Department of Medicine, Section of General Pathology, University of Verona (I), Italy, Italy
Corresponding author details:
Paolo Bellavite
Department of Medicine
Section of General Pathology University of Verona (I)
Italy
Copyright: © 2020 Bellavite P. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 international License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Some anecdotal reports of adverse events following vaccination with adenoviral vaccines related to neurological disorders. Although not considered causally related to the vaccine, the critical issue requires the utmost caution. In light of the fact that HEK293 cells, in which the vaccine adenoviruses are grown, are neuronal lineage, and that the virus spike protein has many homologies with human proteins, the possibility of a trigger of neurological autoimmune diseases cannot be ruled out in principle. Understanding this possibility could help to better inspect the antibody and lymphocyte reactions that are triggered by the vaccine, by measuring any autoantibodies against neuronal proteins in the serum of the volunteers.
Researchers and vaccine developers around the world are developing Coronavirus disease 2019 (COVID-19) vaccines and several candidate vaccines are now undergoing evaluation in clinical trials, although none had been approved for general use [1]. At least four of the candidate COVID-19 vaccines use replication-deficient adenoviruses cultivated on the line HEK-293, developed in the lab of molecular biologist Alex van der Eb at Leiden University [2]. The HEK293 kidney embryonal cell line was derived from the transformation of primary cultures of human embryonic kidney cells with adenovirus-5 (Ad5) DNA. Once transformed and cultured in the laboratory, these cells are widely used in research and industry and in the production of new generation vaccines, of which particularly current are those for immunization against Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [3-7]. An adenoviral vector grown on HEK293 is also currently being tested for immunization against tuberculosis [8].
Phase 2/3 trials have been started on healthy volunteers of these vaccine formulas and a few reports of neurological adverse reactions have emerged, the causal link of which with the vaccine cannot be established also because the cases are too few to be of statistical value. This interpretation difficulty is normal in phase 2 and 3 studies for particularly rare reactions. Since the reactions reported, including transverse myelitis, are particularly serious, they even generated a momentary halt to the experiment and alarmed the population. Some concerns have been raised regarding the lack of transparency in reporting the nature and number of such reactions in ongoing trials [9]. Pending the clarification of the causes of neurological diseases, we intend to point out the possibility that they are autoimmune reactions to some vaccine components and the biological plausibility of the phenomenon. Transverse myelitis occurrence after influenza vaccine and other virus vaccines was previously reported [10-16], but according to some authors the evidence for a causal association is inconclusive [17].
Although the HEK cell line is derived from kidney cells of a human embryo [2], subsequent evidence was provided that the transformed line with Ad5 insertion shares many characteristics of neuronal cells [18]. This study done with immunostaining, immunoblot and microarray analysis techniques showed that HEK293 cells develop neurofilaments (NF) and express NF-L, NF-M, NF-H subunits. Additionally, they found α-internexin as well as many other proteins typically found in neurons. Furthermore, other independently derived HEK lines from the originals, once transformed with adenoviruses (Ad5 and Ad12) express NF proteins, suggesting that similarity to neuronal cells is a common feature to cells transformed by adenovirus. This finding may suggest that these adenoviruses have a particular tropism for cells of neuronal lineage. For these reasons, others pointed out that these cells should not be used as kidney cells [19]. More recently, HEK293 cells were used as a model of neuronal cells expressing functional muscarinic receptors blocked by atropine [20].
These biological characteristics of HEK293 cells could generate the hypothesis that some neurological events observed in people treated with
recent coronavirus vaccines are actually autoimmune reactions
against the residual substances of the neuron-like cells in which
the vaccine viruses are grown. This hypothesis is corroborated
by the recent observation that in neurological autoimmunity
a correlation between disease activity and NF-L values was
observed [21] and that anti-NF antibodies have been observed in
various neurological diseases, correlating with progression [22].
Our hypothesis don’t exclude that autoimmune reactions could
be triggered by a cross-reaction with an adenovirus vector itself
or with proteins coded by the RNA vaccine, since a noteworthy
molecular mimicry has bees found between SARS-CoV-2 spike and
human proteins [23]. To confirm or refute the risk of neurological
autoimmune reactions, we suggest that sera from people treated
with adenoviral COVID-19 vaccines are tested for the possible
presence of antibodies against neuronal proteins.
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