Advances in intranasal vaccine delivery: A promising non-invasive route of immunization.

The importance of vaccination has been proven particularly significant the last three years, as it is revealed to be the most efficient weapon for the prevention of several infections including SARS-COV-2. Parenteral vaccination is the most applicable method of immunization, for the prevention of systematic and respiratory infections, or central nervous system disorders, involving T and B cells to a whole-body immune response. However, the mucosal vaccines, such as nasal vaccines, can additionally activate the immune cells localized on the mucosal tissue of the upper and lower respiratory tract. This dual stimulation of the immune system, along with their needle-free administration favors the development of novel nasal vaccines to produce long-lasting immunity. In recent years, the nanoparticulate systems have been extensively involved in the formulation of nasal vaccines as polymeric, polysaccharide and lipid ones, as well as in the form of proteosomes, lipopeptides and virosomes. Advanced delivery nanosystems have been designed and evaluated as carriers or adjuvants for nasal vaccination. To this end, several nanoparticulate vaccines are undergone clinical trials as promising candidates for nasal immunization, while nasal vaccines against influenza type A and B and hepatitis B have been approved by health authorities. This comprehensive literature review aims to summarize the critical aspects of these formulations and highlight their potential for the future establishment of nasal vaccination. Both preclinical (in vitro and in vivo) and clinical studies are incorporated, summarized, and critically discussed, as well as the limitations of nasal immunization.

Naïve CD4+ T Cell Activation in the Nasal-Associated Lymphoid Tissue following Intranasal Immunization with a Flagellin-Based Subunit Vaccine.

The nasal-associated lymphoid tissues (NALT) are generally accepted as an immune induction site, but the activation of naïve T-cells in that compartment has not been well-characterized. I wanted to determine if early events in naïve CD4+ T cell activation and the extent of antigen specific cell division are similar in NALT to that observed in other secondary lymphoid compartments. I performed antigen tracking experiments and analyzed the activation of naïve antigen-specific CD4+ T cells in the nasal-associated lymphoid tissues (NALT). I directly observed transepithelial transport of fluorescently labeled antigen from the lumen of the airway to the interior of the NALT two hours following immunization. One day following intranasal (i.n.) immunization with antigen and adjuvant, antigen-specific CD4+ T cells in the NALT associated as clusters, while antigen-specific CD4+ T cells in control mice immunized with adjuvant only remained dispersed. The antigen-specific CD4+ populations in the NALT and cranial deep cervical lymph nodes of immunized mice expanded significantly by day three following immunization. These findings are consistent with initial activation of naïve CD4+ T cells in the NALT and offer insight into adjuvant mechanism of flagellin in the upper respiratory compartment.

Type 2 diabetes mellitus impaired nasal immunity and increased the risk of hyposmia in COVID-19 mild pneumonia patients.

In patients with COVID-19,type 2 diabetes mellitus (T2DM) can impair the function of nasal-associated lymphoid tissue (NALT) and result in olfactory dysfunction. Exploring the causative alterations of T2DM within the nasal mucosa and NALT could provide insight into the pathogenic mechanisms and bridge the gap between innate immunity and adaptive immunity for virus clearance. Here, we designed a case-control study to compare the olfactory function (OF) among the groups of normal control (NC), COVID-19 mild pneumonia (MP), and MP patients with T2DM (MPT) after a 6-8 months' recovery, in which MPT had a higher risk of hyposmia than MP and NC. No significant difference was found between the MP and NC. This elevated risk of hyposmia indicated that T2DM increased COVID-19 susceptibility in the nasal cavity with unknown causations. Therefore, we used the T2DM animal model (db/db mice) to evaluate how T2DM increased COVID-19 associated susceptibilities in the nasal mucosa and lymphoid tissues. Db/db mice demonstratedupregulated microvasculature ACE2 expression and significant alterations in lymphocytes component of NALT. Specifically, db/db mice NALT had increased immune-suppressive TCRγδ+ CD4-CD8- T and decreased immune-effective CD4+/CD8+ TCRß+ T cells and decreased mucosa-protective CD19+ B cells. These results indicated that T2DM could dampen the first-line defense of nasal immunity, and further mechanic studies of metabolic damage and NALT restoration should be one of the highest importance for COVID-19 healing.