First-generation vaccines against coronavirus reduce disease severity and mortality. However, these vaccines do not confer sterilizing immunity and cannot completely prevent infection and subsequent virus spread. The reason is that existing vaccines cause predominantly systemic reactions but do not form substantial upper respiratory tract (URT) mucosal immunity. Coronavirus transmission cannot be prevented without triggering immune responses in the URT.
The danger of suboptimal immunity is that the continuously spreading coronavirus mutates, creating highly virulent vaccine-resistant strains. One of these strains was Omicron, which can elude the immune response.
Scientists from leading UK, France, and Luxembourg universities have proposed intranasal interferon-alpha during vaccination against coronavirus. This approach:
- reduce the need to refine vaccines for new strains;
- reduce the rate of transmission of coronavirus by early suppression of infection in the upper respiratory tract;
- slow down the evolution of the virus due to less efficient virus replication;
- increase the duration of protection generated by the vaccine.
The Role of Upper Respiratory Mucosal Immunity in Vaccine Efficacy and Longevity
The respiratory tract, mouth, and mucous membranes of the eyes are the main routes of coronavirus entry. They provide the first line of defense against infection. If the immunity of the mucous membrane of the upper respiratory tract at an early stage of infection can suppress the coronavirus, the virus will not penetrate the lower respiratory tract, and the disease will not progress. In addition, the mucosa of the upper respiratory tract can generate a sterilizing immunity that blocks virus transmission.
Even those vaccinated get sick with the coronavirus, which could encourage the emergence of new vaccine-resistant strains that are more infectious and better able to bypass immune defenses. The reason is that natural selection usually eliminates highly virulent strains of viruses that cause severe illness and death since the virus is also destroyed. However, vaccines that improve survival but do not prevent transmission allow strains to emerge that cause more severe diseases. This scenario could increase mortality among the unvaccinated and immunocompromised, including older patients, patients with chronic inflammatory diseases, and obesity. If the vaccine can prevent the transmission of the virus, the evolution of the virus towards strains that cause severe disease is blocked.
The level of IgG antibodies to the coronavirus spike protein and the level of neutralizing antibodies can judge the vaccine’s effectiveness.
However, because the coronavirus infects the mucous membranes of the respiratory tract, the vaccine must also activate the immunity of the upper respiratory tract mucosa to prevent infection, not just symptomatic disease. SARS-CoV-2 specific IgA antibodies of the upper respiratory tract mucosa can protect against coronavirus infection, and stable T-cell responses specific to SARS-CoV-2 in the upper respiratory tract mucosa can contribute to the formation of sterilizing immunity.
Mucosal Immunity Provides Long-Term Protection against Coronavirus
The antiviral immune response formed by the vaccine rapidly decreases by half in 4-5 months after vaccination.
Tissue-resident memory T cells (TRMs) protect mucosal membranes from infection and can trigger a rapid, specific immune response. Airway TRMs provide strong protection against respiratory pathogens even without neutralizing antibodies. The decrease in the severity of COVID-19 has been associated with an increase in the number of TRM helpers and TRM killers in the airways. However, pulmonary TRMs can only provide temporary protection as they are depleted and significantly reduced in number over time. Conversely, nasal TRMs can persist for a long time and provide long-term protection against influenza, preventing the development of severe lung disease.
Coronavirus primarily affects the nasopharynx and oral mucosa. Therefore, the TRM of the upper respiratory tract and not the pulmonary TRM can suppress the infection before it reaches the lower respiratory tract and causes pulmonary pathology.
Developing vaccines that elicit potent upper respiratory TRM responses in addition to antibody production could provide long-term protection against coronavirus infection. In addition, the immune response of the VRT may contribute to the formation of trained immunity, increasing the efficiency of the response of innate immunity cells to the virus. The advantage of trained immunity is that it is activated immediately upon encountering a virus. It can enhance the body’s defense reactions, overcoming the immunosuppression caused by the virus and also facilitating the formation of adaptive immunity.
Respiratory Tract Mucous Membranes Immunity Depends on The Method of the Vaccine Administration
The ability of mRNA vaccines to activate airway mucosal immunity has been questioned, while some vector vaccines have elicited an airway mucosal immune response. Often intramuscular vaccines against respiratory viruses do not cause strong reactions of memory cells of the mucous membrane of the respiratory tract.
Unlike intramuscular, respiratory mucosal vaccination can efficiently generate airway and lung TRMs, follicular T helper cells (Tfh), critical for triggering an antibody response, and mucosal IgA antibodies. A study in mice showed that intranasal but not subcutaneous vaccination completely protects against lethal coronavirus infection. Another study showed that intranasal immunization could provide reliable upper and lower respiratory tract protection against old and new coronavirus strains.
However, many intranasal vaccines are often considered unsafe compared to intramuscular vaccines. The problem is that when administered intranasally, the vaccine dissolves in mucosal secretions, is captured by mucosal gels, undergoes enzymatic cleavage, and is removed from the body, impairing absorption and bioavailability of the vaccine. Therefore, significantly higher doses of the vaccine are needed, which induce an immune response in the mucous membrane of the upper respiratory tract. However, such amounts may be unsafe for humans.
Type I Interferon Signaling in The Upper Respiratory Tract Contributes to The Early Suppression of Infection and The Formation of Sterilizing Immunity
How adequate and durable protection against severe COVID-19 will be after vaccination depends on the ability of innate and adaptive immunity to stimulate the creation of SARS-CoV-2-specific subsets of memory T cells, germinal center-derived memory B cells, and long-lived plasma cells. Germinal centers are temporary microanatomical structures in secondary lymphoid organs where B cells acquire memory.
Innate immunity is vital for forming immunological memory in response to a vaccine, as it provides the necessary signals for activating T cells.
Type I interferons (IFN), among which – IFN-α and IFN-β – are usually produced on the surfaces of mucous membranes in response to the presence of the virus. Interferons trigger an inflammatory cascade leading to the expression of IFN-stimulated genes (ISGs) that interfere with viral replication and trigger an innate and adaptive antiviral response. A fast normal IFN-1 response is essential for effective protection against coronavirus.
IFN-1 promotes Tfh cell differentiation and stimulates germinal center responses, necessary for a sustained antibody response with a solid neutralizing ability and directly stimulating B cell response. IFN-1 signaling can modify the innate immune response to a pathogen, contributing to the creation of trained immunity. IFN-α signaling in the airway mucosa is also crucial for TRM differentiation.
During the first week after infection with coronavirus, ISGs are overexpressed in the nasopharynx. The protection provided by IFN/ISG in the upper respiratory tract can rapidly suppress coronavirus replication, reducing viral load, the possibility of virus transmission, and the risk of severe COVID-19.
IFN-α is critical for early control of coronavirus infection. Patients recovering from mild to moderate COVID-19 showed early transient production of IFN-α and the absence of IFN-β. However, in severe or critical cases, an inadequate or no response to IFN-α was observed, followed by clinical deterioration and transfer of patients to the intensive care unit.
It is unlikely that intramuscular vaccines trigger a significant IFN-1/ISG response or the formation of an antigen-specific immune memory in the upper respiratory mucosa. The reason is that vaccines trigger the production of IFN-1 at the injection site, after which the inflammatory signal of interferon causes a systemic antiviral response but has little effect on the respiratory mucosa. Therefore, vaccines often do not prevent the entry of the coronavirus into the upper respiratory tract and subsequent transmission.
Intranasal Administration of Interferon-Alpha Stimulates Upper Respiratory Immunity and Improve the Efficacy and Longevity of SARS-Cov-2 Vaccines
Intranasal administration of IFN-1 as an adjuvant to vaccines against coronavirus triggers an inflammatory response in the nasopharyngeal mucosa and stimulates the development of TRM of the upper respiratory tract and IgA responses of the upper respiratory tract mucosa. Therefore, intranasal administration of type I interferon at the time of vaccination may increase the efficacy and longevity of vaccines.
Figure. Vaccine-only protection versus vaccine plus intranasal interferon-α
Image source: https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(23)00017-5
Figure details. Benefits of using intranasal IFN-α as an adjuvant for coronavirus vaccines:
- SARS-CoV-2 vaccines predominantly induce systemic, SARS-CoV-2-specific responses but not solid and sustained responses in the upper respiratory tract mucosa. Therefore, vaccines do not confer sterilizing immunity because infection and subsequent transmission cannot be prevented without triggering URT mucosal reactions.
- Supplementation with IFN-α and existing vaccination strategies against SARS-CoV-2 may generate solid mucosal immunity in the upper respiratory tract.
- IFN-α is produced in the mucosa of the upper respiratory tract during SARS-CoV-2 infection. Intranasal administration of IFN-α functionally mimics the body’s natural immune response.
- IFN-α signaling in the upper respiratory tract can create an inflammatory environment that recruits lymphocytes to form TRM cells in the upper airways.
- TRMs provide the first line of defense against respiratory pathogens, even without neutralizing antibodies. TRM TRMs can persist for a long time and block the spread of the virus before it reaches the lungs and causes lung disease.
- IFN-α signaling is involved in the formation of TRM killers.
- IFN-α signaling triggers the production of cytokines that stimulate TRM differentiation. Cytokines include TNF-α, IL-2, IL-12, and IL-15.
- The production of IL-12 and IL-15 promotes the activation of TRM helpers, which can subsequently differentiate into polyfunctional T cells with potent antiviral functions.
- SARS-CoV-2 can suppress the IFN-1 response. Therefore, SARS-CoV-2 infection triggers a weaker IFN-1 response than other respiratory RNA viruses, which may be responsible for inadequate URT TRM responses in both vaccinated and unvaccinated individuals. Adding intranasal IFN-α may solve this problem and promote a more extended TRM response.
- IFN-α promotes Tfh cell differentiation and stimulates germinal center responses required for a sustained antibody response with strong neutralizing capacity.
- IFN-α signaling in the upper respiratory tract triggers IgA responses in the nasopharyngeal mucosa, which may provide early suppression of infection.
- Intranasal IFN-α, given as an adjuvant at the same time as intramuscular SARS-CoV-2 vaccines, may enhance the systemic response to vaccination.
- Adding IFN-α as an adjuvant to existing vaccines allows the use of first-generation vaccines against SARS-CoV-2 without refining vaccines for new strains.
Conclusion
When co-administered with intramuscular vaccines against coronavirus, intranasal interferon-alpha stimulates the formation of a reliable immunological memory of the upper respiratory tract mucosa, contributing to the early suppression of infection in the upper respiratory tract, preventing the progression of the disease to a severe form, blocking the transmission of the virus and creating long-term protection against infection.
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Reference
Upper respiratory tract mucosal immunity for SARS-CoV-2 vaccines
