SARS-COV-2 Nano-vaccine :A polymersome based innovation

12 May 2021

The outbreak of novel corona virus disease has put threat on public health. The treatment was made after analyzing the pathophysiology of disease based on previous experiences and evidence based approach, mainly to suppress the immune reaction caused by cytokine storm. Development of vaccine for novel corona virus disease has been the major concern for the whole global health care sector. Development of vaccine can contributed to a significant decrease in incidence and prevalence of this contagious disease.The novel corona virus disease vaccines made are based on traditional approaches as either attenuated or live viruses, where their margin of safety strictly underly with biosafety level (BSL).mRNA vaccines formulated with lipid nano-particles offer a new platform for a highly immunogenic and durable subunit vaccine. The nano-vaccine is produced by conjugating spike antigen to polymersome (PS) surface and this subunit vaccine target on the spike protein of SARS-CoV-2 and deliver antigen and adjuvant to endosomes of dendritic cells.

 

Immunogenicity of a protein can be enhanced when encapsulated within a polymersome. This principle is being utilised for the development of polymersome based subunit vaccine. ACM (Artificial cell membrane) polymersomes are self-assembling vesicles made of an amphiphilic block copolymer made of polybutadiene-b-polyethylene glycol (PBD-PEO) and a cationic lipid 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP). These mimic the cell structures and are actively taken up by the dendritic cells in which it can be customised upon their size and surface characteristics according to the specificity of dendritic cells. ACM polymersomes act as a carrier, where the amphiphilic block polymer form a thermodynamically stable bilayer of PBD block inside and water soluble PEG block towards the surface. DOTAP encapsulate antigens (spike trimer, S2 and S1S2 protein) and adjuvants in separate vesicles as ACM trimer (ACM-S2, ACM-S1S2 and ACM-CpG). These encapsulated nano-particles can increase the bioavailability, prevent biodegradation with capability to regulate ROS and provide sustained release of drug. ACM Polymersomes have been used early for development of veterinary vaccine against coronavirus in pigs causing porcine epidemic diarrhoea. They adopt immunological cues to mimic pathogenic characteristics by adopting innate and adaptive immunity to respond against vaccine. Polymersomes as ROS regulators aid in suppression of pro-inflammatory cytokines and hence reduce SARS-COV-2 propagation.

 

SARS-COV-2 belongs to the family of Coronaviridae, in genus Betacoronavirus. The virion consist of a single stranded mRNA, surrounded by a lipid bilayer into which spike (S), membrane and envelope proteins are incorporated. Main structural proteins are S, envelope (E), membrane (M) and nucleocaspid (N) proteins. S protein with crown shaped surface which facilitates viral entry into host cell is the main target for drug development process. Spike proteins are trimer of S proteins on the surface of virion consisting of two subunits S1 and S2. The interaction of receptor binding domain (RBD) in S1 subunit with peptidase domain of ACE2 of host cell leads to cleavage of S1-S2 junction by host cell proteases inducing structural derangement enabling entry of virus where, S2 facilitates membrane fusion.

 

Immunity can be classified as innate and adaptive, where innate immunity provide defence at the site of entry, like mucosa protection and cellular effectors such as macrophages and dendritic cells. While adaptive immune response is based on T cells and B cells providing long term immunity.

Polymersome with both surface-bound RBD and encapsulated RBD were evaluated with an adjuvant monophosphoryl lipid A-encapsulated PS (MPLA PS).Study was conducted on mice and given booster dose after three weeks. Anti-RBD response was taken by ELISA and noted for production of pro-inflammatory cytokines. Epitope specificity was determined using peptide arrays. Surface-RBD PS developed high titres of neutralizing antibodies to SARS­CoV­2, AMC polymersomes are taken by dendritic cells, and release antigen to CD8+ Tcells or CD4+ T cells through MHC-I orMHC-II complexes.IgG1, IgG2 and IIgG3 antibodies are produced where mucosal immunity is rendered by IgA.The antibody response was increased without destroying cellular immune response in such a way that they resemble viral like particles (VLPs).In contrast, the encapsulated-RBD antigen showed effective recognition of a broader range of linear epitopes. CpG regulates the production of pro-inflammatory mediators by T cell and B cell activation, developed high titres of neutralising antibodies. The ability to compartmentalize antigens and CpG adjuvant in the aqueous compartment of polymersomes enhances immunogenicity.

 

Polymersomes possess unequalled permeability to membrane and are highly stable due to long hydrophobic segments. The studies demonstrated in C57BL/6 mice reported strong and durable humoral and cellular immunity by polymersome based nanovaccine against SARS-COV-2 infection. These RBD polymersomes are stable up to 6 months or longer at 4˚C promising large scale vaccination. Intranasal vaccine administration of polymersome based formulation can activates mucosal immunity. They can also withstand vector neutralising antibodies. However, issues regarding stability, which require an ultra-cold chain to preserve mRNA integrity and expense are the strategies to overcome for a hassle free and bulk distribution of vaccines.

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