (13). Furthermore, Luke A. J. O’Neill and Mihai G. Netea claimed that the BCG vaccine might well be a bridge to a specific COVID-19 vaccine due to the trained immunity induced by BCG.
Although this hypothesis offered a glimmer of hope to the panicked and helpless people in the early days of the COVID-19 pandemic, it still needed a lot of evidence to prove it. In the early months of the COVID-19 pandemic, findings from the ecological and analytical studies indicated that countries with low BCG coverage had significantly higher rates of COVID-19 morbidity and mortality than countries with high BCG coverage (14–40). On the contrary, other ecological and analytical studies found that BCG vaccination could not provide adequate protection against COVID-19 infection (41–50). The results of these ecological and analytical studies were contradictory, and the heterogeneity of these findings may originate from some confounding factors, such as population density, ethnicity, age structure, income, healthcare access and quality index, COVID-19 transmission progression, COVID-19 testing rate, non-pharmaceutical interventions, and geographical distribution (2, 5, 51–53). Therefore, these findings should be investigated by randomized clinical trials.
Latest Evidence on BCG Prevention of COVID-19
Recently, results of a double-blind, randomized, placebo-controlled clinical trial (NCT04379336), which aimed to evaluate the efficacy of BCG vaccination in delivering protection against COVID-19 in healthcare workers (HCWs) in South Africa, were published in the journal eClinicalMedicine and attracted wide attention (54). The study reported that BCG revaccination failed to protect HCWs from SARS-CoV-2 infection, severe COVID-19, hospitalization, and respiratory tract infections (RTIs), on the contrary, resulting in an unexpected trend toward more symptomatic and severe RTIs. Nevertheless, it is plausible that BCG offered protection from death. The results indicated that BCG had no statistically significant effect on COVID-19, which in our opinion, maybe still controversial.
A large number of COVID-19 immune-tolerant rather than sensitive participants recruited in the study may have influenced or masked the true protective effect of the BCG vaccine. However, the COVID-19-seropositive population, with a rate of 15.3% resistant to COVID-19-related severe disease, were not excluded. Considering that M. tuberculosis-infected mice were resistant to secondary SARS-CoV-2 infection (48), it’s not inconceivable that the latent tuberculosis infection in the HCWs occupied 48.5% of all the participants might play resistant roles and influence the significant difference between groups. However, they were not excluded, either. More importantly, all the participants had previously received at least one dose of the BCG vaccine due to the vaccination policy of South Africa before the trial, which also could decrease the variation between the BCG revaccination and placebo groups. Interestingly, the only clinical trial to obtain results similar to this one also recruited volunteers who had received the BCG vaccine before in Poland (55), indicating the limitation should not be ignored.
Considering that many clinical trials began in the early days of the pandemic like this study, there must have been various drawbacks in their design due to the lack of understanding of the disease and its interaction with the BCG vaccine at that time. For instance, the BCG vaccination-caused scars would expose the participants’ group and make the double-blind experimental design impossible. Furthermore, the young and middle-aged participants being relatively more resistant to COVID-19 than older people may mask the real efficacy of the BCG vaccine. Here we summarize the designs, results, and deficiencies of all published clinical studies (Table 1) (55–59) and hope to provide helpful information for more clinical studies involving the efficacy of BCG vaccination against COVID-19 or other virus infections in the future. After all, though more than 50 clinical trials have been registered, results of less than ten clinical trials have been published so far (2).
Table 1 Summary of the designs, results, and deficiencies of all published clinical studies.
Conclusion
The hypothesis that BCG has a protective effect against COVID-19 has not been robustly verified. Therefore, the interpretation of any clinical trial results used to confirm this hypothesis should follow the principles of objectivity, science, and prudence. Considering the ongoing pandemic and the possibility of novel variants or other pathogens emerging, the potential effect of BCG on COVID-19 needs to be further confirmed in rigorous randomized clinical trials.
Author Contributions
Conceptualization: WG, YQ, and HA; Data curation: JW and PC; Formal analysis: YQ; Funding acquisition: WG; Methodology: HA, JW, and PC; Writing - original draft: WG and YQ; Writing - review and editing: HA, YQ, and WG. All authors contributed to the article and approved the submitted version.
Funding
This study was funded by the Beijing Municipal Science & Technology Commission (Grant No. 19L2065) and the Chinese PLA General Hospital (Grant No. QNC19047) to WG.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: BCG (Bacille Calmette-Guérin), COVID-19, Mycobacterium tuberculosis, clinical trial, hospitalization, protective effect
Citation: Gong W, An H, Wang J, Cheng P and Qi Y (2022) The Natural Effect of BCG Vaccination on COVID-19: The Debate Continues. Front. Immunol. 13:953228. doi: 10.3389/fimmu.2022.953228
Received: 26 May 2022; Accepted: 20 June 2022;
Published: 08 July 2022.
Edited by:
Julia Y. Wang, Curandis Inc., United StatesReviewed by:
Irina V. Kiseleva, Institute of Experimental Medicine (RAS), RussiaCopyright © 2022 Gong, An, Wang, Cheng and Qi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wenping Gong, Z3dwODkxMDE1QHdodS5lZHUuY24=; Yong Qi, cXNsYXJrQGdtYWlsLmNvbQ==
†These authors have contributed equally to this work