Repurposing BCG and MMR Vaccines for Combating COVID-19: A Review and Opinion Based on Clinical Evidence

Abstract

Our review comprehends past and recent developments encircling the two vaccines, BCG and MMR, which have efficacy lasting 10 years and are known to trigger the production of Interferon and various cytokines. BCG has depicted long-lasting effects, reduction in mortality, and hospitalizations associated with various diseases in different age groups as per studies across Sweden, West Africa, Spain, and Indonesia. Clinical trials are in progress in Holland, Australia, and Germany to study its effects on COVID-19. Most Asian countries with childhood BCG vaccination programs have shown lower COVID-19-related per capita death rates. The MMR vaccination has shown a reduction in hospitalizations and COVID-19-related deaths in about 11 countries, and a randomized clinical trial has been proposed in New Orleans. Reasons such as inhibition of pulmonary inflammation and structural similarity have been cited for such consequences. BCG and MMR may serve to shorten the duration of infection, minimize harmful pathology, reduce hospitalization rates, and curb the spread of the disease, but more research is required to assess the associated risks, especially for the elderly and people with comorbidities who are prone to severe complications of COVID-19.

1. Introduction

Ever since the coronavirus disease (COVID-19) emerged, there has been an onset in development of multiple vaccine candidates across the globe. On the one hand, scientists are developing specific vaccines, while on the other hand, existing vaccines are getting explored for repositioning. The latter offers to reduce the overall cost and time.

The novel coronavirus SARS-CoV-2 disease was reported in Wuhan, and the underlying causative agent was found to belong to the family Coronaviridae [1, 2]. Human-to-human transmission via physical contact and respiratory droplets when an infected individual coughs or sneezes is preventable via strategies such as social distancing and maintenance of hygiene [1, 3]. The virus comprises a single-stranded, positive-sense RNA genome containing 29,903 nucleotides. Orf1ab gene encodes nonstructural proteins. Some genes encode structural proteins, some of which include spike (S), membrane (M), nucleocapsid (N), and envelope (E) while other genes encode the accessory proteins such as orf3a, orf6, orf7, and orf10 [1, 2].

The disease has been progressing for a while now. Although there is a cut-throat race among nations to launch their vaccine candidates, there is a lot underway that is meant to prove each candidate’s safety, efficacy, and superiority over the other. The vaccine candidates are in various stages of development. Whereas a vaccine usually takes years to reach a market, vaccine development has increased in speed in recent times. In such moments of immense vigor to be ahead in the race, there are two nonspecific vaccine candidates, Bacillus Calmette-Guérin (BCG) and Measles, Mumps, and Rubella (MMR) vaccine, which appear promising.

The popular BCG and MMR vaccines confer broad immunity against diseases not limited to tuberculosis (TB) and measles, mumps, and rubella. Substantial clinical and nonclinical evidence proves their nonspecific nature alongside their safety and efficacy. With such time constraints, they could stand a chance to be candidates to combat COVID-19. The study thus compares and comprehends the practicality of the two vaccine candidates, giving them the basis of global clinical evidence, underlying mechanisms of immunity conferment, and their current prospects to test whether they stand a chance in combating COVID-19.

2. Bacillus Calmette-Guérin (BCG) vaccine

The Bacillus Calmette-Guérin (BCG) is a renowned vaccine known to confer prevention and cross-protection against Mycobacterium tuberculosis infection. It is composed of Mycobacterium bovis in the attenuated form [4, 5]. This vaccine was first used on humans in 1921 [6]. BCG vaccination of newborns and infants reduces the risk of pulmonary TB by about 50% [7], and it is administered in infants intradermally post-birth [1]. Nearly 100 million newborns are administered the BCG vaccine annually [5]. It is protective in young children previously not infected by the severe forms of tuberculosis [8]. Although it has shown clear protection in children, its effects have been inconsistent in adults [9].

BCG vaccination has broad protective effects that are not specific to Mycobacterium tuberculosis infection, which has been proven with sufficient evidence.

2.1 Clinical evidence for broad protective effects against COVID-19

In 1927, Swedish children who were administered the BCG vaccine at birth showed a mortality rate almost threefold lower than the unvaccinated children [10]. On similar grounds, a BCG vaccination scar and a positive tuberculin reaction conferred better survival during early childhood in an area with high mortality in West Africa [11]. The long-lasting effect of BCG was recognized in a study based in Spain, wherein the hospitalizations associated with respiratory infections other than TB in 0–14-year-old children were found to be substantially lower in BCG-vaccinated children. This protection in 14-year-olds confirmed the enduring broad protective effect of BCG [12]. Two separate randomized human clinical trials are being conducted to test the prospect and likeliness of its conferment of protection against COVID-19. These are in progress in Holland [1, 13] and Australia [1, 14]. In these studies, health workers are being administered either the BCG vaccine or a placebo saline injection. A small study in Indonesia found that vaccination of adults in the age group of 60–75 years with BCG prevented acute upper respiratory tract infections by an increase in IFN-γ levels. The study involved the administration of the BCG vaccine once every month for 3 months. The placebo group received solvent for the BCG vaccine [15].

There is a possibility that the innate immune response to vaccination depends on the strain of BCG and the route of administration. Even short-span protection may help individuals at high risk, such as front-line workers, until there is the availability of a specific vaccine. Most Asian countries have active universal BCG vaccination programs. However, with no direct evidence from clinical trials, it is not yet advisable to recommend the use of BCG to prevent COVID-19.

A report found the presence of a strong correlation between the BCG index and COVID-19 mortality in European countries. The index is an estimation of the degree of universal BCG vaccination deployment in a given country. With every 10% increase in this index, there was a 10.4% reduction in mortality associated with COVID-19 [16].

2.2 Basis of broad protective effects against COVID-19

Clinical and laboratory experimental evidence suggests prevention against viral infections in humans [17]. Trained immunity and long-lasting protection from the respiratory tract’s viral infections are offered by BCG vaccination, which eventually becomes a basis for its potential protective effect against COVID-19 [16].

Prevention of vaccinia virus infection is conferred via an enhancement in interferon-gamma production (IFN-γ) from CD4+ cells in BCG-vaccinated mice [18], which is attributed to adaptive immunity. There is a rise in levels of pro-inflammatory cytokines such as Interleukin-1β (IL-1β) involved in immunity against viruses [19]. Interleukin-2 (IL-2), TNF-α (tumor necrosis factor), and IFN-γ (interferon- γ) are released because of the activation of CD4+ T cells [20].

T-helper cells are activated once BCG gets internalized by antigen-presenting cells. MHC class II molecules expressed on the surface of APCs and recognized by the CD4+ T cells via the T-cell receptor (TCR) bring about this activation. This interaction between MHC II molecules and TCR is governed by the binding of co-stimulatory molecules (CD28) to B7–1 on the T cells, and this binding causes an upregulation of adhesion molecules such as LFA-1 (lymphocytes function associated antigens-1). The LFA-1 binds to the macrophages via ICAM-1 (intracellular adhesion molecule-1) [21].

There is evidence for the conferment of immunity against listeria and influenza in murine models [22, 23]. Various controlled trials have shown that BCG vaccination reduces the severity of infections by several viruses with structural similarity to SARS-CoV-2 [1].

In 2015, a placebo-controlled randomized trial revealed that the immunogenicity of the H1N1 vaccine was augmented in healthy adults because of BCG vaccination [24].

2.3 The current status

At present, three active ongoing advancing clinical trials are examining whether the BCG vaccination prevents SARS-CoV-2 infection in healthcare workers [1].

Currently, the World Health Organization (WHO) does not recommend using the BCG vaccine to cope with COVID-19 as there is no firm evidence suggesting prevention of the SARS-CoV-2 infection [25]. Whether the BCG vaccine administered decades ago in childhood will prevent or treat COVID-19 now is debatable [1]. There is a possibility that the BCG vaccine may upregulate the immune system, aggravating the severity of COVID-19 in a few patients. Its supply is already low, and a false sense of security might mislead the population, eventually compromising the fulfillment of the needs of infants for protection against tuberculosis in high-risk zones [26, 27].

Japan, China, Korea, India, and the Russian Federation have continued to conduct childhood BCG vaccination. Compared with the countries with no mandatory mass BCG vaccination, the per capita death rate associated with COVID-19 in the countries mentioned above is lower. Japan, Brazil, and Russia incorporate BCG vaccines containing original strains compared with the European countries where the vaccine contains modified strains [28].

A team is conducting a study at the Max Planck Institute for Infection Biology in Germany to test whether VPM1002, a recombinant BCG vaccine strain, can protect healthcare workers or older patients from COVID-19 [28, 29, 30].

The cause-and-effect relationship between the BCG vaccine and COVID-19 is yet to be proven with concrete evidence. There is a limitation associated with the above understandings. In low-income countries where there could be reduced testing capabilities, substantial under-reporting of the number of cases and deaths may undermine the possibility of getting an exact correlation between COVID-19-related mortality and BCG [31]. Although it appears as if the countries without mandatory mass BCG vaccination policies [32], such as the United States and Italy, have higher mortality rates, there may be a dependence of mortality rate associated with COVID-19 [16] on factors such as temperature, percentage of population 65 years or older in a particular region, GDP, population density, and its variation from state to state.

There is a lack of mandatory vaccination programs in countries such as the United States, Canada, Italy, and the Netherlands [32]. The vaccine is administered at birth and offers protection against tuberculosis for 10 years [5].

3. Measles, mumps, and rubella (MMR) vaccine

The Measles, Mumps, and Rubella (MMR) vaccine is a combination vaccine used to confer immunity against measles, mumps, and rubella infections [33]. This live attenuated multi-dose vaccine [34] possesses various combinations of strains of the viruses mentioned earlier to immunize the patient against MMR infections [35]. The first dose of the vaccine needs to be given between 12 and 15 months of age, and the second dose between 4 and 6 years of age [34]. The MMR vaccination program in the United States has proven to be successful in bringing down measles, mumps, and rubella [33]. The vaccine is contraindicated in pregnancy [35].

3.1 Clinical evidence for broad protective effects against COVID-19

It has been recapitulated by Miller [36] that ephemeral protection is provided by the MMR vaccine against heterologous viral infections [37]. A study of 11,004 Italian children was carried out to analyze the effectiveness of MMR vaccinations in terms of the need for hospitalizations for targeted and nontargeted infections. About 2,302 (20.9%) children had not been immunized with the MMR vaccine, 5,392 (49%) had received one dose of the vaccine, and 3,310 (30.1%) had received both doses. The study showed lowered hospitalizations (414 in all) for children suffering from all sorts of infectious diseases. About 262 hospitalizations among nonvaccinated and 82 and 70 hospitalizations among single-dose and double-dose recipients, respectively, were reported. Only 809 hospitalizations out of 11,004 children battling respiratory diseases were reported [38]. To benefit healthcare workers, airport staff, and foreign domestic helpers, Hong Kong instituted the MMR vaccination program in 2019 and continued it in 2020. This program brought down COVID-19-associated deaths and led to zero deaths during the 7 weeks ending on May 3, 2020. In 2019, 7.2 million out of 20.26 million people in Madagascar were immunized with the MMR vaccine, and as of May 4, 2020, no deaths were reported of patients suffering from COVID-19 [39].

It is mandatory for every man from South Korea between 18 and 28 years of age to join the South Korean military due to the country’s new vaccination policy formed by the 2012 Military Healthcare Services Act. Every recruit compulsorily receives two doses of MMR vaccine apart from childhood immunizations, and maximum immunity can be witnessed among these individuals. South Korea also vaccinated its entire population post measles outbreak in 2001–2002. South Korea has shown an unusually low incidence of deaths due to COVID-19 as compared with other countries with a similar timeline of initial infection [39, 40].

A study of 2,135 pediatric patients with COVID-19 in China reveals that over 90% of the patients displayed mild or moderate symptoms or were asymptomatic [41]. As per the data dated March 18, 2020, the Korean Center for Disease Control and Prevention states that only 1.03% of the total 8,413 COVID-19 cases included children as patients. These data expound on the benefit of MMR vaccination in producing innate immunity, making children less prone to COVID-19 [42]. Immunization with the MMR vaccine successfully curbs pulmonary inflammation and sepsis, which is one of the prominent causes of COVID-19 mortality and confers protection to children from COVID-19 by making them less susceptible to this horrid disease [43].

Until April 30, 2020, 1,102 people on the U.S.S Roosevelt had tested positive for COVID-19, wherein only one death and seven hospitalizations were reported. This could be attributed to the fact that all recruits are provided MMR vaccinations by the U.S. military before their admission. The hospitalization rate for Navy recruits was about 20 times lower than that for the usual population of the same age group. Another example to substantiate the correlation between MMR vaccination and the COVID-19 death rate is the lack of sufficient MMR vaccination in Italy, which has proven controversial and inconsistent [44], leading to a vast measles outbreak in 2017 that also justifies a higher death rate due to COVID-19 [39].

Pediatric patients in China older than 1 year manifested mild symptoms, whereas those of a year or less exhibited severe symptoms [45]. Introducing a dose of MMR after a year post-birth explains the study’s result in China [46].

According to Roser, up until May 14, 2020, 4,477,573 cases and 299,958 deaths worldwide due to COVID-19 were reported, while only 2.2% of the cases involved children between 0 and 17 years of age [37]. It has also been reiterated by Verdoni that the course of COVID-19 involving respiratory problems is benign [47]. These pieces of evidence lean toward the possibility of boosted immunity by MMR vaccine, offering protection against COVID-19.

In North Korea, Turkmenistan, Cook Islands, Marshall Islands, Solomon Islands, and Tuvalu, many adults between the ages 29–45 receiving MMR immunizations reported zero or near-zero deaths from COVID-19 [39].

Using epidemiological parameters such as the fraction of undocumented infections and their contagiousness previously estimated from US county-level data between February 21, 2020 and March 13, 2020, [48], an SEIR model has been put up priming large populations in the United States and China to estimate spread and growth of the virus [49, 50]. Priming has reduced the infection period and chance of complications by 33%, and after the priming agent was administered slightly before the infection rate peaked, the rate of hospitalizations reduced to 25%.

In order to prevent the immune pathology in severe COVID-19 cases, some suggest that the immune system could be primed with live attenuated viruses in vaccines such as MMR, which could trigger trained innate immunity [50].

3.2 Basis of broad protective effects against COVID-19

S-glycoprotein is an immunogenic protein encoded by SARS-CoV-2 that plays a pivotal role in binding to the ACE2 receptor on the epithelial cells of the respiratory system [51]. Since MMR immunization confers broad immunity against viral infections, it has been postulated that there might be similarities between antigenic epitopes of surface proteins of the live attenuated viruses used in the MMR vaccine and the S-glycoprotein. Thus, the antibodies produced by MMR vaccination could cross-react with antigenic epitopes of the S-glycoprotein and could also provide cross-protection against COVID-19 [42].

A homology search was carried out for the chain A amino acid sequence of SAR-COV-2 S-glycoprotein against the proteomic sequences of live attenuated viruses in MMR vaccines. Fusion (F1) glycoprotein of the measles virus and E-glycoprotein of the rubella virus shared similarities in 30 amino acid residues with the S-glycoprotein. More experimental data are required in this area [42].

Lymphopenia and a decrease in cytotoxic CD8+ T cells are exhibited in patients suffering from COVID-19 [52]. Upon routine childhood immunization, secretion of many cytokines such as IL-2, IL-12, and IFN gets induced post CD4+ T helper 1 cell stimulation, which then provokes maturation of CD8+ T cells. This also elevates cytotoxicity of NK cells, destroying cells infected with coronavirus [45].

Pattern recognition receptors (PPRS) recognize viral components such as viral nucleic acids and proteins, eliciting innate immune response [53, 54]. A response to the respiratory infection due to coronavirus has been elicited by endosomal toll-like receptors 3, 7, and 8 and intracellular cytosolic PRRS. The above key sensors trigger a downstream signaling cascade, leading to the induction of IFN secretion, which activates thousands of IFN-stimulated genes, generating an antiviral response and eventually protecting the patient from harm immunopathology [50].

3.3 The current status

The benefits of the MMR vaccine, coupled with its FDA approval, ease of administration, cost-effectiveness, and availability, indicate an advantage to vaccinating the population to spare mortality associated with COVID-19 to a certain extent [55].

A randomized clinical trial with MMR vaccine for healthcare workers and first responders has been proposed to be performed in New Orleans to corroborate the data [43].

The MMR vaccination triggers innate immunity by inducing IFN secretion and escalating cytotoxicity of NK cells [45]. However, treatment with therapeutic interferons is costly. It leads to undesirable side effects, while vaccine-induced IFNS and NK cells are more robust, efficient, and potent, suggesting the use of MMR vaccination, which confers antibody-mediated cross-protection for prevention or amelioration of SARS-CoV-2 infection [55, 56].

The SARS-CoV-2 virus has an incubation period of approximately 5 days and up to 14 days and longer [57, 58] and is thought to evade the innate immune system causing delay or suppression of antiviral responses [50]. Priming the individual with MMR vaccine before the infection would trigger a broad innate immune response, which would prevent immune system evasion by the virus and prepare a susceptible individual to counter the viral attack [50].

Even though COVID-19 is affecting individuals of all age groups, it is evident that children, who are being less commonly affected by the disease and show mild symptoms, are associated with a low COVID-19-death rate and can recover faster compared with other age groups owing to the routine MMR vaccination that boosts immunity and confers cross-protection [59]. Commonalities shared by MMR viruses and SARS-CoV-2 in terms of primary replication in the upper respiratory tract [55], structural and functional similarities between them, cross-protection offered by MMR vaccine, and age-related declining immunogenicity of measles vaccine suggest the use of MMR vaccine for prophylaxis or to avoid severe complications in COVID-19-positive individuals and eventually limit COVID-19 death rates [60].

Countries such as Australia and Belgium lack mandatory vaccination programs [61]. The vaccine offers protection against measles, mumps, and rubella for 10–12 years [59]. The first dose is administered between 12 and 15 months of age, while the second dose is administered between 4 and 6 years of age [34].

Currently, WHO has not yet recommended putting MMR vaccination in use for the ongoing pandemic because of the lack of concrete evidence about the cause-and-effect relationship between the MMR vaccine and SARS-CoV-2. Sufficient evidence of the efficacy of the vaccine against this disease will pave the way to begin the mass production of the vaccine to fight the pandemic.

4. Opinion on repurposing BCG vaccine and MMR vaccine for COVID-19

There is a tremendous spike in the number of cases of COVID-19 across the globe, which calls for an emergency and fruitful strategy that would cause a flattening of the curve while saving the lives of vulnerable populations or people with comorbidities who are more susceptible to this disease. While there is a call for research aiming to develop specific vaccines, vaccine repositioning has not taken a backseat. With vaccines such as BCG and MMR showing considerable evidence for their inherent ability to resist various infections, alongside their well-established safety and efficacy for their target infections, there is great promise for a new development to combat the existing pandemic [4, 5, 12, 33, 38].

The broad protective effect of both BCG and MMR vaccines has been clinically proven. Their effect lasts nearly 10 years. BCG vaccination has been impactful in reducing mortality associated with various diseases as per studies conducted across Sweden and West Africa. Its long-lasting effect was observed in a study based in Spain, whereas protection against upper respiratory infections was depicted in a study based in Indonesia involving citizens above the age of 60. Two randomized clinical trials are in progress in Holland and Australia to study BCG’s effects on COVID-19. A link between COVID-19-related mortality and the BCG index has been observed, where an increase in the index has shown a decrease in mortality in European countries [16]. Most Asian countries such as Japan, China, Korea, India, and the Russian Federation have continued to conduct childhood BCG vaccination compared with countries such as the United States, Canada, Italy, and the Netherlands. Compared with the countries with no mandatory mass BCG vaccination, the per capita death rate associated with COVID-19 in the countries mentioned above is lower [28]. Many of these countries incorporate BCG vaccines containing original strains compared with the European countries. Currently, a study in Germany is assessing the effects of a modified strain of BCG against COVID-19.

Few countries such as Australia and Belgium lack a mandatory MMR vaccination program. A study in Italy showed a reduction in the hospitalization of children associated with respiratory diseases because of MMR vaccination [38]. MMR vaccination programs for front-line workers in Hong Kong, Madagascar, the South Korean military, the U.S. military, adults of North Korea, Turkmenistan, Cook Islands, Marshall Islands, Solomon Islands, and Tuvalu have brought down COVID-19-associated deaths in such regions. Most of the vaccinated children in China were asymptomatic or showed mild/moderate symptoms of COVID-19. A randomized clinical trial with MMR vaccine for healthcare workers and first responders has been proposed in New Orleans. The MMR vaccine plays a key role in limiting pulmonary inflammation, a key factor in SARS-CoV-2 mortality [43]. It has reduced the impact of COVID-19 because of the structural similarity between glycoproteins of COVID-19 virus and measles and rubella viruses. The SARS-CoV-2 virus has an incubation period of approximately 5 days and up to 14 days. So, priming the individual with MMR vaccine before infection can trigger a broad innate immune response, preventing immune system invasion by the virus and preparing a susceptible individual to counter the viral attack.

The BCG vaccine can confer trained immunity against many viral infections. Therapeutic interferons are expensive. Both BCG and MMR vaccines trigger the production of IFN and various cytokines, lessening the need for interferon administration [55, 56].

For the time being, MMR appears to show more human data for COVID-19 protection than BCG [39, 42]. With no concrete evidence of BCG- or MMR-conferred protection against COVID-19, WHO refrains from advising the use of such vaccines to cope with it, especially to avoid unforeseen consequences that may include upregulation of the immune system contributing to exacerbation of one’s condition. Also, a surge in its sudden demand may cause a shortage of its supplies and an inability to meet the needs of infants and newborns.

5. Conclusion

The BCG and MMR vaccines require randomized clinical trials before they can be considered for repositioning against COVID-19. However, past evidence of the vaccines’ ability to support to confer cross-protection against multiple viral infections can become a basis for their candidature for prospective clinical trials. Overall, the vaccines may shorten the duration of infection, minimize the harmful pathology, reduce the hospitalization rates, and help flatten the curve, helping to curb the spread of the disease. More research needs to be done to assess the risks and adverse effects of this method, especially for the elderly and people with comorbidities prone to severe complications due to COVID-19. Until there is evidence stating a direct cause-and-effect relationship between COVID-19 and BCG/MMR vaccine, the world will have to wait.

Acknowledgments

Authors are very much thankful to Dr. Paraag Gide, Principal, Hyderabad (Sindh) National Collegiate Board’s Dr. L. H. Hiranandani College of Pharmacy, Ulhasnagar, for his continuous support, guidance, and encouragement.

Conflict of interest

The author(s) declare that there is no conflict of interest regarding publication of this article.

Funding

None.

Availability of data and materials

The data supporting the findings of the article will be made available from the corresponding author [Dr. Harshal Ashok Pawar] upon reasonable request.

Abbreviations

COVID-19	Coronavirus disease 2019
BCG	Bacillus Calmétte Guerin
MMR	Measles, Mumps, and Rubella
SARS-CoV-2	Severe Acute Respiratory Syndrome Coronavirus 2
RNA	Ribonucleic acid
S	Spike
M	Membrane
N	Nucleotide
E	Envelope
TB	Tuberculosis
IFN- γ	Interferon- γ
CD4+	Cluster of differentiation 4
1IL-1β	Interleukin-1β
IL-2	Interleukin-2
TNF-α	Tumor necrosis factor- α
MHC	Major histocompatibility complex
APCs	Antigen-presenting cells
TCR	T-cell receptor
CD28	Cluster of differentiation 28
B7-1	Binding protein
LFA-1	Lymphocytes function associated antigen-1
ICAM-1	Intercellular adhesion molecule-1
H1N1	Swine flu
WHO	World Health Organization
U.S.	United States
GDP	Gross Domestic Product
U.S.S	United States Ship
SEIR	Susceptible-Exposed-Infectious-Recovered
ACE2	Angiotensin-converting enzyme 2
F1	Fusion
CD8+	Cluster of differentiation 8
NK	Natural Killer Cells
PPRS	Pattern Recognition Receptors
FDA	Food and Drug Administration