Long‐Residence Pneumonia Vaccine Developed Using PEG‐Grafted Hybrid Nanovesicles from Cell Membrane Fusion of Mycoplasma and IFN‐γ‐Primed Macrophages

Abstract

and no commercial vaccines are currently available for humans. [1,2] Great progress has been achieved in the development of mycoplasma vaccines. Inactivated vaccines have been developed and tested in clinical trials, with an overall efficacy of approximately 40% against Mycoplasma pneumoniae infection in humans. [3] Live attenuated or inactivated vaccines have been widely used to control Mycoplasma hyopneumoniae infection in pigs. [4][5][6][7][8] Compared to live attenuated vaccines, inactivated vaccines provide high safety with limited efficacy due to protein denaturation and degradation. [9] Therefore, it is highly desirable to develop safe and effective vaccines against mycoplasma infection.CD8 + T cell responses play a critical regulatory role in protection against mycoplasma infection-related respiratory diseases. Studies have shown that the depletion of CD8 + T cells exacerbated pneumonia in a murine model of mycoplasma infection. [10][11][12] Compared to vaccines without adjuvant, inactivated vaccines with an adjuvant that was capable of inducing CD8 + T cell responses reduced lung lesion size in pigs with M. hyopneumoniae infection. [13] Live attenuated wholecell bacteria were used as attenuated mycoplasma vaccines, which induced activation of lung CD8 + T cells in vivo. [14,15] CD8 + T cell responses play a critical regulatory role in protection against mycoplasma infection-related respiratory diseases. Nanovesicles derived from cell membranes have been shown to induce CD8 + T cell responses. Moreover, the short residence time of mycoplasma membrane-related vaccines in local lymph nodes limits the efficacy of current mycoplasma vaccines. Here, a long-residence pneumonia vaccine is developed using nanovesicles prepared by cell membrane fusion of Mycoplasma hyopneumoniae and interferon-γ (IFN-γ )-primed macrophages, which are grafted with polyethylene glycol to increase residence time in the lymph nodes. Upregulation of intercellular adhesion molecule-1 (ICAM-1) on the membrane of IFN-γ-primed macrophages increases the targeting of the hybrid nanovesicle vaccine to the local lymph nodes, with increased CD8 + T cell activation. A mechanistic study reveals that CD8 + T cell activation is achieved via a pathway involving upregulation of C-C motif chemokine ligand 2/3 expression by E26 transformation-specific sequences, followed by increased immune-stimulatory activity of dendritic cells. In vivo, prophylactic testing reveals that the hybrid nanovesicle vaccine triggers a long-term immune response, as evidenced by a memory CD8 + T cell response against mycoplasma infection. The current study provides a new design strategy for mycoplasma vaccines that involves a hybrid method using biological sources and artificial modification.

Recent Advances of Engineered Cell Membrane‐Based Nanotherapeutics to Combat Inflammatory Diseases

“…[ 103 ] Therefore, a mixed nano‐vesicle from mycoplasma and IFN‐γ‐induced macrophages was further functionalized by polyethylene glycol (PEG) and used as a vaccine against Mycoplasma pneumoniae infection (Figure 9B). [ 104 ] In this system, the PEG functionalization increased the residence time in lymph nodes, mycoplasma membrane activated CD8+ T cell response, IFN‐γ‐induced macrophage membrane expressing the upregulated intercellular adhesion molecule‐1 (ICAM‐1) and major histocompatibility complex class II (MHC‐II) increased the targeting of local lymph nodes and activation of CD8+ T cells. In the mouse model of Mycoplasma pneumonia , the ECMN‐based vaccine was preferentially absorbed by DCs in lymph nodes, maturing DCs and further inducing CD8+ T cell response.…”

“…The vaccine was preferentially absorbed by DCs in lymph nodes, maturing DCs and further inducing CD8+ T cell response. Reproduced with permission [104]. Copyright 2021, John Wiley and Sons.…”

Promoting Cell Fusion by Polyvalent DNA Ligands

“…Cell fusion, arising from the merge of cells, is a biological phenomenon that widely exists in nature, which is found fundamental for development, repair of tissues, and the pathogenesis of disease. − Inducing cell fusion in vitro can create a model system to study the biological fate of fused cells, or to produce engineered cells of designated functions, which has become an increasingly important technique in biology. − However, construction of artificially fused cells with high efficiency remains technically challenging. Conventional techniques for in vitro cell fusion include a polyethylene glycol (PEG)-mediated chemical induction method, − electrical and laser irradiating-mediated physical induction method, − and virus-induced biological method. ,, Among these, the PEG-induced method has been widely used due to its relative ease of operation and high safety; nevertheless, the fusion efficiency of this method is typically in the low range of 4–8%, which largely hinders its practical applications. , …”