Is There a Rationale for Using Bacillus Calmette–Guerin Vaccine in Coronavirus Infection?

Abstract

Coronavirus disease 2019 (COVID-19) has become a global pandemic in 2020. The pathogen responsible for the COVID-19 has been found to be coronavirus (2019-nCoV) with human transmission through droplets, airway secretions, and even direct contact with host. Currently multiple drugs and their combinations are being tried for the treatment of the COVID-19 disease, but none approved. In absence of definitive and approved treatment, it is imperative that prevention of COVID-19 infection is of utmost importance. For the same, face masks, hand hygiene, isolation, and quarantine are being practiced all over the world. However much successful these methods be, they cannot be used for a very long time. Thus, it becomes necessary that a vaccine be developed for the disease so that the further spread could be halted. Some reports suggest the use of Bacillus Calmette–Guerin (BCG) vaccine as the prophylaxis for coronavirus. BCG vaccine is a live attenuated vaccine, used for prophylaxis of Mycobacterium tuberculosis and is present in the essential list of the World Health Organization as well as immunization programs of many countries. Immunostimulatory antiviral effects of BCG vaccine are well known. At present, there are no published evidence available to support the use of BCG vaccine for the prevention of coronavirus infection. However, there have been speculations on enhanced immunity with BCG vaccine, which might be useful in prevention of coronavirus infection. Results from the clinical studies of BCG vaccine in vulnerable population are required to confirm this hypothesis.

Introduction

Coronavirus disease 2019 (COVID-19) has become a global pandemic in 2020, afflicting over 216 countries with 11,125,225 confirmed cases, and 528,204 deaths across the globe (35). The pathogen responsible for the COVID-19 has been found to be the novel coronavirus (2019-nCoV) or severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) with its origin in bats (27). The pathogen has a human to human transmission and spreads via respiratory droplet infection. The disease presents with fever, malaise, respiratory symptoms such as cough, dyspnea, which may or may not progress to severe respiratory syndrome, pneumonia, multiorgan failure, or even death (36). Infection could happen in all age groups, however, severe COVID-19 disease happens more commonly in elderly (>60 years of age) as well as people with comorbid conditions such as diabetes, cancer, cardiovascular diseases, chronic respiratory diseases, and so on. Mortality rates of the disease may range from <1% in patients aged 20–54 years age group to 10–27% in patients aged >85 years (10).

Coronavirus is a single stranded RNA virus, first isolated in 1937. SARS-CoV-2 is one of the seven human coronaviruses identified. Others are HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, and MERS-CoV (Middle East Respiratory Syndrome Coronavirus). These coronaviruses are generally predominant among animals, with transmission between animal to human and rare human to human transmission. The latter is the method of spread in SARS-CoV-2 rendering the disease highly contagious (2). Prolonged aerosol exposure in a closed room might also contribute to the spread particularly in caretakers of the diseased, including the immediate family as well as the health care professionals (8). According to recent reports, among the confirmed COVID-19 cases, thousands of health care workers, including doctors and nurses, are included (32). This is despite following of WHO guidelines on minimizing the possibility of exposure of health care professionals, by using gloves, masks, gowns, glasses to prevent conjunctival exposure, other personal protective equipment, during patient care and during handling of biological specimens from these patients (37). Considering the gravity of this situation, the Indian Council of Medical Research has recently recommended the use of age-old antimalarial drug Hydroxychloroquine as prophylaxis of COVID-19 in health care workers and caretakers of the diseased (18).

The rapid rise in number of cases in a very short period further weakens the chance of discovering and approval of a new antiviral drug against COVID-19. Hence, many existing strategies and molecules such as Convalescent plasma therapy, Ribavirin, Interferons, Remdesivir, Favipiravir, Oseltamivir, Lopinavir-Ritonavir, Umifenovir, Favipiravir, Azithromycin, Vitamin C, Tocilizumab, Ivermectin, Anakinra, Corticosteroids, Chloroquine, and Hydroxychloroquine are being tried and prevention of infection to limit the spread is being focused upon. For the same, use of facemasks, hand hygiene, lockdown, isolation, and quarantine are being practiced all over the world (27). One of the other methods of prophylaxis is development and usage of a vaccine against the novel coronavirus. A development in this area is that after several potential candidates being tested in preclinical and in vitro studies, one of them, that is, mRNA-1273 vaccine manufactured by Moderna TX against the 2019-nCoV prevention has entered the Phase I clinical trials in 45 healthy volunteers. The mRNA-1273 is a novel lipid nanoparticle-encapsulated mRNA-based vaccine that encodes for a full-length, prefusion-stabilized spike (S) protein of 2019-nCoV. This vaccine is given as an intramuscular injection of 0.5 mL in two doses 28 days apart. All subjects will be followed up at regular intervals for a period of one year. While, this is undoubtedly a positive development in the fight against this serious problem, arrival of full-fledged effective and approved vaccine is a long haul (13).

In the meantime, considering the gravity of the situation, it becomes imperative to have as many effective options, so as to combat the spread and severity of COVID-19. In such a situation to look at the tried and tested existing options we have is a wise approach. One such option as suggested by experts from different countries is the use of Bacillus Calmette–Guerin (BCG) vaccine against 2019-nCoV (5,24).

Rationale Behind Choosing BCG Vaccine

BCG is a live attenuated vaccine, used for prophylaxis of Mycobacterium tuberculosis infection since the beginning of 20th century. It is a safe, cheap, and one the most widely used vaccines globally, with more than 4 billion BCG-vaccinated individuals worldwide (23).

BCG vaccine provides protection against disseminated tuberculosis (TB), tubercular meningitis, and military TB. Although the efficacy against preventing pulmonary TB is limited and range from 0% to 80%, BCG vaccination is a part of national health immunization of countries such as India, Brazil, Central and South America, Iran, etc. (16). The reason for this is that in various observational studies as well as randomized controlled clinical studies and meta-analysis, BCG vaccination has been shown to reduce neonate, infant, and overall childhood mortality rates. The amount of reduction varies according to different geographical locations and this benefit has been clearly shown to be not related to the reduction in occurrence of TB. The same has been explained to be due to some nonspecific immunostimulatory effects of BCG vaccine and hence enhanced responses to other infectious diseases, including a variety of viral infections (23).

Multiple in vitro studies have been performed to observe the effect of BCG vaccine for various viral infections. In vitro studies have shown that BCG vaccine has antiviral effects extending to both RNA and DNA viruses such as herpes virus and influenza virus. Various animal studies conducted in different mice models have shown that BCG vaccination protects from infection, enhances survival, delays occurrence of symptoms, or enhances immunological mechanisms in terms of increased antibody and interferon production, against a variety of viral infections such as Herpes Simplex 1 and 2, Influenza A, Hepatitis B, Japanese Encephalitis, Vaccinia, Ectromella, and Encephalomyocarditis virus (23).

BCG Vaccination and Prevention of Other Viral Infections: Clinical Evidence

Human trials showing the antiviral effects of BCG vaccination are limited. We have tried to summarize the key findings of such studies as given in Table 1.

Table 1.

Human Trials Showing the Antiviral Effects of Bacillus Calmette–Guerin Vaccination with Some Key Findings

S. No.	Title	Author and Year	Study design	Study results	Suggested mechanisms of benefits with BCG vaccine
1	Randomized trial of BCG vaccination at birth to low birth weight Children: beneficial nonspecific effects in the neonatal period?	Aaby et al. 2011 (1)	RCT, n = 2320, BCG versus control	17%↓ in IMR 45% ↓ in NMR, 57% ↓ in IMR in LBW (<1.5 g)	• Fewer cases of neonatal sepsis, respiratory infections and fever • Enhanced innate immunity generating an effective response to infectious agents • Stimulation of toll like receptor-4 • Control of excess inflammation
2	Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls community bases case control study	Stensballe et al. 2004 (30)	Case control study, n = 772	OR = 2.87 (boys), OR = 4.45 (girls) in ALRI BCG unvaccinated infants	• Nonspecific protective effect against ALRI caused by RSV
3	The efficacy of Bacillus-Calmette Guerin Vaccinations for prevention of acute upper respiratory tract infection in elderly	Wardhana et al. 2011 (33)	Prospective, RCT, age = 60–75 years, BCG (0.1 mL) versus PBO once a month for 3 months, n = 34, Duration = 6 months	Reduced rate of AURTI in control versus BCG, Significantly higher levels of IFN-γ and IL-10 in BCG versus Control	• Higher rate of infections in control group due to insufficient IFN-γ levels in Control group.
4	Treatment of common and plane warts in children with topical viable Bacillus-Calmette Guerin	Salem et al. 2012 (26)	RCT, n = 80, age = 3–14 years, Viable, topical paste of BCG versus saline, once weekly for 12 weeks	Complete response in 65% cases having common Warts, Complete Response in 45% cases having plane Warts	• Activation of CD4+ Lymphocytes • ↑ in IL-1 • ↑ in IL-2 • ↑ in TNF-α
5	Nonspecific effect of Bacillus Calmette-Guerin vaccine on the immune response to routine immunizations	Ritz et al. 2013 (25)	Non RCT, n = 126, age = infants >35 weeks, BCG administered versus non-BCG administered	Increase antibody response to pneumoccal, tetanus, hemophilus influenza vaccines Decrease antibody response to Hepatitis B vaccine	Nonspecific protective effect against infections.
6	Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis.	Decastro et al. 2015 (9)	Retrospective epidemiological study, hospital admission rates of BCG-vaccinated children versus non-BCG vaccinated, n = 464,611	Total preventive factor was 41.4% of BCG vaccinated children versus that of non-vaccinated.	BCG alters the immune response to nontuberculous pathogens.
7	BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza vaccination in healthy volunteers: A randomized, placebo-controlled pilot study.	Leentjens et al. 2015 (20)	RCT, n = 40, healthy volunteers, BCG versus PBO	Enhanced innate immune responses Enhanced functional antibody responses against H1N1	Immunostimulatory effect of BCG vaccine on cytokine production
8	BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity.	Arts et al. (4)	RCT, BCG vaccine versus PBO	Reduction in viremia (attenuated yellow fever virus), increase in Interleukin 1b	Immunostimulatory, increase in IL-1β and trained immunity

ALRI, acute lower respiratory infection; AURTI, acute upper respiratory tract infection; BCG, Bacillus Calmette–Guerin; IFN, interferon; IL, interleukin; IMR, infant mortality rate; LBW, low birth weight; NMR, neonatal mortality rate, randomized trial; OR, odds ratio; PBO, placebo; RCT, randomized controlled trial; RSV, respiratory syncytial virus; TNF-α, tumor necrosis factor-α.

Proposed Immunomodulatory Mechanisms Responsible for the Antiviral Effects of BCG Vaccine

Induction of heterologous lymphocyte response which in turn increases immune response of body to unrelated infection resulting in an increased production of interferon gamma (IFN-γ) by the CD⁺4 cells (17,21). It has been reported that further to BCG vaccination in murine models as well as human infants, enhanced proliferation of lymphocytes, increased production of IFN-γ, interleukin (IL)-5, IL-13, IL-17, IL-22 from CD⁺4 memory T cells, and peripheral blood mononuclear is seen, in response to various viral and bacterial infections (7).

BCG vaccination may also modulate cytotoxic T-lymphocyte subsets such as Th1, Th17, and Th22 responses via activation of CD⁺4 and CD⁺8 cells (24,29). Increased production of IL-2 and enhanced proliferation of CD8⁺ Bordetella pertussis-specific T cells have been reported further to BCG-vaccination in human immunodeficiency virus-exposed South African human infants (7).

Trained/nonspecific immunity: Further to BCG vaccination, there is a functional modification of innate immunity system, such that on any secondary infection an effective heterologous response is initiated. There is induction of immunological memory in immune cells such as natural killer cells, myeloid cells such as monocytes and macrophages that form a part of innate immunity, and increased proinflammatory cytokine-mediated responses (15,19). The same has been explained by transcriptional and epigenomic revamping of the hematopoietic stem and progenitor cells of bone marrow for myelopoiesis. This trained immunity response further to BCG vaccination has been shown in clinical studies conducted in BCG-vaccinated newborn human infants who show an increase in neutrophil count and peripheral blood mononuclear cells further to nonspecific bacterial and fungal infections, for a period until few months (11).

Increase in proinflammatory cytokines such as i IL-1β and tumor necrosis factor-α may lead to better clinical outcome with viral infection. This was seen in a study that used live attenuated yellow fever vaccine in human volunteer to resemble viral infection. They observed decreased viral load compared to placebo in patients who were vaccinated with BCG vaccine (4).

Understanding the Role of BCG Vaccine in Coronavirus Infection

Having seen convincing evidence illustrating the nonspecific immunomodulatory benefits of BCG vaccine and understanding the current burden of the pandemic of COVID-19 in terms of large number of new cases as well as mortality, a try-out of BCG vaccine as an immunity booster seems worth considering. BCG vaccine being made from a weakened strain of Mycobacterim bovis, makes understandable, that it is not a targeted vaccine for specific coronavirus infection prevention, but might have some role in improving the health of vulnerable population like elderly and comorbid diseased states. In a reported study, it has been shown that middle- and high-income countries that withdrew BCG vaccination from their national policy, on account of decline in rate of TB infection, suffered from increased morbidity and mortality in elderly due to COVID-19 infections, compared to lower, middle, as well as higher income countries that retained BCG vaccination policies (22).

Another such high vulnerability is implied to health care workers too, who are also the most valuable resource for combating this pandemic at present. The reasons why health care workers are more at risk is because they are more exposed to virus particles during management and procedure such as intubation, resuscitation, ventilate, and so on. Abundant stress and long working hours might also make their immune system more vulnerable than others. Considering all these points, scientists in different nations, Australia, United Kingdom, Germany, Netherlands, and India, have announced initiation of clinical trials for testing BCG vaccine in health care professionals like doctors, nurses, and population at high risk of getting coronavirus infection like relatives of diseased and elderly too (12). For the utmost priority of maintaining continuous patient care, availability, well-being, and health of front-line warriors, the health care workers, is a priority. In an ongoing clinical trial, a lower work absenteeism rate in health care workers directly taking care of corona virus diseased patients further to administration of BCG vaccine is being studied (14).

It is very early to comment about what should be the effective dose and dosing regimen of BCG vaccine for COVID-19 infection prevention, and whether the vaccine should be more effective and safe as multiple dosing or a single dose, as seen in the scenario of BCG vaccine usage in superficial bladder cancer and type 1 diabetes (6). Also, currently over a dozen licensed formulations of BCG vaccine are available in the market. Variations in manufacturing processes of different attenuated strains of Mycobacteria might alter not just the clinical efficacy but also the induced intensity of immunological response. Furthermore, well designed clinical trials are needed to address these issues and generate robust evidence of BCG vaccine in COVID-19 disease.

Furthermore, a rush into the usage of BCG vaccine in COVID-19 disease, without assessing the results of rationally designed randomized controlled clinical trials, might pose a risk of exhaustion of the existing supply of BCG vaccine for its approved uses such as TB prevention in neonates (3).

Based on the review of existing evidence, the hypothesis is such that a boosted immunity with the help of BCG vaccine might not just help in preventing infection but might also play a role in preventing serious COVID-19 (28).

Safety of BCG Vaccine

BCG vaccine has been used for variety of indications, including protection from infectious and noninfectious disease, as a treatment option in bladder cancer, suggested treatment option for type 1 diabetes mellitus, allergies, multiple sclerosis, and also as diagnostic tool in Kawasaki disease. Intradermal BCG vaccination has been conducted over a very long time and has quite a well-established safety profile. BCG administration leads to formation of a red, tender papule, which indurates and forms an ulcer in due course. The ulcer later heals forming a scar. The reactivation of erythema, a form of delayed hypersensitivity reaction, in this BCG vaccination site is considered a diagnostic tool for Kawasaki Disease (38). Well-known local injection site side effects as well as systemic manifestations of a “flu-like” syndrome such as fever, anorexia, myalgia, and neuralgia might occur. Lymphadenitis and rarely suppuration and fistulae formation, BCG immune reconstitution inflammatory syndrome, and eye problems, including uveitis, optic neuritis, and lupus vulgaris, have been reported. BCG being a live attenuated vaccine is contraindicated in impaired immunological responses such as HIV infection, severe combined immunodeficiencies, chronic granulomatous disease, any malignancy such as leukemia and lymphoma, and immunodeficient states such as long-term administration of steroids, radiation, and anticancer chemotherapy for the risk of causing disseminated infection (34).Therapeutic use of intravesical BCG vaccine in superficial bladder cancer has also been associated with systemic side effects and rarely asymmetric reactive arthritis of larger joints is reported (38). BCG vaccination is also not recommended during pregnancy and lactation, however, its harms to the fetus and newborn is not known. A thorough evaluation of intact immune system of elderly patient is to be conducted before BCG vaccine administration (31).

Conclusion

BCG vaccine has been in use for decades for prophylaxis of TB. There is convincing preclinical evidence as well as human studies that show the immunostimulatory antiviral effects of the vaccine. Although there is lack of both preclinical and clinical studies with the use of BCG vaccine as treatment or as prophylaxis for COVID-19 at present, and it might not eliminate or prevent the infection, it might offer some heterological enhanced nonspecific immunity by induction of lymphocyte response and cell mediated as well as innate immunity against coronavirus infection. This approach might help the vulnerable population and at the same time buy some time until the specific vaccine finishes Phase 3 clinical trials and becomes available to the population. Results from the clinical studies of BCG vaccine in vulnerable population are required to confirm this hypothesis.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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