Phase II Clinical trial for Evaluation of BCG as potential therapy for COVID-19

Abstract

Bacillus Calmette Guerin (BCG) is widely used in national vaccination programs worldwide. It is accepted that BCG alleviates both pathogen and allergy induced respiratory diseases that could also include Covid-19. To investigate this possibility, we randomly assigned 60 Covid-19 patients, after admission to the hospital with pneumonia and requirement for oxygen therapy in a 1:1 ratio to receive either a single adult dose of intradermal BCG or normal saline with concomitant standard of care (SoC) medications. Primary endpoints were favorable prognosis of Covid-19 as deduced from resolution of pneumonia, viremia and secondary outcome were enumeration of ICU admissions, duration thereof and mortalities. Results Both primary and secondary endpoints were significantly improved in the BCG+SoC group. This could be seen from reduction in oxygen requirement due to Covid-19 associated pneumonia decreasing from day 3-4, improved radiological resolution from day 7-15. There were a total of 6 (10%) adverse events in the study of which 2 deaths and 4 ICU admissions were in SoC group (1 ICU admission culminated in death of the subject) and in contrast only 1 ICU admission in the BCG+SoC group. While there was an increase in Covid-19 specific IgG levels in the BCG+SoC group, there was no evidence of BCG induced cytokine storm in this group. Four patients showed localized inflammatory response at the injection site in the BCG+SoC group. Conclusions BCG+SoC administration resulted in a significantly higher percentage of patients with favorable outcomes than did SoC. A third of the patients were naive for childhood BCG vaccination. This mimicked elderly patients in countries with no universal vaccination policy for BCG. No BCG related adversity was seen in this group. The study shows that BCG is a safe, cost-effective treatment that can be introduced as a standard of care in patients with moderate Covid-19 that can reduce requirement of oxygen supplemented beds and disease burden in low resource countries, with additional long-term benefits of reducing risk for tuberculosis.

BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial)

“…In a recent report, administration of BCG at the time of hospital admission for COVID-19 did not raise any safety concerns. 48 In addition, there was no evidence of increased severity of COVID-19 among participants who participated in BCG trials prior to the pandemic. 49 …”

The Influence of Cross-Reactive T Cells in COVID-19

“…Mouse studies have shown that BCG can protect against SARS-CoV-2 and influenza infection via the engagement of the innate and adaptive immune system, particularly CD4+ T helper cells [ 107 ]. Clinical trials assessing the outcome of SARS-CoV-2 infection in BCG-vaccinated individuals showed mixed results ( Table 2 ) with 10 trials and retrospective observational studies showing a protective effect (NCT04659941, NCT04369794, NCT04414267, NCT04417335, CTRI/2020/05/025013, NCT04475302, CTRI/2020/07/026668) [ 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 ], whereas 7 trials showed no protective effect (NCT04373291, RBR-4kjqtg, NCT04328441, NCT04537663, NCT04648800, NCT04379336, NCT04327206) [ 118 , 119 , 120 , 121 , 122 , 123 ]. Each study looked at the protective effect that the BCG vaccination has for COVID-19 in different ways, and each study assessed different populations, which may explain the mixed results between trials.…”

BCG Vaccine Derived Peptides Induce SARS-CoV-2 T Cell Cross-Reactivity

“…The majority of clinical trials addressing this are currently recruiting or ongoing. To date, at least 4 have concluded and shown BCG can provide some benefit in COVID-19 (20)(21)(22)(23). Additionally, large country-level epidemiological analyses, as well as a study of > 6000 health care workers, have shown a negative correlation between BCG vaccination status, COVID-19 disease severity and SARS-CoV-2 IgG seroprevalence (24)(25)(26)(27).…”