Probiotic-Based Vaccines May Provide Effective Protection against COVID-19 Acute Respiratory Disease

Abstract

Severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2) infection, the causative agent of COVID-19, now represents the sixth Public Health Emergency of International Concern (PHEIC)-as declared by the World Health Organization (WHO) since 2009. Considering that SARS-CoV-2 is mainly transmitted via the mucosal route, a therapy administered by this same route may represent a desirable approach to fight SARS-CoV-2 infection. It is now widely accepted that genetically modified microorganisms, including probiotics, represent attractive vehicles for oral or nasal mucosal delivery of therapeutic molecules. Previous studies have shown that the mucosal administration of therapeutic molecules is able to induce an immune response mediated by specific serum IgG and mucosal IgA antibodies along with mucosal cell-mediated immune responses, which effectively concur to neutralize and eradicate infections. Therefore, advances in the modulation of mucosal immune responses, and in particular the use of probiotics as live delivery vectors, may encourage prospective studies to assess the effectiveness of genetically modified probiotics for SARS-CoV-2 infection. Emerging trends in the ever-progressing field of vaccine development re-emphasize the contribution of adjuvants, along with optimization of codon usage (when designing a synthetic gene), expression level, and inoculation dose to elicit specific and potent protective immune responses. In this review, we will highlight the existing pre-clinical and clinical information on the use of genetically modified microorganisms in control strategies against respiratory and non-respiratory viruses. In addition, we will discuss some controversial aspects of the use of genetically modified probiotics in modulating the cross-talk between mucosal delivery of therapeutics and immune system modulation.

Keywords: COVID-19; SARS-CoV-2; coronavirus; mucosal immunization; probiotics; vaccines.

Figure 1

Schematic representation of the structure of important SARS-CoV-2 proteins, targeting the ACE2 receptors and promoting viral entry in infected cells. The SARS-CoV-2 spike (S) protein mediates membrane fusion by binding to these cellular receptors (retrieved from https://app.biorender.com/biorender-templates (access date: 6 March 2021)): “SARS-CoV-2 Targeting of ACE2 Receptor and Entry in Infected Cell”).

Figure 2

Diagram illustrating the development of the first oral COVID-19 vaccine candidate based on recombinant Bifidobacterium longum which has been engineered to deliver plasmids containing synthetic DNA encoding spike protein from SARS-CoV-2 (adapted from https://app.biorender.com/biorender-templates (access date: 6 March 2021)).

Figure 3

Schematic representation of the stimulation of immune responses with genetically modified probiotics expressing therapeutic factors in the gut and the lung. The crosstalk and the reciprocal interaction of the gut and lung mucosa (gut-lung axis) is mediated by immune cells moving between the two districts via the bloodstream and the lymphatic ducts, leading to modulation of the immune response in both sites. Delivery of antigen via recombinant probiotic to antigen-presenting cells in Peyer’s patches causes the stimulation of naive B and T cells and induction of several immune factors, such as Th1 and Th2 cytokines. As a result, cells and immune factors migrate to the thoracic duct and the BALT through circulation and enhance the production of secretory IgA and the activation of effector CD4⁺ and CD8⁺ T cells, preventing the onset and progression of respiratory viral infections. IgA, immunoglobulin A, IL-4: interleukin-4, IFN-γ: interferon-gamma, Th1: T-helper cell type 1, Th2: T-helper cell type 2, BALT: bronchi-associated lymphoid tissue (adapted from https://app.biorender.com/biorender-templates (access date: 24 November 2020).