Preprint Case Report Version 1 This version is not peer-reviewed

Avoiding COVID-19 Complications with Diabetic Patients Could Be Achieved by Multi-Dose Bacillus Calmette–Guérin Vaccine: A Case Study of Beta Cells Regeneration by Serendipity

Version 1 : Received: 6 April 2020 / Approved: 9 April 2020 / Online: 9 April 2020 (05:03:24 CEST)

How to cite: Ayoub, B.M.; Ramadan, E.; Ashoush, N.; Tadros, M.M.; Hendy, M.S.; Elmazar, M.M.; Mousa, S.A. Avoiding COVID-19 Complications with Diabetic Patients Could Be Achieved by Multi-Dose Bacillus Calmette–Guérin Vaccine: A Case Study of Beta Cells Regeneration by Serendipity. Preprints 2020, 2020040134 (doi: 10.20944/preprints202004.0134.v1). Ayoub, B.M.; Ramadan, E.; Ashoush, N.; Tadros, M.M.; Hendy, M.S.; Elmazar, M.M.; Mousa, S.A. Avoiding COVID-19 Complications with Diabetic Patients Could Be Achieved by Multi-Dose Bacillus Calmette–Guérin Vaccine: A Case Study of Beta Cells Regeneration by Serendipity. Preprints 2020, 2020040134 (doi: 10.20944/preprints202004.0134.v1).

Abstract

Diabetes mellitus (DM) is one of the major risk factors for COVID-19 complications as it is one of the chronic immune-compromising conditions especially if patients have uncontrolled diabetes, poor HbA1c &/or irregular blood glucose levels. Diabetic patient’s mortality rates with COVID-19 are higher than cardiovascular or cancer patients. Recently Bacillus Calmette–Guérin (BCG) has shown successful results in reversing diabetes in both rats and clinical trials based on different mechanisms from aerobic glycolysis to Beta cells regeneration. BCG is a multi-face vaccine that has been used extensively in protection from TB and leprosy and has been repositioned for treatment of bladder cancer, diabetes & multiple sclerosis. Recently, the COVID-19 epidemiological study confirmed that universal BCG vaccination reduced morbidity and mortality in certain geographical areas. Countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies that have shown low numbers of reported COVID-19 cases. Some countries have started clinical trials that included a single dose BCG vaccine as prophylaxis from COVID-19 or an attempt to minimize its side effects. This proposed research aims to use BCG vaccine as a double-edged weapon countering both COVID-19 & diabetes, not only as protection but also as therapeutic vaccination. The work includes a case study of regenerated pancreatic beta cells based on improved C-peptide & PCPRI laboratory findings after BCG vaccination for a 9 years’ patient. The patient was re-vaccinated based on a negative tuberculin test & no scar at the site of injection of the 1st BCG vaccination at birth. Furthermore, the authors in the present article described a prospective BCG multi-dose clinical study in full details that they will apply in case of acceptance of their submitted grant & the ethical committee approval. The aim of the clinical study is to check if double dose BCG (4 weeks apart) will show a significant difference in the protection of health care professionals in Egypt. The authors suggest and invite the scientific community to take into consideration the concept of direct BCG re-vaccination (after 4 weeks) because of the reported gene expressions & exaggerated innate immunity consequently. As the diabetic MODY-5 patient (mutation of HNF1B, Val2Leu) was on low dose Riomet® while eliminating insulin gradually, a simple analytical method for metformin assay was recommended to ensure its concentration before use as it is not approved yet by the Egyptian QC labs.

Subject Areas

COVID-19; multi-dose BCG; beta cells regeneration; improved C-peptide; serendipity

Comments (2)

Comment 1
Received: 14 April 2020
The commenter has declared there is no conflict of interests.
Comment: First, I would like to know this work is original article or review article or just opinion as it doesn't follow the guidelines of any of them. Second, it talked about an observation took place occasionally at ER for only one patient, that mean it is observation rather than scientific research and the authors didn't follow the scientific ethics for clinical trials on children which is not allowed by low. Third, the authors mentioned that full pancreatic regeneration ( '''However, upon BCG re-vaccination, after 5 weeks, the patient was near normo-glycemic range with no insulin therapy, so we presumed there was restored insulin secretion due to pancreatic beta cells regeneration''') is that scientifically approved, only 5 weeks enough to regenerate such number of cells with atrophy?. Fourth, the rest of the article! jumped to COVID-19 based on assumption without introducing any scientific evidence relating BCG and COVID-19. The second part of the article the authors talk about human clinical trial protocol that they will start lacking the minimal safety measure or ethical scientific guidelines required for trials on human. I think this observation has to be followed up and studied on scientific bases before publishing.
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Response 1 to Comment 1
Received: 15 April 2020
Commenter: Bassam Ayoub
The commenter has declared there is no conflict of interests.
Comment: Dear respected colleague First of all, this "preprint" is still a "draft" for the authors' work on BCG Vaccine. The authors preferred to share their observation about BCG muli-face vaccine with the scientific community especially during the current COVID-19 outbreak. Regarding your comment about ethical committee approval for clinical trial on children, The "draft" did not mention at all that it was a clinical trial but on the contrary, the authors confirmed even in the title that "observational" improved C-peptide was by "Serendipity". A 9 years old child was re-vaccinated by BCG because of the absent scar and FH of TB but his C-peptide and insulin secretion was suddenly improved after 5 weeks. As the name of the patient was not announced and as BCG re-vaccination was not targeting diabetes, there is no ethical approval as the findings were found by serendipity. Moreover, as the case study was the son of one of the authors, all laboratory investigations (before & after BCG by serendipity) were submitted for "review only" either to the journal &/or preprint server to keep the patient data unpublished so I was just wondering which part is related to your comment "clinical trial on children is prohibited by law ?". Regarding your comment about the beta cells regeneration & if that is possible in only 5 weeks ?. The authors reported the case findings and re-generated insulin secretion supported with all laboratory investigations. Honestly, the authors got comments from journal reviewers asking for more data &/or laboratory tests but that is still "under processing" with the journal and authors. The authors "suggested" that regenerated insulin secretion may be due to BCG re-vaccination (by serendipity.........by serendipity.......not intended.......off label) especially there are no reported cases of MODY-5 diabetes with BCG research at all. The authors confirmed here how BCG is multi-face vaccine based on their own experience. Regarding your comment about the first "draft" of the "suggested" clinical trial in Egypt, this clinical trial draft (with more information not published...BCG strain.....Hospitals involved....other factors...) was approved by the ethical committee in the British University in Egypt (Approval Code: CL/2005 on 2 April 2020). All the other ethical details will be shared and published in the finalized article if BCG revaccination showed a significant difference against COVID-19. More safety measures and ethical guidelines were mentioned in the authors' proposal for grant submission in Egypt including for example "tuberculin test" results. The authors were keen to get the ethical committee approval before even submission of the "Draft". Regarding your comment about BCG & COVID-19, Kindly be informed that BCG was already used by many countries (till date) as a clinical trial against COVID-19 based on its reported well established role in Innate immunity or trained immumity (& not as a specific vaccine of course) and reported high safety profile. The authors suggest using 2 doses of BCG (4 weeks apart) similar to US study on human volunteers that was targeting diabetes. The US study showed interesting results with high safety profile. So based on the authors' own experience with BCG (by serendipity), they suggested using the mentioned multi-dose after extentive search of the literature and ethical committee approval (CL/2005). Finally, as the authors are still working on every part of this article draft, they decided to share their ideas and clinical study suggessions before commencing the work for two reasons: 1- It is not the time for publishing or patents but it is the time of sharing information and ideas to fight against COVID-19 2- It will be good opportunity to receive and discuss valuable comments like those mentioned above from a respected colleague. Finally, I would like to confirm that the authors in the descibed "draft" did not discuss or request any clinical trials on children & their suggested work on human volunteers was preliminary and approved by the ethical committee. Moreover, they presented the case study with "suggested" explanations that are still under review. This draft was a merged version of 1- A letter to the editor (COVID-19 & BCG) 2- Case report (Repurposing of BCG as antihyperglycemic agent for MODY-5 diabetes) 3- Research Grant (Protection of Egyptian Health care professionals from COVID-19 Complications using BCG) But as BCG was the common factor in the three projects, the authors decided to share the preliminary work as one draft. Thank you for your valuable comments.

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