Next Generation Mucosal Vaccine Strategy for Respiratory Pathogens

Abstract

Inducing humoral and cytotoxic mucosal immunity at the sites of pathogen entry has the potential to prevent the infection from getting established. This is different from systemic vaccination, which protects against the development of systemic symptoms. The field of mucosal vaccination has seen fewer technological advances compared to nucleic acid and subunit vaccine advances for injectable vaccine platforms. The advent of the next-generation adenoviral vectors has given a boost to mucosal vaccine research. Basic research into the mechanisms regulating innate and adaptive mucosal immunity and the discovery of effective and safe mucosal vaccine adjuvants will continue to improve mucosal vaccine design. The results from clinical trials of inhaled COVID-19 vaccines demonstrate their ability to induce the proliferation of cytotoxic T cells and the production of secreted IgA and IgG antibodies locally, unlike intramuscular vaccinations. However, these mucosal vaccines induce systemic immune responses at par with systemic vaccinations. This review summarizes the function of the respiratory mucosa-associated lymphoid tissue and the advantages that the adenoviral vectors provide as inhaled vaccine platforms.

Keywords: COVID-19; SARS-CoV-2; adenovirus; influenza; inhaled vaccines; mRNA; mucosa-associated lymphoid tissue; mucosal immunity; respiratory infections.

Figure 1

Mucosa-associated lymphoid tissues. The immune system associated with various mucosal surfaces constantly surveils these points of entry for pathogens. Humans do not have a defined bronchi-associated lymphoid tissue (BALT), but rather the BALT is induced upon infection. The upper and lower respiratory tract mucosa includes undifferentiated basal cells, ciliated epithelial, pulmonary neuroendocrine (PNEC), and secretory goblet cells. The mucus secreted by the goblet cells provides a barrier to debris, allergens, and potential pathogens but also to mucosal vaccines. Created with BioRender.com.

Figure 2

Immune surveillance at the respiratory mucosa. Within the mucus layer are innate immune factors such as antimicrobial peptides, proteases, complement system factors, and secretory IgA and IgM antibodies. The dendritic cells (DCs) in the airways become activated on antigen capture and traffic to draining lymph nodes via afferent lymphatics. In T cell zones, the DCs present the antigens on MHC class II receptors to CD4+ T cells and on MHC class I receptors to CD8+ T cells, along with CD80/CD86 co-stimulation. This antigen presentation by DCs promotes the maturation and expansion of naive CD4+ and CD8+ T cells. CD4+ T cells with Th1 polarization assist in the maturation of cell-based cytotoxic immune responses, whereas Th2 polarized CD4+ T follicular helper (T_FH) cells migrate to the T-B zone border and assist in the maturation of B cells by TCR-MHC II engagement and CD40/CD40L co-stimulation. The T-B cell pairing causes B cell migration to the germinal centers and their clonal expansion. Within the germinal centers, activated B cells (assisted by follicular dendritic cells (FDC) and T_FH) undergo somatic hypermutation followed by further expansion. Through this iterative cycle B cells with high affinity to the target antigen are selected, followed by class-switching to either plasma cells or memory B cells, which traffic back to the site of infection in the respiratory mucosa. Created with BioRender.com.

Figure 3

Strategies to improve the delivery, penetration, uptake, and immunogenicity of respiratory mucosal vaccines. Vaccines targeting the respiratory mucosa can be delivered nasally (drops, spray, or inhalation) or orally (drops, oral inhalation, aqueous drink, or capsule/tablet). The target antigens can be delivered as nucleic acid or protein subunit vaccines packaged in different lipid/non-lipid nanoparticles or by traditional live-attenuated or inactivated whole virus vaccines. Post-COVID, the adenoviral vector system has gained interest as an intranasal/inhaled vaccine delivery platform. Facilitating antigen delivery by nanoparticles involves mucoadhesive, mucopenetrating, or mucolytic strategies. Created with BioRender.com.

Figure 4

Advantages of adenoviral vectors for mucosal vaccines. Naturally existing adenoviruses cause respiratory tract infections and therefore can overcome the mucosal barrier. Adenoviral vectors are capable of transducing multiple types of cells and have a high carrying capacity for large or multi-cistronic antigens. Compared to other viral vectors, adenoviruses are easy to modify, have greater thermostability, and are easy to scale up for mass production. Created with BioRender.com.