Over the past years, several zoonotic viruses have crossed the species barrier into humans and have been causing outbreaks of severe, and often fatal, respiratory illness. The 21st century has seen the worldwide spread of three recognized coronaviruses (CoVs) which can cause pneumonia and severe acute respiratory symptoms (SARSs), SARS, MERS, and recently SARS-CoV-2. Herein, it is raising concerns about the dissemination of another new and highly lethal pandemic outbreak. Preparing for a pandemic outbreak involves a great deal of awareness necessary to stop initial outbreaks, through recognizing the molecular mechanisms underlying virus transmission and pathogenicity. CoV spike protein S is the key determinant of host tropism and viral pathogenicity which can undergo variations and makes the CoV a highly pathogenic and diffusible virus capable of sustained human-to-human transmission and spread easily. The three mentioned CoVs exhibit some similarities in S protein whereby constitute a promising target for the development of prophylactics and therapeutics in the future.
Sterilizing Immunity, Based on the CoV S Protein
An efficient strategy recommended against virus infectivity is sterilizing immunity against virus spike protein, wherein protein and SiA receptors are reduced on target cells and innate immunity against virus infection is induced in the target organ. In sterilizing immunity, pre-infection with intranasal inoculation of low-dose virus can induce efficient antigen-specific T cell response in the lungs, where prevents subsequent effective infection of a challenge with the lethal dose of the same strain of virus or reduced infectivity by a lethal dose of homologs virus. In sterilizing immunity, local antigen-specific host immune response is induced to block virus infection and clear it before the establishment of effective infection. Only intranasal inoculation induces sterilizing immunity, whereas intramuscular injection does not block subsequent infection but may provide protection with enhanced virus clearance. For example, intranasal vaccination with a low-dose CoV S protein can generate memory CD4 T cells in the airway which would be induced and mediate protection following a CoV challenge. These cells could induce anti-viral innate responses at an early stage of infection by stimulating dendritic cell migration whereby could facilitate CD8 T-cell responses. The stimulation of memory CD4 T cells in the airway has been indicated as an essential part of any strategy mentioning CoV vaccine development. Accordingly, these memory CD4 T cells target a conserved epitope within the S protein that can cross-react with some other CoVs.Another example is intranasal pre-infection with the nH1N1 influenza virus which induces sterilizing immunity whereby decreases susceptibility to the next homologous influenza virus challenge in the host. Intranasal pre-infection with nH1N1 influenza virus induced virus receptor reduction and antigen-specific T cell immune response in the lungs of mice. Receptor reduction decreases susceptibility across different strains of the influenza virus, but sterilization only takes effect with the challenge of the same strain of influenza virus. Similar results have been reported after intranasal vaccination with MERS or SARS-CoV, while intravenously inoculated vaccines may induce harmful immune responses that may lead to the liver damaging in vaccinated animals or enhanced infection by a following homologous SARS-CoV challenge. Accordingly, intranasal inoculation of transgenic mice with a low-dose of SARS or MERS-CoV would result in the production of neutralizing antibodies protecting the animals from following lethal challenges with the virus. These results could probably reflect the situation in infected humans during an epidemic disease. However, there may be nasal turbinate in the upper respiratory tract and a high titer of virus replication in the lungs of the lower respiratory without any signs of morbidity or mortality in the animal models of SARS-CoV infection. Accordingly, intranasal vaccinations based on the S1 protein or RBD could induce antibodies to block virus-receptor interaction and membrane fusion or neutralize the infectious virus. The S protein is known to be the main antigenic component among all structural proteins of MERS, SARS and SARS-CoV-2, that is responsible for inducing host immune responses, neutralizing antibodies, and/or protective immunity against virus infection. In infection by SARS-CoV strains, neutralizing antibodies against S protein raised against amino acids 485–625 in S1 or 1029–1192 in S2.Although full-length S protein-based SARS vaccines can induce neutralizing antibody responses against SARS-CoV infection but should mention harmful immune responses induced by full-length S protein that cause liver damage of the vaccinated animals or enhanced infection after challenge with homologous SARS-CoV, which here raising concerns about the safety and ultimate protective efficacy of vaccines that contain the full-length SARS-CoV S protein. Immunization of mice and rabbits with RBD-Fc induces long-term protective immunity against the next challenge with homologous SARS-CoV strain. The RBD-Fc induced highly potent neutralizing antibodies against SARS-CoV with great neutralizing titer in rabbits.Reports show that produced antibodies effectively cross-neutralized infection by SARS pseudoviruses that bear S proteins of both homologous and heterologous SARS-CoV isolates, including the representative strains of human 2002–2003 and 2003–2004 SARS-CoV and palm civet SARS-CoV. Herein, the fastest strategy to develop a treatment and sterilization immunity is to use a fusion protein that contained the RBDs (S1-CTD and S1-NTD) linked to human IgG1 Fc fragment (designated S1-CTD-NTD-Fc), as an immunogen successfully induced highly potent neutralizing antibodies, as well as, blocking virus-binding receptor (eg ACE2/DPP4). For instance, administration of the key domain RBD that binds the ACE2 receptor during entry, 193 amino acids in size, effectively blocked the entry of SARS in cell cultures
Reference & Source information:https://www.dovepress.com/
Read More on: