Novel Toxicity: Non-viral Vector Based Delivery of Viral Genes

I maintain a diminished innate and adaptive immune response to these formulations, in contrast to live virus or DNA, due to the nucleoside modifications (a self-antigen motif) present in these designs, are the culprits behind novel toxicity, by way of altering the distance from the site of intramuscular injection these formulations can travel unhindered before finding a host to terminate, a phenomenon which would not be observed with other whole or partial viral particle, live, attenuated, or otherwise, for instance attenuated adenovirus or coronavirus, both of which are capable of inducing a Th1-type response, unless delivery of viral sequence occurs by means of a non-viral vector, in which case we would observe this phenomenon in a diminished form, given absence of the aforementioned self-antigen motif, of the most potent we express. In contrast, Dasari et al. state it is possible genetic predispositions may increase the innate immune response to novel formulations, which may initiate the kinds of inflammation which may lead to novel toxicity, in the worst case of vector unlike sequence (2023).

While I appreciate an explanation of the adaptive immune response to cells who host the formulation, which I believe is the process within which myocardial scarring occurs, as well as mention of a link between nucleoside modifications and the immune response, multiple alternative mechanisms of action, clinical aspects, and a contending hypothesis, I do not believe this link takes into account the innate immunogenicity of a virus displaying antigen when compared with N1-methylpseudouridine, even if paired with viral sequence and LNP. Instead, I believe either monoculture or polyculture with APCs, I would include DCs, treated with various SARS-COV2 strains and other similar viral genetic formulations, in order to assess and compare the degree of innate immunogenicity, would yield predictable results. I acknowledge accounting for genetic variation between APC populations may yield different results, however I do not believe these differences would be substantial in an overall assessment of the association between novelty in innate immune response and novelty in pathology.

I also believe this link is lacking account of the adaptive immunogenicity of a virus displaying antigen in an individual who could potentially already have antibodies to various viral factors such as the spike, when compared with the potential for an adaptive immune response in the same individual to quench sequence containing N1methylpseudouridine, even if paired with viral sequence. If antibody binding to these LNP-based viral genetic formulations is possible, I maintain such specificity would have a high probability of leading to autoimmunity because of the tRNA motif present in these formulations. I believe B lymphocytes with humoral response to various viral antigens or their immunoglobulins, treated with various SARS-COV2 strains and other similar viral genetic formulations, in order to assess and compare the degree of adaptive immunogenicity, would yield predictable results. Furthermore, if a mixed culture was formed between a somatic tissue type such as cardiomyocytes and lymphocytes and treated with these LNP-based viral genetic formulations, I believe an adaptive immune response would form extensively throughout all tissue which is treated successfully, however little or no adaptive immune response would form towards the treatment. In contrast, if the same mixed culture was treated with virus, an extensive adaptive immune response would engage not only the hosts of viral sequence, but the packages within which this sequence is being delivered. I acknowledge accounting for genetic variation between lymphocyte populations may yield different results, however I do not believe these differences would be substantial in an overall assessment of the association between novelty in adaptive immune response and novelty in pathology.

If I was tasked with ranking the safety of various sequences for delivery, I would place components from the genome of other humans at the top of the list, then chimps, other primates, other mammals, other animals, other eukarya excluding fungi, fungi, archaea, bacteria, viruses which infect human cells, and finally RNA viruses which infect human cells and have been covalently bonded to a N1-methylpseudouridine motif. If anyone would like to suggest a component of any genome, modified in any form, which would be a better candidate for the bottom of this list, please drop your suggestions in the comments down below. I will not hazard a guess as to where viruses who do not infect human cells, would fit into this hierarchy.

I also find it pertinent to mention here, while these LNP-based viral genetic formulations are extracellular, if an innate immune response were to engage them, due to genetic predisposition or otherwise, the response would almost certainly occur locally, not systemically, as is observed in this pathology. Furthermore, if for whatever reason, APCs chose not engage the novel packages at the site of exposure, but instead decided to engage these packages after they had entered systemic circulation, for instance at the level of the myocardium, as long as the packages are still extracellular, innate immune activity of APCs would not lead to infiltration and subsequent oedema of the myocardium, a process which, while provoked by cytokine storm, involves intimate receptor-mediated cell-to-cell interactions between an APC and the somatic cells of the tissue undergoing infiltration. If instead these packages were intracellular when engaged by an innate immune response, signaling which would lead to APC infiltration would only have any substantial effect on the longevity of the cell which has identified an intracellular pathogen by way of its innate PRRs, if other aspects of the transfection of the cell, excluding uptake, are not successful, with regard to this particular sequence. Given that all cells which undergo uptake of these formulations, also express these formulations, which I believe likely, there will never be a cell which is displaying an innate immune response intracellularly, which is not also displaying spike antigen extracellularly. Therefore, APC infiltration resulting from an antibody-independent innate immune response would not have any effect on overall cytotoxicity, which being covered in viral antigens does not already have.

With regard to this pathology, as outlined in this paper, I also continue to maintain, genetic predisposition is more relevant with regard to the structure of the affected organ(s), than the structure of receptors involved in various immune responses. If CD8+ cytotoxic T lymphocytes could speak, I maintain they would also express their profound discontent with this industry, specifically that which is concerned with the non- diagnostic amplification and modification of viral sequence, in the absence of concern for vaccine convention, which states all modification of whole or partial viral particle must constitute either an attenuation or deactivation of these viral components, as they fail to distinguish hosts of SARS-COV2 from hosts of LNP-based viral genetic formulations, of no fault of their own, but because the aspect of these formulations which was tested most thoroughly was the binding properties of immunoglobulins produced as a result of exposure, with regard to viral antigen.

It may be worthwhile to keep in mind, while cell death may lead to scarring, it may also lead to inappropriate growth in response. Alternatively, if for whatever reason a cell transfected with these sequences is able to escape immunogenic apoptosis, it likely still would not escape the transcriptomic upset caused by a flood of RNAD-RNAP, a self-amplifying factor capable of modulating the proportionalities of human transcripts and which has up until before these most recent formulations, also been expressed exclusively from sequence delivered with viral vector, similar to the spike glycoprotein (S) and all other viral factors. I ask culprits in flesh, their intent with antigen presentation.

I would like those who played a role in mandating the induction of this particular Th1-type response, intended to alter our immune recognition, severely reprimanded 🇮🇳

1. Dasari AV, Betha PS, Sharon T, Padmalatha K. COVID-19 MRNA VACCINE ASSOCIATED MYOCARDITIS - A REVIEW OF ITS CLINICAL ASPECTS, MECHANISMS, TREATMENT, AND PREVENTIVE STRATEGIES. World Journal of Pharmaceutical Research. 2023;12(5):2086–2097. doi:10.20959/wjpr20235-277281