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      Safety and Efficacy of Combined Intramuscular/Intranasal RAZI-COV PARS Vaccine Candidate Against SARS-CoV-2: A Preclinical Study in Several Animal Models

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          Abstract

          Several vaccine candidates for COVID-19 have been developed, and few vaccines received emergency approval with an acceptable level of efficacy and safety. We herein report the development of the first recombinant protein-based vaccine in Iran based on the recombinant SARS-CoV-2 spike protein in its monomeric (encompassing amino acid 1-674 for S1 and 685-1211 for S2 subunits) and trimer form (S-Trimer) formulated in the oil-in-water adjuvant system RAS-01 (Razi Adjuvant System-01). The safety and immunity of the candidate vaccine, referred to as RAZI-COV PARS, were evaluated in Syrian hamster, BALB/c mice, Pirbright guinea pig, and New Zeeland white (NZW) rabbit. All vaccinated animals received two intramuscular (IM) and one intranasal (IN) candidate vaccine at 3-week intervals (days 0, 21, and 51). The challenge study was performed intranasally with 5×10 6 pfu of SARS-CoV-2 35 days post-vaccination. None of the vaccinated mice, hamsters, guinea pigs, or rabbits showed any changes in general clinical observations; body weight and food intake, clinical indicators, hematology examination, blood chemistry, and pathological examination of vital organs. Safety of vaccine after the administration of single and repeated dose was also established. Three different doses of candidate vaccine stimulated remarkable titers of neutralizing antibodies, S1, Receptor-Binding Domain (RBD), and N-terminal domain (NTD) specific IgG antibodies as well as IgA antibodies compared to placebo and control groups (P<0.01). Middle and high doses of RAZI-COV PARS vaccine significantly induced a robust and quick immune response from the third-week post-immunization. Histopathological studies on vaccinated hamsters showed that the challenge with SARS-CoV-2 did not induce any modifications in the lungs. The protection of the hamster was documented by the absence of lung pathology, the decreased virus load in the lung, rapid clearance of the virus from the lung, and strong humoral and cellular immune response. These findings confirm the immunogenicity and efficacy of the RAZI-COV PARS vaccine. Of the three tested vaccine regimens, the middle dose of the vaccine showed the best protective immune parameters. This vaccine with heterologous prime-boost vaccination method can be a good candidate to control the viral infection and its spread by stimulating central and mucosal immunity.

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          Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

          Structure of the nCoV trimeric spike The World Health Organization has declared the outbreak of a novel coronavirus (2019-nCoV) to be a public health emergency of international concern. The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics. Wrapp et al. determined a 3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by cryo–electron microscopy. Using biophysical assays, the authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor. They also tested three antibodies known to bind to the SARS-CoV spike protein but did not detect binding to the 2019-nCoV spike protein. These studies provide valuable information to guide the development of medical counter-measures for 2019-nCoV. Science, this issue p. 1260
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            A simple practice guide for dose conversion between animals and human

            Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.
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              Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19

              Coronavirus disease 2019 is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. In this review, we highlight recent research advance in the structure, function and development of antivirus drugs targeting the S protein.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                26 May 2022
                2022
                26 May 2022
                : 13
                : 836745
                Affiliations
                [1] 1 Department of immunology, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO) , Karaj, Iran
                [2] 2 Department of Physico Chemistry, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO) , Karaj, Iran
                [3] 3 Department of Epidemiology, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO) , Karaj, Iran
                [4] 4 Department of Research and Development, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO) , Karaj, Iran
                [5] 5 Department of Quality Assurance, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO) , Karaj, Iran
                [6] 6 Clinic of Pediatrics, Institute of Interventional Allergology and Immunology , Bonn, Germany
                [7] 7 Animal Population Health Institute of College of Veterinary Medicine and Biomedical Sciences, Colorado State University , Fort Collins, CO, United States
                [8] 8 Department of Immunology, School of Medical Sciences, Tarbiat Modares University , Tehran, Iran
                [9] 9 Department of Pathology, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO) , Karaj, Iran
                [10] 10 Department of Quality Control, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO) , Karaj, Iran
                Author notes

                Edited by: Michael Vajdy, EpitoGenesis, United States

                Reviewed by: Pedro A Reche, Complutense University of Madrid, Spain; Qingmei Jia, UCLA Health System, United States

                *Correspondence: Seyed Reza Banihashemi, Reza7471@ 123456gmail.com

                This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2022.836745
                9179012
                35693788
                d3b1e100-8561-4bc5-8a4b-919f0530da99
                Copyright © 2022 Banihashemi, Es-haghi, Fallah Mehrabadi, Nofeli, Mokarram, Ranjbar, Salman, Hajimoradi, Razaz, Taghdiri, Bagheri, Dadar, Hassan, Eslampanah, Salehi Najafabadi, Lotfi, Khorasani and Rahmani

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 December 2021
                : 25 April 2022
                Page count
                Figures: 9, Tables: 2, Equations: 0, References: 79, Pages: 20, Words: 12730
                Funding
                Funded by: Razi Vaccine and Serum Research Institute , doi 10.13039/501100013221;
                Categories
                Immunology
                Original Research

                Immunology
                razi-cov pars,covid-19,sars-cov-2 preclinical study,vaccine,spike protein
                Immunology
                razi-cov pars, covid-19, sars-cov-2 preclinical study, vaccine, spike protein

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