Intranasal vaccines for SARS-CoV-2: From challenges to potential in COVID-19 management

Abstract

Unlike conventional Coronavirus 2019 (COVID-19) vaccines, intranasal vaccines display a superior advantage because the nasal mucosa is often the initial site of infection. Preclinical and clinical studies concerning intranasal immunization elicit high neutralizing antibody generation and mucosal IgA and T cell responses that avoid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in both; the upper and lower respiratory tract. A nasal formulation is non-invasive with high appeal to patients. Intranasal vaccines enable self-administration and can be designed to survive at ambient temperatures, thereby simplifying logistical aspects of transport and storage. In this review, we provide an overview of nasal vaccines with a focus on formulation development as well as ongoing preclinical and clinical studies for SARS-CoV-2 intranasal vaccine products.

Keywords: Antigen-presenting cells (APCs); COVID-19; Dendritic cells; Nasal spray; Nasal vaccine; SARS-CoV-2.

Graphical abstract

Figure 1

Genomic organization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Spike (S)-protein structure. (a) Genome organization of SARS-CoV-2. (b) The genomic organization of SARS-CoV-2, highlighting the viroporins ORF3a (blue), E (green), and ORF8 (purple), as well as their propozed topology/3D structures. (c) Schematic of the S-protein–receptor binding mechanism of SARS-CoV-2. (d) The S-protein of SARS-CoV2 comprises two subunits, S1 and S2, and is commonly represented as a sword-like spike. The Protein Data Bank (PDB) model of this glycoprotein reveals how the subunits are formed of different regions that are fundamental to the infection process. S1 and S2 are linked by a polybasic amino acid bridge, which might be important for viral targeting.

Figure 2

Replication cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the host cell.

Figure 3

Immunological and pathological consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the host. (a) Depletion and exhaustion of lymphocytes because of impaired T cell function as viruses invade T cells through angiotensin-converting enzyme 2 (ACE2) receptors, aided by proinflammatory mediators. Lymphopenia occurs as a result of the damaging effect of SARS-CoV-2 on the spleen and lymph; the increase in lactic acid also impacts T cell proliferation. (b) Neutrophils increase in response to infection caused by lymphopenia. (c) A cytokine storm results from increased monocyte production, which promotes IL-1β production, whereby Th17 cells impart synergism and CD4 + T cells mediate the increase in IL-6. (d) A neutralising antibody attacking the virus will increase virus entry into cells through the Fc region of the antibody attached to the Fc receptor (FcR) on cells; this is linked to disease progression and adverse outcomes in patients with coronavirus 2019 (COVID-19). Adapted under Creative Commons Attribution 4.0 from.

Figure 4

Effect of nasal vaccines on the upper and lower respiratory tract for the generation of mucosal and systemic immunity. (a) Protective immune responses in the nasopharynx-associated lymphoid tissue (NALT), with the pathogen-mediated reaction resulting mainly from by secretory IgA antibodies generated by mucosal epithelial cells. (b) Humoral immune response in the lower respiratory tract with bronchus-associated lymphoid tissue (BALT) having humoral as well as mucosal/local immune responses. Abbreviations: CTL, cytotoxic T lymphocyte; DC, dendritic cell; NK, natural killer; TCR, T cell receptor.

Figure 5

Advantages of nasal vaccines over conventional coronavirus 2019 (COVID-19) vaccines.

Figure 6

Infographics of nasal vaccine development for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).