During Phase I, small groups of people (hundreds) receive the trial vaccine to evaluate safety and immunogenicity

During Phase I, small groups of people (hundreds) receive the trial vaccine to evaluate safety and immunogenicity.?If satisfactory Rabbit polyclonal to AMIGO2 results are obtained, the vaccine candidate proceeds to Phase II with the objective to expand safety evaluation, identify the optimal dose, and study the efficacy in a larger population (25C1000 or several hundred volunteers) [90]. clinic of nanotechnology-enabled messenger ribonucleic acid vaccines and examine in detail the types of delivery systems used, their mechanisms of I-191 action, obtained results during each phase of their clinical development and their regulatory approval process. We also analyze how nanotechnology is impacting global health and economy during the COVID-19 pandemic and beyond. family, with a distinctive crown-like membrane envelope composed of spike glycoproteins localized into their surface [9]. Four genera of CoVs exist: [10]. To date, seven CoVs are known to affect humans, 229E and NL63 from the genus, and HKU1, OC43, MERS-CoV, SARS-CoV and SARS-CoV-2 from the genus [11]. Four main structural proteins, essential for the complete assembly of the viral particle are encoded by the coronaviral genome: the spike S protein, the nucleocapsid N protein, the membrane M protein, and the envelope E protein (Fig.?2a) [12]. Each protein has a specific function: the S protein mediates virus adherence to the host cell receptors and subsequent fusion; the N protein binds to the CoV RNA genome, arranges the nucleocapsid and participates in the viral replication cycle; the M protein forms the main structural part of the viral envelope and interacts with all other structural proteins; and the E protein, the smallest integral membrane structural protein incorporated in the viral envelope, is important for the virus production and maturation [13]. The S protein of SARS-CoV-2 consists of two subunits: the S1 subunit contains a receptor-binding domain (RBD) that binds to angiotensin-converting enzyme 2 (ACE2) on the surface of host cells, whereas the S2 subunit mediates fusion between the membranes of the virus and the host cell (Fig.?2a) [14]. Open in a separate window Fig. 2 a Schematic representation of SARS-CoV-2 and spike glycoprotein main structural features. b The?viral replication cycle initiates by the activation of the serine protease TMPRSS2 and angiotensin-converting enzyme 2 (ACE2) receptors SARS-CoV-2, the causative pathogen of COVID-19, has produced a global pandemic due to a highly infectious mechanism based on the co-expression of TMPRSS2 and ACE2 receptors on the cellular membrane of host cells [15] (Fig.?2b). Although ACE2 receptor is expressed on respiratory epithelial human cells, ACE2 is not limited to the lungs, and extrapulmonary spread of SARS-CoV-2 in ACE2-positive tissues has been observed, including the gastrointestinal tract [16C19]. In addition, it has been observed that apical cilia on airway cells and microvilli on type II pneumocytes may be important to facilitate SARS-CoV-2 viral entry [20]. SARS-CoV-2 infection is assisted by TMPRSS2, a cellular serine protease, by two independent mechanisms: cleavage of S glycoprotein to activate host entry, and proteolytic cleavage of ACE2 to promote I-191 viral uptake [19, 21, 22]. The priming of the S protein by TMPRSS2 or other proteases is followed by the affinity, binding of the viral S1 protein domain to the ACE2 receptor, and cellular internalization initiated by plasma membrane fusion and acidic-pH-dependent endocytosis [19, 23]. Intracellular replication is then facilitated by RNA-dependent polymerases, and assembly of new viral nucleocapsids from genomic RNA and N proteins occurs in the cytoplasm, whereas new particles are produced by the synergistic action of both the endoplasmic reticulum and the Golgi compartments [14]. Lastly, assembly of the genomic RNA and structural proteins into new viral particles leads to their release via exocytosis [14, 24, 25]. The evolution of SARS-CoV-2 has led to the emergence of multiple variants containing amino acid mutations, some of which have been classified as ‘variants of concern’ (VOC) that impact virus characteristics, including transmissibility and antigenicity [26]. Reports from several countries on the identification of VOCs (United KingdomB.1.1.7 [alpha], South AfricaB.1.351 [Beta], Japan/BrazilP.1 [Gamma], IndiaB.1.617.2 [Delta]) and variants of interest (PeruC.37 [Lambda], ColombiaB.1.621 [Mu], U.S.A.B.1.427 and B.1.429 [Epsilon]), confirm amino acid substitutions and/or deletions acquired in key antigenic sites, such as the RBD and N-terminal domain (NTD) of the S protein, which facilitate viral cell entry [27C32]. Evidence has shown that some of these mutations (N501Y, particularly) are convergent, arisen independently in different lineages (B.1.351, P.1 [sublineage of B.1.1.28]) [26]. Although no significant evolutionary changes occurred approximately 11?months after the emergence of SARS-CoV-2 in late 2019, multiple mutations were identified since late 2020, and novel lineages are expected to emerge for the duration of the COVID-19 pandemic?[26]. Clinical manifestations of COVID-19 may include flu-like symptoms such as cough, fever, and fatigue to more serious clinical consequences including shortness of breath, anosmia, pneumonia, coagulopathy, acute kidney injury, and accelerative inflammation referred to as a cytokine storm [33]. Other manifestations have been reported in the gastrointestinal I-191 tract, liver, heart, skin, and central nervous system [34]. High mortality rate and clinical complications of COVID-19.