SARS-CoV-2: Immunity, Challenges with Current Vaccines, and a Novel Perspective on Mucosal Vaccines

Abstract

The global rollout of COVID-19 vaccines has played a critical role in reducing pandemic spread, disease severity, hospitalizations, and deaths. However, the first-generation vaccines failed to block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and transmission, partially due to the limited induction of mucosal immunity, leading to the continuous emergence of variants of concern (VOC) and breakthrough infections. To meet the challenges from VOC, limited durability, and lack of mucosal immune response of first-generation vaccines, novel approaches are being investigated. Herein, we have discussed the current knowledge pertaining to natural and vaccine-induced immunity, and the role of the mucosal immune response in controlling SARS-CoV2 infection. We have also presented the current status of the novel approaches aimed at eliciting both mucosal and systemic immunity. Finally, we have presented a novel adjuvant-free approach to elicit effective mucosal immunity against SARS-CoV-2, which lacks the safety concerns associated with live-attenuated vaccine platforms.

Keywords: APC targeting; COVID-19; SARS-CoV-2; adjuvant; human FcγRI; immunity; intranasal vaccine; mucosal vaccine.

Figure 1

Antibody mediated protection against SARS-CoV-2: Created with BioRender.com (https://www.biorender.com/ accessed on 3 March 2023).

Figure 2

T-cell mechanism of protection against SARS-CoV-2: CD4/CD8 CTL recognize virally infected cells via MHC-peptide TCR interaction, which leads to killing of the virally infected cells (A). Th1 cell-secreted cytokines mediate antiviral effect (B). T_FH cells help in the generation and maintenance of antibody response by helping B cells (C).

Figure 3

α-hCD64-targeted vaccine design: (A) The map of the candidate vaccines. (B) Folding of the α-hCD64 and antigen moieties. (C) The α-hCD64-Antigen binds to the hFcγRI on APCs. (D) APCs in turn process and present the antigens to the naïve T cells.

Figure 4

Immune response elicited by hFcgRI-targeted vaccines. Following intranasal immunization, the fusion proteins (FPs) containing the APC-targeting component α-hCD64 and the antigen crosses through M cells (M) at the nasal-associated lymphoid tissues (NALT). Following transcytosis, the FPs are taken up by antigen-presenting cells including DCs (D) and macrophages (Mp). APCs can either present the antigens to the T cells (T) at the NALT or at the draining lymph nodes, ensuing adaptive immune response including the generation of antigen-specific IgG, IgA, and Th17 and Th22 responses. The IgG and IgA at the mucosa are secreted (Transcytosis: arrow across the epithelium) to the mucosa thereby preventing the invasion of the cognate pathogen. E: Epithelial cells, Dc: follicular dendritic cells.

Figure 5

Binding of α-hFcγRI-MBL with inactivated SARS-CoV-2: ELISA plates were coated with inactivated SARS-CoV-2 overnight and blocked with 5% BSA. PBS, α-hFcγRI-MBL, and MBL were added in appropriate wells and incubated for one hour at 4C. The binding of α-hFcγRI-MBL was evaluated by sequential treatment with anti-MBL antibody and alkaline phosphatase-conjugated secondary antibody. Result: In comparison with PBS, the increase in ELISA signal with α-hFcγRI-MBL indicates binding of the fusion protein to inactivated SARS-CoV-2, while the reduction in signal in the presence of MBL signifies specificity of binding.