According to recent epidemiologic data, BCG vaccination may provide some protection against COVID-19 infection and may reduce the severity of it. (1) However, it is alarming that achieving high levels of neutralizing antibodies to the spike protein of SARS-CoV-2 is proposed to be achieved by aluminum adjuvant formulations of traditional vaccine formulations. (2) It is assumed, that the “assertion that aluminum-adjuvanted vaccines induce autism or other chronic illnesses has been thoroughly discredited.” This may be a superficial assumption based on misinterpreted research results.

It is a disturbing finding that Shank3 gene expression is downregulated in human neuronal-glial cells by aluminum sulfate. Downregulated Shank3 protein may contribute to altered neurotransmission in multiple neuropsychiatric disorders. Shank3 is an essential scaffolding protein that appears to be commonly and significantly reduced in synaptosomal preparations of brain tissues obtained from Alzheimer’s disease, autism spectrum disorder, bipolar disorder, Phelan McDermid syndrome, and schizophrenia patients. (3) The genetic studies on the Phelan McDermid syndrome revealed that Shank3 related gene expression deficits have a causative role in mental defects. (4)

Aluminum may also increase the permeability of BBB by changing its ultrastructure and the expression of occludin and F-actin. (5) According to a meta-analysis chronic aluminum exposure is associated with 71% increased risk of Alzheimer’s disease. (6) Aluminum may cause neurotoxic autoimmune reactions induced by microglial hyperactivation in the injured brain. (7) Excessively activated cofilin mediates microglial cell activation. (8) The important role of cofilin – the actin severing protein – is further highlighted by the fact that Shank3 deficiency causes also the excessive activation of cofilin playing an important role in the autistic symptoms. Inhibiting cofilin to stabilize actin rescues behavioral and cognitive deficits in Shank3 deficient mice. (9) Proinsulin c-peptide is a promising therapeutic candidate to inhibit the excessive activation of cofilin because it is regulating the pathways responsible for its inactivation. (10) Intranasal administration of proinsulin c-peptide may be an effective way to exploit its therapeutic potential because if it is centrally applied may also increase the parasympathetic nerve activity decreasing systemic inflammation by engaging the cholinergic anti-inflammatory pathway. (11)(12)(13)(14) Patients with insulin-dependent diabetes mellitus lacking pancreatic proinsulin c-peptide production have one of the highest mortality rates of COVID-19 infection and for this reason, may especially benefit of the therapeutic effect from central proinsulin c-peptide. (15)

(1) Redelman-Sidi, G. Could BCG be used to protect against COVID-19?. Nat Rev Urol 17, 316– 317 (2020). 

(2) Hotez, P.J., Corry, D.B., Strych, U. et al. COVID-19 vaccines: neutralizing antibodies and the alum advantage. Nat Rev Immunol (2020). 

(3) Alexandrov, P.N. et al.: Deficits in the Proline-Rich Synapse-Associated Shank3 Protein in Multiple Neuropsychiatric Disorders, Front Neurol. 2017; 8: 670. 

(4) Rubeis, S.D. et al.: Delineation of the Genetic and Clinical Spectrum of Phelan-McDermid Syndrome Caused by SHANK3 Point Mutations, Mol Autism. 2018 Apr 27;9:31. 

(5) Song Yang, et al.: Effects of Acute Exposure to Aluminum on Blood-Brain Barrier and the Protection of Zinc, Neurosci Lett. 2008 Nov 7;445(1):42-6. 

(6) Wang Zenjin et al.: Chronic exposure to aluminum and risk of Alzheimer’s disease: A meta- analysis, Neuroscience Letters, Volume 610, 1 January 2016, Pages 200-206 

(7) Jovanova-Nesic Katica et al.: Aluminum Excytotoxicity and Neuroautotoimmunity: The Role of the Brain Expression of CD32+ (FcγRIIa), ICAM-1+ and CD3ξ in Aging, Curr Aging Sci. 2012 Dec;5(3):209-17. 

(8) Alhadidi Quasim et al.: Cofilin Mediates LPS-Induced Microglial Cell Activation and Associated Neurotoxicity Through Activation of NF-κB and JAK-STAT Pathway, Mol Neurobiol. 2018 Feb;55(2):1676-1691. 

(9) Duffney L.J. et al.: Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators, Cell Rep. 2015 Jun 9; 11(9): 1400–1413. 

(10) Aleksic M. et al.: Signalling Processes Involved in C-peptide-induced Chemotaxis of CD4- positive Lymphocytes, Cell Mol Life Sci. 2009 Jun;66(11-12):1974-84. 

(11) Okamoto S. et al.: Proinsulin C peptide obviates sympathetically mediated suppression of splenic lymphocyte activity in rats., Diabetologia, 01 Dec 2000, 43(12):1512-1517 

(12) Kimora K. et al.: Proinsulin C-peptide Activates Vagus Efferent Output in Rats, Peptides. 2005 Dec;26(12):2547-53. 

(13) Derkach, K.V., Perminova, A.A., Buzanakov, D.M. et al. Intranasal Administration of Proinsulin C-Peptide Enhances the Stimulating Effect of Insulin on Insulin System Activity in the Hypothalamus of Diabetic Rats. Bull Exp Biol Med 167, 351–355 (2019). 

(14) Johansson B.L. et al.: C-peptide Improves Autonomic Nerve Function in IDDM Patients, Diabetologia. 1996 Jun;39(6):687-95.

(15) Holman Naomi et al.: Type 1 and Type 2 diabetes and COVID-19 related mortality in England: a cohort study in people with diabetes, content/uploads/2020/05/Valabhji-COVID-19-and-Diabetes-Paper-2-Full-Manuscript.pdf