New inhalable COVID-19 vaccine

A recent study published in the Nature Biomedical Engineering illustrated a novel inhalable SARS-CoV-2 vaccine candidate centered on exosomes (Exos) coupled to the receptor-binding domain (RBD) of recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Exosomes decorated with a recombinant SARS-CoV-2 receptor binding domain as an inhalable COVID-19 vaccine. Image Credit: WESTOCK PRODUCTIONS / Shutterstock

Background

The COVID-19 pandemic is affecting nearly every aspect of people’s daily lives around the world, as hundreds of thousands of people are dying from coronavirus disease 2019 (COVID-19) every day. There are currently approximately 36 SARS-CoV-2 vaccines available worldwide.

The two initially approved SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccines, i.e. Moderna and Pfizer/BioNTech, require a cold chain for storage and transport. In addition, they trigger systemic immunity by intramuscular injection.

The early penetration of pathogens is significantly influenced by the immune response of the airway mucosa, which results in humoral and cell-mediated immune responses that lead to systemic reactions. As respiratory droplets are the primary means of transmission for SARS-CoV-2 and the respiratory mucosa is the initial site of viral entry, inadequate mucosal immunity may restrict the effectiveness of COVID-19 vaccinations administered intramuscularly.

About the study

The goal of the current study was to create a vaccine option for SARS-CoV-2 that effectively stimulates mucosal immunity, allows for a non-invasive, needle-free method of administration, and is lyophilizable and stable at room temperature. (rt) for months. Scientists have developed an inhalable vaccine by combining the SARS-CoV-2 RBD with an Exos surface derived from lung spheroid cells (LSC-Exo), i.e. RBD-Exo, to create a virus-like particle ( VLP) which mimics the morphology of the native virus.

From a human lung donor sample, the team produced LSCs. They have previously used rodent models of idiopathic pulmonary fibrosis (IPF) to analyze the biodistribution and safety of LSC-Exo. LSC-Exo was native nanoparticles (NPs) for lung therapeutics obtained from distinct lung cell populations, such as type I and II pneumocytes and mesenchymal cells.

Researchers validated the optimal distribution of Exo in the parenchyma and bronchi of rodent lungs. They evaluated the retention and biodistribution of NPs (liposomes or LSC-exosomes) in the murine lung. In addition, microscopic visualization and ex vivo imaging were performed using commercially available red fluorescent protein (RFP)-loaded liposomes (RFP-Lipo) and LSC-Exo (RFP-Exo).

Results and conclusions

According to study results, the SARS-CoV-2 RBD-Exo vaccine elicited cellular and humoral immune responses that protected mice from infection with a SARS-CoV-2 mimic and SARS infection. -Alive CoV-2 in a hamster model.

RBD-Exo vaccination resulted in significant concentrations of RBD-selective immunoglobulin A (IgA) and CD8+ and CD4+ T cells and potent IgG antibodies in the lungs. These components were essential to prevent infection with SARS-CoV-2 D614G and the wild-type variant and to defend the lungs against viral invasion of the airway mucosa. Based on the data presented in this study, if Exos is the vaccine carrier, inhalation was a safe and reliable approach to inducing potent mucosal immunity.

The authors discovered Exo biodistribution on liposomes in the lungs of healthy CD1 mice. They chose Exos as the basis for the VLPs they created because of their exceptional lung retention and enhanced antigen-presenting cell (APC) specificity. Exos’ average diameter was slightly improved by RBD decoration, according to Nanoparticle Tracking Analysis (NTA). The results of the study validated the generation of RBCD-Exo VLPs.

Current data showed that RBD-Exo had significant physical and antigenic stability at all tested temperatures, possibly surpassing currently approved COVID-19 vaccines. Additionally, pulmonary dendritic cells (DCs) preferentially collected and processed RBD-Exo. Unlike RBD-Exo, the team also found little free uptake of RBD by APCs present in the lungs.

Ex vivo imaging and confocal laser scanning microscopy (CLSM) implicated that RBD-Exo VLP vaccinations promoted rapid clearance of SARS-CoV-2 mimics in CD1 mice. Additionally, administration by nebulization caused faster clearance of SARS-CoV-2 mimics in all groups than intravenous (IV) injection. This inference indicated that nebulization was a more efficient and targeted method for delivering RBD-Exo vaccines. Inhalation of RBD-Exo VLP caused the strongest induction of RBD-selective IgG antibodies in mouse sera, according to an enzyme-linked immunosorbent assay (ELISA).

While RBD-Exo nebulization elicited a T-helper type 1 (Th1)-biased immune response, RBD-Exo IV injection elicited a Th2-biased immune response with selective IgG1 antibody production. Compared to RBD-Exo IV therapy, RBD-Exo VLP significantly increased the generation of RBD-selective IgA antibodies in IgG isotype complementary serum.

Current results showed that inhalation of RBD-Exo resulted in the production of anti-RBD neutralizing antibodies and secretory IgA (SIgA) responses. RBD-Exo with long-term storage (LTS) and RBD-Exo elicited asymmetric Th1 cellular immune responses in mouse lung. The RBD-Rhodamine (RhB) treatment group showed a decrease in RBD signal in major organs compared to the RBD-Exo nebulization cohort.

Splenocytes from RBD-Exo inhalation-treated animals had higher percentages of CD40+, CD86+, and CD80+ DCs, implying that more DCs were stimulated. In the absence of allergic-type reactions, inhalation of RBD-Exo strongly elicited a systemic T-cell immune reflex that may further protect participants from viral replication. Histological data strongly suggest that RBD-Exo vaccination could significantly prevent live SARS-CoV-2 infection in hamster lungs. In addition, IgA antibodies induced by RBD-Exo VLP have greater cross-activity than IgG antibodies.

Overall, the investigators noted that rt and freeze-dried COVID-19 vaccines, such as the SARS-CoV-2 RBD-Exo VLPs developed in the present study, have a longer shelf life and, therefore, could reduce transportation costs, making them more widely available. .

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