Pathogenic priming likely contributes to serious and critical illness and mortality in COVID-19 via autoimmunity

Abstract

Homology between human and viral proteins is an established factor in viral- or vaccine-induced autoimmunity. Failure of SARS and MERS vaccines in animal trials involved pathogenesis consistent with an immunological priming that could involve autoimmunity in lung tissues due to previous exposure to the SARS and MERS spike protein.

Exposure pathogenesis to SARS-CoV-2 in COVID-19 likely will lead to similar outcomes. Immunogenic peptides in viruses or bacteria that match human proteins are good candidates for pathogenic priming peptides (similar to the more diffuse idea of “immune enhancement”).

Here I provide an assessment of potential for human pathogenesis via autoimmunity via exposure, via infection or injection. SAR-CoV-2 spike proteins, and all other SARS-CoV-2 proteins, immunogenic epitopes in each SARS-CoV-2 protein were compared to human proteins in search of high local homologous matching.

Only one immunogenic epitope in a SARS-CoV-2 had no homology to human proteins. If all of the parts of the epitopes that are homologous to human proteins are excluded from consideration due to risk of pathogenic priming, the remaining immunogenic parts of the epitopes may be still immunogenic and remain as potentially viable candidates for vaccine development.

Mapping of the genes encoding human protein matches to pathways point to targets that could explain the observed presentation of symptoms in COVID-19 disease. It also strongly points to a large number of opportunities for expected disturbances in the immune system itself, targeting elements of MHC Class I and Class II antigen presentation, PD-1 signaling, cross-presentation of soluble exogenous antigens and the ER-Phagosome pathway. Translational consequences of these findings are explored.

Discussion

These results could explain in part the high rates of serious illness associated with SARS-CoV-2. They could also explain the lengthy asymptomatic period prior to presentation of symptoms characteristic of COVID-19. SARS-CoV-2 could impair the immune response, at first, and then, over time, the immune system could begin to mount an attack on the myriad of proteins. Most of the identified human target proteins had low overall homology but high local homology over short segments of their epitopes. The Protein Atlas results indicated that numerous proteins are expressed in a variety of tissues as noted in Table 1.

Unintended consequences of pathogenesis from vaccines are not new, nor are they unexpected. They are unanticipated only if those who develop them do not include available knowledge in their formulation plan. For example, the H1N1 influenza vaccine used in Europe led to narcolepsy in some patients, resulting from homology between the human hypocretin (aka, orexin) receptor 2 molecule and proteins present in the vaccine. This was established via the detection of cross-reactive antibodies in the serum of patients who develop narcolepsy following H1N1 vaccination in Europe [5].

The fact that pathogenic priming may be occurring involving autoimmunity against multiple proteins following CoV vaccination is consistent with other observations observed during autoimmunity, including the release of proinflammatory cytokines and cytokine storm. Similar to the SARS-CoV animal studies [6], found that mice vaccinated against MERS-CoV (Middle East Respiratory Syndrome) development exaggerated pulmonary immunopathology when challenged with the MERS virus following vaccination. They reported that lung mononuclear infiltrates were observed in all groups after virus challenge, and that increased infiltrates that contained eosinophils and the eosinophil promoting IL-5 and IL-13 cytokines were observed only in the vaccinated animals.

Pathogenic priming may be more or less severe in vaccine or infection induced immune responses to some proteins than for others due to original antigenic sin; the immunologic reaction against self-antigens may be made less severe as fast-evolving viruses evolve away from the original vaccine type. Thus, the screening of immunogenic epitopes for pathogenic priming potential via homology may be augmented by studies of autoantibodies that cross-react with epitopes included in vaccines.

SARS-CoV-2 has some unexplained pathogenic features that might be related to the table of putative pathogenic priming peptides. Exposure to these specific peptides – via either infection or vaccination – might prime patients for increased risk of enhanced pathogenicity during future exposure due either to future pandemic or outbreaks or via universal vaccination programs. While the mechanisms pathogenesis of COVID-19 are still poorly understood, the morbidity and mortality of SARS has been extensively studied. Thus, the involvement of pathogenic priming in re-infection by COVID-19 is a theoretical possibility; of course no vaccine against SARS-CoV-2 has yet been tested in animals and therefore we do not yet know if pathogenic priming is in fact expected. Such studies should be undertaken before use of any vaccine against SARS-CoV-2 is used in humans.