Preprint Review Version 3 Preserved in Portico This version is not peer-reviewed

Low-Dose Interferon I and III-Based Nasal Sprays: A Good-Looking COVID-19 Vaccine Candidate?

Version 1 : Received: 6 December 2022 / Approved: 8 December 2022 / Online: 8 December 2022 (10:02:23 CET)
Version 2 : Received: 20 December 2022 / Approved: 21 December 2022 / Online: 21 December 2022 (02:31:00 CET)
Version 3 : Received: 18 February 2023 / Approved: 20 February 2023 / Online: 20 February 2023 (02:28:09 CET)
Version 4 : Received: 20 February 2023 / Approved: 21 February 2023 / Online: 21 February 2023 (02:38:38 CET)

How to cite: Carp, T.; Metoudi, M.; Brown, B.; Ojha, V. Low-Dose Interferon I and III-Based Nasal Sprays: A Good-Looking COVID-19 Vaccine Candidate?. Preprints 2022, 2022120155. Carp, T.; Metoudi, M.; Brown, B.; Ojha, V. Low-Dose Interferon I and III-Based Nasal Sprays: A Good-Looking COVID-19 Vaccine Candidate?. Preprints 2022, 2022120155.


The SARS–CoV-2 infection has caused both acute and chronic COVID19 disease during the recent pandemic with emerging more transmissible SARSCoV2 Omicron variants (BQ1 and XBB1) that have increased demands for more effective immunogens and therapeutic approaches to protect the lives of numerous SARS–CoV-2 affected individuals and reduce overall disease burden that could be affected by concurrent other pathogens causing diseases. Following a worldwide campaign of mass vaccination, there is still a significant demand to quell the harmful effects of novel SARSCoV2 infections due to higher mutation rates within specific areas of the SARS–CoV-2 domain, leading to enhanced viral entry, especially within individuals with one or more significant comorbidities, and there is still a dilemma of how prevention of future pandemics will occur as within host animal mutations and cross species transfer naturally occurs. Concerns intersect at a specific point; a gained evolutionary ability of several viruses over the previous centuries to remain undetected during the first stages of infection by means of capping the 5' end of their DNA and RNA genes respectively. This may occur by reducing the rate of host Type I and Type III Interferons (IFN) cellular synthesis, that would usually occur and affect both apoptotic pathways, that facilitate viral replication and clearance, as well as immune cells, that process and present pathogenic antigen epitopes. Furthermore, although methods of vaccination exist, other methods in clinical development remain that could evoke an immune response in different cellular, serum or mucosal compartments being cellular, serum and mucosal that evoke differential antibody responses. Antibodies are classed as natural and adaptive. Natural antibodies are further classed into neutralizing and non-neutralizing, whilst adaptive antibodies are also further classed into monoclonal and polyclonal. As a result of single cell study transcriptome research, viruses do utilize an array of protein receptors for receptor-mediated cellular entry. This, therefore suggests that potential differential production of antibody immunoglobulins (Ig) within serum and mucosal areas remains affected by cytokines, adhesion molecules and chemokines that can be upregulated or downregulated upon host viral infection. Serum plasma antibodies can be multimeric that may not efficiently cross the nasal epithelium cell layer, therefore offering less protection against mucosal inflammation due to mucin proteins. On the other hand, antibodies produced by mucosal plasma cells at epithelial surfaces are known to provide effective immune responses in some viral infections. The existence of developments that stimulate mucosal immune responses has so far only been seen with influenza nasal immunogens. Nevertheless, scientists developed ways of immunization and early treatment worldwide that generally showed good success rates and fewer risks of adverse events, and the still early present stages of COVID-19 research should also be taken into consideration. For example, the administration of human interferons I and III into the nasal mucosa cellular layer, as key mediators of antiviral activity, can stimulate cellular activity to train the innate and adaptive immune system cells to develop and appropriately stimulate an adequate immune response through B and T cells. Recently, it was discovered that specific plants secrete proteins that also stimulate the production of Type I Interferons. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. Naturally-selected polymorphic viruses through genetic recombination pose challenges to traditional concepts of cellular and molecular immune system neutralization of these viruses during the first stages of cellular infection. It is until the scientific community realizes this potentially crucial aspect that we will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades, evidenced with dengue fever and more recently monkeypox. Type I IFNs tend to be produced faster than Type III IFNs, and the first induce slightly more abundant pro-inflammatory signals than the latter, meaning that type III IFNs, if produced early, may further decrease the extent of excessive proinflammatory signals. Hence, we believe that nasal sprays containing a low dosage of Type I and Type III IFNs not only represent a relevant COVID-19 therapeutic, but also a potential unknown modulatory therapy of the future. Of note, it has been indicated that IFN I and / or III display significant early therapeutic effects for other viral evoked diseases like Influenza (A)H1N1 (Influenza), Rabies lyssavirus (rabies), measles virus (measles), Rubivirus rubellae (rubella), Hepatitis B, HIV-induced AIDS, as well as bacterial diseases, such as lower respiratory tract infectious disease induced by Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus, and a number of oncological diseases, like hepatic melanoma.


covid-19; pandemic; immune evasion; first-line immunity; viral evolution; interferon; dendritic cells; cytokines; chemokines; innate immunity; vaccinology


Biology and Life Sciences, Virology

Comments (1)

Comment 1
Received: 20 February 2023
Commenter: Theodor-Nicolae Carp
Commenter's Conflict of Interests: Author
Comment: We have added further details of the diverse methods pathogens develop to evade first-line immunity and we have found further evidence that Type I and Type III Interferons could be used in a low dosage as effective immunizing and early therapeutic agents against microbes of major concern, but particularly against microbes with more developed evolutionary abilities to evade Toll-Like Receptor detection, to cleave mRNA encoding Interferon I and III, and to tamper with signalling cascades that are responsible with the activation of Interferon-Stimulated Genes. We have added further details of clinical trials involving the usage of Interferon I and III-based products, whether in a low dosage, which are administered orally or intranasally, or in a high dosage, which are administered via intramuscular injections.
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