Niti K Vora1, Priya N Shah2, Darshini H Vora3, Sonia A Amin4, Nisha K Vora5, Eshan V Prasad6, Akshat T Parekh7*
1Medical Associates of Marlboro, USA
2Rutgers School of Dental Medicine, USA
3The Zucker Hillside Hospital, USA
4University at Buffalo, USA
5Drexel University, USA
6Elon University, USA
7Rutgers Robert Wood Johnson Medical School, USA
*Corresponding author: Akshat T Parekh. Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane West Piscataway, NJ 08854, USA.
Submission: April 04, 2020;Published: April 21, 2020
Volume3 Issue4April, 2020
Bacille Calmette-Guérin (BCG) vaccine is part of the routine vaccination schedule in most developing countries where tuberculosis (TB) and leprosy are highly endemic. The ongoing global pandemic of COVID-19 demonstrates low levels of COVID-19 mortality / Infections ratio [of ≤ 3.2 %] in countries [Japan, India, and Brazil] that have had at least an 80-year policy of BCG vaccination of newborns. Contrarily, the top three countries [USA, Italy, and Spain], together represent > 50% of COVID-19 related infections and deaths [and death/infection ratio of ≥ 8.6%]. These countries had scattered, late, or no implementation of the BCG vaccination. Furthermore, they showed a higher rate of COVID-19 related infection [≥ 60 times], and related death [≥ 160 times] when compared to BCG vaccinating countries. Thus, given the ability of the BCG vaccine to protect adults against respiratory and various viral infections, it appears to protect against COVID-19 as well. Prior studies suggest that the trained immunity of the innate immune system may be the underlying mechanism of this BCG related protection. Socioeconomic, political, and cultural factors also contribute to the variations in COVID-19-related pandemic, infections, and deaths. The aforementioned correlation mentioned above with the BCG vaccination and COVID-19 pandemic merits reevaluation of its usage in the USA and other Western countries.
Keywords: COVID-19, BCG, Trained Immunity, Lessons learned
Recent advances in trained immunity have unveiled an essential and previously unsung property of human immune responses . Trained immunity involves metabolic and epigenetic reprogramming of the innate immune response to pathogens, including viral infections. The innate immune cells adjust to time-delayed heterologous stimulation of trained immunity of various epitopes . Briefly, vaccination of any foreign epitope primes and activates the innate immune system via histone modifications and functional reprogramming of cells, which include macrophages, monocytes, and natural Killer (NK) cells. This phenomenon is termed “trained immunity” or “innate immune memory,” or is a de facto innate immune memory .
COVID-19 is caused by severe acute respiratory syndrome triggered by Coronavirus-2 (SARS-CoV-2). The virus attaches to angiotensin-converting enzyme 2 (ACE2) on cells of the lungs and heart tissues, thereby causing respiratory illness . More than 50% of deceased patients are over the age of 60 years with various comorbidities including hypertension, heart disease, cerebrovascular disease, diabetes, and cancer . The primary symptoms of COVID-19 are loss of smell and taste, fever, cough, and fatigue. Eventually, respiratory failure and sepsis syndrome/multiple organ failure remain the leading causes of death .
Hypothesis and background
Bacille Calmette-Guerin (BCG) vaccination induces trained immunity towards COVID-19 and mitigates the severity of COVID-19 symptoms.
More than 30% of people in the world suffered from tuberculosis (TB) in the early 1900s, and 1 in 7 lost their lives to TB . A BCG vaccine was developed in 1920 using an attenuated strain derived from an isolate of Mycobacterium bovis. This vaccine protected individuals from tuberculosis for a short period. It is not surprising that the BCG vaccination policy was discontinued in most western nations due to the vaccine’s low efficacy, failed vaccine batches (such as the Lübeck disaster of 1930), and the risk of developing mycobacterium infection . Recently, the long term, heterologous, and non-specific protective effects of the BCG vaccine against other diseases, viruses, and reduction in the neonatal mortality rate have been recognized . Furthermore, the BCG vaccination in Africa has shown a significant (≥ 50%) decrease in respiratory viral infections and mortality . In India, complete clearance of viral warts in ~50% of BCG vaccinated individuals was observed . A safe and efficient BCG vectored vaccine (rBCG-N-hRSV) against the Respiratory Syncytial Virus (RSV) has shown promising results with increased levels of IFN-g, which in turn, attenuates the RSV induced inflammatory events in newborns. BCG vaccination displayed beneficial effects against complex diseases such as allergy asthma, multiple sclerosis, and diabetes . Furthermore, BCG based immunization exhibited resistance to several types of viruses (e.g., Herpes type 1 and 2, Yellow Fever Virus, Influenza A viruses, Metapneumovirus) in animal or human studies [9,10]. The mechanism of action of BCG is attributed to an increase in IFN-g production by CD4 T-cells to heterologous antigens. Thus skewing Th1 responses and modulating the immune responses by induction of T regulatory cells . Furthermore, functional responses of innate cells were changed, leading to an increased cytokine production (IL-6, IL-1b, and TNFa) in response to a secondary stimulus. This phenomenon, also termed as innate memory, is derived from NK cells, monocytes, and macrophages . These innate memory responses trained by BCG immunization may contribute to an improved clinical outcome for secondary viral infections .
Recently, data from a preprint health sciences server, medΧRiv publication by Miller et al. , has speculated that heterogeneity in COVID-19 pandemic, morbidity, and mortality may partially be attributed to the policy of BCG vaccination in different countries. Fifty-five countries that currently have a universal BCG vaccination policy had an average of 0.78 ± 0.40 COVID-19 deaths per million people . These numbers keep on changing with the progression of the pandemic. Currently, more than 1.4 million people are infected by COVID-19, resulting in over 80,000 deaths. As of April 19, 2020, we compared the data between the top three countries (USA, Italy, and Spain), which represented > 50% of global infections and deaths. USA, Italy, and Spain were designated as Group 1 and compared with their respective BCG vaccinations programs (Table 1). Group 2 represented Japan, India, and Brazil, which exercised BCG vaccination policy equal or prior to 1947. We examined their current status with COVID-19 infections and related deaths in Table 1 and [13,15]. The pandemic of COVID-19 is seen in all the five continents . The total worldwide infection was 1,436,198 which resulted in the mortality of 11 people per million. The global death per infection percentage was 5.95%. The Group 1 countries showed high levels (mean 2,212.6 ± 974.6 per million) of COVID-19 infected individuals. There was an increase in COVID-19 related deaths (mean 214.0 ± 152.2 per million) in Group 1. The average death per infection percentage in Group 1 was 8.61%. USA, Italy, and Spain never applied a universal BCG-vaccination policy in newborns or were delayed in implementing the BCG vaccination policy (Table 1). The low number of COVID-19 infections (mean 35.5 ± 30.3 per million) were observed in Group 2 countries. The Group 2 countries showed a reduced mortality rate (mean 1.3 ± 1.6 per million) of COVID-19 related deaths. It should be noted that the percent of COVID-19 related deaths per infection in Group 2 countries was 3.18%, which is less than the average global fatality rate (5.95%).
Table 1: Comparison of BCG Vaccination Commencement to COVID-19 Related Infections and Deaths
*Ceased in 1981
Modified from Zwerling [5,13] and Coronavirus Disease 2019 (COVID-19) Situation Report-80, 2020 . Data was recorded on April 19, 2020, and significance levels were calculated using the student’s t-test where n = 3, mean ± SD, and p ≤ 0.05 was considered as significant.
The COVID-19 associated infections in Group 1 countries, were significantly ( p ≤ 0.009) higher than Group 2. The COVID-19 related deaths in Group 1 nations were significantly (p ≤ 0.035) higher than those observed in Group 2. There was a direct correlation between the (high or low) rates of COVID-19 infections and deaths in countries that exercised pre- or post-1947 BCG vaccination programs. The mean rate of COVID-19 infection and related deaths in Group 1 nations as compared to Group 2 nations was ≥ 60 and ≥ 160 times higher, respectively.
These mystifying differences in COVID-19 related infections and deaths have been adjudicated to different policies in BCG vaccinations, cultural norms, medical facilities, national policies in combating the COVID-19 pandemic, immigrants from countries that practice policies of BCG vaccinations, and differences in medical care standards . For example, India has a population of over one billion and has had a BCG vaccination policy since 1947 . A nationwide clampdown in India, social distancing and technology based tracking of “hot spots” currently exhibits a COVID-19 infection and death rate lower than Spain, Italy, and the USA; the three countries affected the most by the COVID-19 pandemic . This observation suggests that irrespective of the variables described above, BCG vaccination may be one of the factors that may reduce viral infections and/or mortality rates associated with COVID-19. It has been demonstrated that trained immunity associated with BCG vaccination protects against bacterial infections, viral infections, and sepsis; therefore, BCG vaccination could provide indirect beneficial effects on COVID-19 . These observations may gain further validation when COVID-19 related mortalities in the USA are further evaluated against immigrants vaccinated with BCG. The above hypothesis is currently being tested in three randomized controlled trials using BCG vaccination. The first clinical trial aims to address how fast a protective COVID-19 immune response may develop . Investigators at Murdoch Children’s Research Institute in Australia are currently conducting a randomized, multi-center clinical trial to test the BCG vaccine against COVID-19 in 4000 healthcare workers and mitigate the severity of COVID-19 symptoms. It is based on the hypothesis that BCG reduces the level of several types of viruses, including those that are similar to SARS-CoV-2 [9,17]. The primary objective of the second clinical trial is to examine if BCG vaccination can reduce absenteeism among healthcare workers who are directly in contact with COVID-19-affected patients during the epidemic phase . The secondary objective is to reduce the severity of symptoms, hospital/ICU admissions, and/or death in healthcare workers with direct patient contact during the epidemic phase of COVID19 . The third clinical study involves VPM1002, a weakened but safe tuberculosis-like bacteria similar to BCG from scientists at the Max Planck Institute. It will be tested against SARS-CoV-2. The study is in the planning stages .
Lessons and recalibration from the COVID-19
A recent article by Pisano et al., 2020 used Italy’s response to COVID-19 to identify barriers and deficiencies that contributed to the country’s current status of having the most COVID-related deaths. The article highlights the detrimental effects of cognitive biases, which delayed both the government and public response and contributed to a series of partial solutions and a failure to adopt interventions from countries with improved containment . Until February 2020, COVID-19 was perceived as a “China problem,” contributing to public officials and media outlets downplaying the severity of the pandemic and conservative approach to containment . Even as the epidemic proceeded, North American & European countries were slow to adopt social distancing measures and travel limitations compared to Asian countries such as Singapore, South Korea, and Hong Kong . The United States does not currently support BCG vaccination . BCG-vaccination is frequently associated with countries where tuberculosis and leprosy remain a threat . However, suspension of prior biases and learning from our Asian counterparts, who have been more successful in disease containment, is required to combat this pandemic. Thus, BCG vaccination policy must be reevaluated to reduce overall mortality in future pandemics like COVID-19.
In summary, the hypothesis that BCG vaccination can reduce fatal infections by protection against heterologous or unrelated pathogens due to trained immunity will be tested epidemiologically and clinically during the current COVID-19 pandemic and the clinical trials described below while some countries such as India, Brazil and the UK have already implemented the combination use (of antimicrobial and antiviral activities) of Azithromycin and hydroxychloroquine for the intervention of COVID-19, other countries like the USA have recently added this intervention to evaluate its efficacy in New York City which is a “hot spot” of COVID-infections in the USA. A booster dose of the BCG vaccine in the fifty-five countries where there is a national policy of childhood vaccination could be recommended due to the safety record of the vaccine . This vaccine may recall and augment the functions of the trained innate immune cells, protecting against viral infections in the lung. Since each country faces its own set of challenges such as culture, access to medical facilities, and national preparedness, evaluation of their problems and recalibration of their responses to this virus need to be individualized.
© 2020 Akshat T Parekh. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and build upon your work non-commercially.