Evaluation of BCG as potential therapy for COVID-19
Background and Introduction
The novel coronavirus nCoV-19 (or SARS-CoV-2 or 2019-nCoV), responsible for the global pandemic COVID-19 was isolated from human airway epithelial cells from patients from Wuhan, China in December 2019 (Wang et al, 2020; Zhu et al, 2020). Seven coronaviruses (CoVs) have been described so far infecting humans of which the SARS-CoV (Kuiken et al, 2003), MERS-CoV and nCoV-19 are serious threats to humans. No therapies or vaccines have been approved for SARS or MERS thus far, demonstrating the need to develop effective therapies or vaccines.
BacilleCalmette-Guérin, BCG is a vaccine against tuberculosis that is prepared from a strain of the attenuated (weakened) live bovine tuberculosis bacillus, Mycobacterium bovis. The bacilli have retained enough strong antigenicity to become an 80% effective vaccine for the prevention of human tuberculosis. Overall, BCG vaccine reduces the risk of pulmonary and extra-pulmonary tuberculosis (TB) by approximately 50%, but it has 64% efficacy against TB meningitis and 78% against disseminated TB disease. India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so. BCG as a vaccine is safe to be used in children within a week of their birth and is in the Universal immunization programs of many countries in South East Asia and Africa.
BCG vaccine also provides some protection against leprosyand non-tuberculous mycobacterial infections. In addition, it has been used in the treatment of superficial carcinoma of the bladder.
It has been shown to reduce severe respiratory distress in children from Africa and conferred beneficial immunity and favorable outcomes to malarial infections. Revaccination with BCG has been tried in some populations (Japanese adults). However the longevity of immune protection due to re-vaccination has not yet been confirmed.
Currently, five main strains account for more than 90% of the vaccines in use worldwide with each strain possessing different characteristics. The strains include the Pasteur 1173 P2, the Danish 1331, the Glaxo 1077 (derived from the Danish strain), the Tokyo 172-1, the Russian BCG-I,and the Moreau RDJ strains (Hayashi et al, 2009).
Each strain of BCG has a different reactogenicity profile - The Pasteur 1173 P2 and Danish 1331 strains are known to induce more adverse reactions than the Glaxo 1077, Tokyo 172-1, or Moreau RDJ strains (Hayashi et al., 2009). The strain is one of the important factors that has been implicated in incidence of adverse events following BCG vaccination (Milstienet al,1990, Lotte et al.,1984). The BCG to be used in this protocol is Tubervac (Serum Institute of India) is derived from the Russian strain, also known as Moscow strain.
Safety of use of BCG
WHO estimates that 80% of the world is covered by BCG i.e. atleast 100 million children with one year of birth are given the vaccine worldwide, a statistic which speaks for the safety of the vaccine.
One of the most common side effects of BCG vaccinations are local complications (injection site reactions and suppurative or non-suppurative lymphadenitis). Management of the same varies between clinicians, and the optimal approach remains uncertain. In addition, the following adverse events have been noted in dispersed populations.
Skin lesions distinct from the vaccination site. Tuberculosis infection can cause a number of cutaneous lesions (such as TB chancre, lupus vulgaris, scrofuloderma, papulonecrotic tuberculids etc). There are case reports of cutaneous lesions, distinct from the site of vaccination, thought to have occurred after BCG vaccination (Bellet et al., 2005). It is important to note that multiple cutaneous lesions may signal disseminated BCG disease usually in an immunocompromised host. There are case reports of lupus vulgaris, scrofuloderma following BCG vaccination.
Lymphadenitis. When severe, this includes nodes which become adherent to overlying skin with or without suppuration. Suppuration has been defined as "presence of fluctuation on palpation or pus on aspiration, the presence of a sinus, or large lymph node adherent to the skin with a caseous lesions on excision" (Lotte et al., 1984). If BCG is administered in the recommended site (deltoid) the ipsilateral axillary nodes are most likely to be affected but supra-clavicular or cervical nodes may also be involved (Hengster et al., 1992). The onset of suppuration may be variable with cases presenting from one week to 11 months following vaccination (de Souza et al., 1983). Lymphadenitis presenting within 2 months of vaccination and larger nodes (+ 1cm) may be less likely to resolve spontaneously (Caglayan et al., 1991). Suppurative lymphadenitis is now rare, especially when BCG inoculations are performed by well-trained staff, with a standardized freeze-dried vaccine and a clearly stated individual dose depending on the age of the vaccinated subjects.
Osteitis and Osteomyelitis. This is a rare and severe complication of BCG vaccination which has primarily been reported in Scandinavia and Eastern Europe and typically associated with changes in BCG vaccine strain. There was a report of an increase in osteitis to 35 per million in Czechoslovakia after a shift from the Prague to Russian strain BCG (Lotte, et al., 1988). Both Finland and Sweden reported increases in osteitis after 1971 when they shifted to a Gothenburg strain produced in Denmark. Sweden reported rates as high as 1 in 3,000 vaccine recipients, which declined rapidly when the national programme shifted to a Danish (Copenhagen, 1331) vaccine strain (Lotte et al., 1988). More recently reports of osteitis have become infrequent.
Disseminated BCG disease or systemic BCG-itis. This recognized but rare consequence of BCG vaccination traditionally has been seen in individuals with severe cellular immune deficiencies. The risk (fatal and non-fatal) is thought to be between 1.56 / million and 4.29 cases / million doses (Lotte et al., 1988). This is based on pre-HIV data. However, the exact incidence is debated because few centers are able to differentiate Mycobacterium Bovis BCG from other forms of Mycobacterium in patients presenting with disseminated disease. In a recent retrospective case series review of Mycobacteriunm tuberculosis complex 5% of cases were found to have the M. Bovis BCG strain (Hesseling et al., 2006). Additional data from studies in South Africa confirm the significantly high risk of disseminated BCG (dBCG) disease in HIV-positive infants, with rates approaching 1% (Hesseling et al., 2009). In one series of 60 cases of BCG-itis the case fatality rate was approximately 50% although other smaller studies have documented a higher mortality rate (Lotte et al., 1988, Talbot et al., 1997). As expected the cellular primary immunodeficiency predisposes to the condition. This includes severe combined immunodeficiency, chronic granulomatous disease, Di George syndrome and homozygous complete or partial interferon gamma receptor deficiency (Jouanguy et al., 1996; Jouanguy et al., 1997; Casanova et al., 1995).
Early recognition and diagnosis is critical to management. In patients with primary immunodeficiency disorders the disease may be fatal without reconstitution of immunity through stem cell transplant.
Immune reconstitution inflammatory syndrome (IRIS). This has recently been identified as a BCG vaccine-related adverse event in immunocompromised individuals due to HIV started on antiretroviral therapy (ART) (DeSimone et al., 2000). It usually presents within 3 months of immune restoration and manifests as local abscesses or regional lymphadenitis usually without dissemination. No fatal cases have yet been documented. A number of rare events have been reported as case reports or series. These include sarcoidosis, ocular lesions (conjunctivitis, choroiditis, optic neuritis), and erythema nodosum. Tuberculous meningitis (due to the BCG) has been described but is exceptionally rare (Tardieu et al., 1988)
Therefore, as noted above, most of adverse effects of the use of BCG is due to two factors (1) Strain used or change in strain (which has happened in some countries, when they switch suppliers) and (2) Immune status of the individual / population and widespread use of the BCG has demonstrated some advantages, such as excellent immune adjuvant activity, long-persisting effects, safety, and low cost.
Rationale to use BCG as a therapy for COVID-19
Miller et al, 2020 show a negative correlation between BCG immunization status of a country and mortalities due to COVID-19. In particular, Miller et al., 2020 have presented epidemiological data,that suggests that BCG could be effective against nCoV-19 or SARS-CoV-2. The data (yet to be peer reviewed) found that countries that do not have a BCG immunization policy have more COVID-19 deaths and cases. These countries include the US, the Netherlands and Italy. Countries like Iran which started giving the vaccine late in 1984, had high mortality, suggesting that BCG protected the vaccinated elderly population, whereas countries like Japan have reported lesser cases and mortalities.
In addition, Two international trials are on for assessing BCG as a prophylactic agent in healthcare workers in Australia and Netherlands against COVID-19.
BCG is known to induce a potent Th1-type response (in particular to increase IFN-gamm) and promote the production of both Th1- and Th2-type cytokines in response to unrelated vaccines. In the latter case, it is likely, however, that BCG stimulates general immune response. This results in faster response to infections that could reduce severity of disease and lead to faster recovery.
This protocol aims to evaluate the effects of BCG used as an interventional therapy on nCoV-19 positive subjects and establish a direct link between BCG inoculation and favorable COVID-19 outcome.