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Progress and Prospects on Vaccine Development Against SARS-Cov-2

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Progress and Prospects on Vaccine Development Against SARS-Cov-2 Review Progress and Prospects on Vaccine Development against SARS-CoV-2 Jinyong Zhang 1, Hao Zeng 1, Jiang Gu 1, Haibo Li 1, Lixin Zheng 2,* and Quanming Zou 1,* 1 National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing 400038, China; [email protected] (J.Z.); [email protected] (H.Z.); [email protected] (J.G.); [email protected] (H.L.) 2 Laboratory of the Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA * Correspondence: [email protected] (L.Z.); [email protected] (Q.Z.) Received: 11 March 2020; Accepted: 26 March 2020; Published: 29 March 2020 Abstract: In December 2019, the outbreak of pneumonia caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a serious pandemic in China and other countries worldwide. So far, more than 460,000 confirmed cases were diagnosed in nearly 190 countries, causing globally over 20,000 deaths. Currently, the epidemic is still spreading and there is no effective means to prevent the infection. Vaccines are proved to be the most effective and economical means to prevent and control infectious diseases. Several countries, companies, and institutions announced their programs and progress on vaccine development against the virus. While most of the vaccines are under design and preparation, there are some that have entered efficacy evaluation in animals and initial clinical trials. This review mainly focused on the progress and our prospects on field of vaccine development against SARS-CoV-2. Keywords: SARS-CoV-2; vaccine; adjuvant; animal model 1. Introduction In December 2019, a cluster of patients with pneumonia surfaced in Wuhan, China. The culprit was quickly identified as a beta-coronavirus that has never been reported before, and the virus was named by WHO as SARS-CoV-2 [1,2]. By March 26, 2020, more than 80,000 people in China had been confirmed to be infected with the pathogen, and among them, 3293 people died from the infection. Under the aggressive control measures implemented by the Chinese government, the severe domestic epidemic seems to have been effectively contained. However, a global outbreak has caused more than 460,000 confirmed cases in more than 190 other countries, making the SARS-CoV-2 pandemic a general public health event that has stirred up worldwide attention. SARS-CoV-2 is a positive-strand RNA virus that belongs to the group of Betacoronaviruses. The genome of SARS-CoV-2 is approximately 29,700 nucleotides long and shares 79.5% sequence identity with SARS-CoV [3], it has a long ORF1ab polyprotein at the 50 end, which encode 15 or 16 non-structural proteins. The 30 end of the genome encodes 4 major structural proteins, including the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein [4], as shown in Figure1. SARS-CoV-2 binds to the receptor angiotensin converting enzyme 2 (ACE2) on host cell for the virus entry and subsequent pathogenesis [5], resulting in severe respiratory illness with symptoms of fever, cough, and shortness of breath, and severe cases can be fatal [6]. Vaccines 2020, 8, 153; doi:10.3390/vaccines8020153 www.mdpi.com/journal/vaccines Vaccines 2020, 8, 153 2 of 12 Vaccines 2020, 8, x 2 of 12 FigureFigure 1. 1.Schematic Schematic of of the the overall overall structure structure of of SARS-CoV-2. SARS-CoV-2. VaccinesVaccines are are the the most most eff effectiveective and and economical economical means means to prevent to prevent and and control control infectious infectious diseases diseases [7]. The[7]. developmentThe development of an of eff anective effective vaccine vaccine against agains SARS-CoV-2t SARS-CoV-2 infection infection is urgently is urgently required. required. So far, So morefar, more than 40than pharmaceutical 40 pharmaceutical companies companies and academic and academic institutions institutions worldwide worldwide have launched have launched their programstheir programs on vaccine on vaccine development development against SARS-CoV-2.against SARS-CoV-2. Herein, we Herein, will summarize we will summarize the recent the progress recent onprogress this vaccine on this development vaccine development worldwide, worldwide, in particular, in onparticular, candidate on antigens, candidate adjuvants, antigens, evaluation adjuvants, models,evaluation and models, technologies and technologies used in related used research. in related research. 2.2. Antigen Antigen Selection Selection 2.1.2.1. Whole Whole Cell Cell Antigens Antigens TheThe whole whole cell cell antigens antigens (WCA) (WCA) contain contain all all the the elements elements of of the the virus, virus, including including proteins, proteins, lipids, lipids, polysaccharide,polysaccharide, nucleic nucleic acids, acids, and and some some other other components. components. WCAWCA hashasbeen been used used for for developing developing whole-cellwhole-cell killed killed and and live-attenuated live-attenuated vaccines vaccines [ 8[8,9].,9]. Given Given the the complex complex compositions compositions of of WCA, WCA, it it is is unavoidableunavoidable to to face face more more di difficultiesfficulties in in quality quality control control and and consistency consistency evaluation. evaluation. So So far, far, several several institutionsinstitutions have have successfully successfully isolated isolated the the virus virus strains strains of of SARS-CoV-2 SARS-CoV-2 and and started started whole-cell whole-cell killed killed oror live-attenuated live-attenuated vaccine vaccine development. development. However, However, research research on on the the type type of of vaccine vaccine requires requires stringent stringent screeningscreening for for obtaining obtaining strains strains with with assured assured low low or or no no pathogenicity pathogenicity [10 [10].]. 2.2. Spike Protein (S Protein) 2.2. Spike Protein (S Protein) S protein is currently the most promising antigen formulation for SARS-CoV-2 vaccine research. S protein is currently the most promising antigen formulation for SARS-CoV-2 vaccine research. First, it is surface exposure and thus is able to be directly recognized by host immune system [11]. First, it is surface exposure and thus is able to be directly recognized by host immune system [11]. Second, it mediates the interaction with host cell by binding to the receptor ACE2, which is essential Second, it mediates the interaction with host cell by binding to the receptor ACE2, which is essential for subsequent virus entry to target cells and causing subsequent pathogenicity [11,12]. Finally, the for subsequent virus entry to target cells and causing subsequent pathogenicity [11,12]. Finally, the homologue proteins were already used for vaccine development against SARS-CoV and MERS-CoV, homologue proteins were already used for vaccine development against SARS-CoV and MERS-CoV, and were proved to be effective [13–17]. and were proved to be effective [13–17]. The monomer of S protein from SARS-CoV-2 contains 1273 amino acids, with a molecular weight The monomer of S protein from SARS-CoV-2 contains 1273 amino acids, with a molecular weight of about 140 kDa. Self-association naturally assembles the S protein into a homo-trimer, typically of about 140 kDa. Self-association naturally assembles the S protein into a homo-trimer, typically similar to the first class of membrane fusion protein (Class I viral fusion protein). The S protein similar to the first class of membrane fusion protein (Class I viral fusion protein). The S protein contains two subunits (S1 and S2). The S1 subunit can be further defined with two domains termed the contains two subunits (S1 and S2). The S1 subunit can be further defined with two domains termed N-terminal domain (NTD) and the C-terminal domain (CTD). The receptor binding domain (RBD) is the N-terminal domain (NTD) and the C-terminal domain (CTD). The receptor binding domain (RBD) is located in the CTD. S2 subunit contains the basic elements required for membrane fusion, Vaccines 2020, 8, x; doi: www.mdpi.com/journal/vaccines Vaccines 2020, 8, 153 3 of 12 located in the CTD. S2 subunit contains the basic elements required for membrane fusion, including an internal membrane fusion peptide (FP), two 7-peptide repeats (HR), a membrane proximal external region (MPER), and a trans-membrane domain (TM) [18]. Recently, the structure of the SARS-CoV-2 S trimer in the pre-fusion conformation and the RBD domain in complex with ACE2 has been successfully determined [11,12], which has provided valuable information for vaccine design based on this protein. So far, the potential fragments of S protein for use as antigens in vaccine development include the full-length S protein, the RBD domain, the S1 subunit, NTD, and FP. 2.2.1. The Full-Length S Protein Full-length proteins are likely to maintain the correct conformation of the protein, capable of providing more epitopes and exhibiting higher immunogenicity. Pallesen et al. [19] demonstrated that higher titer of neutralizing antibodies in BALB/c mice immunized with recombinant prefusion MERS-CoV S protein. Another research confirmed that S protein produced in baculovirus insect cells was able to assemble into nanoparticles. Mice immunized with these nanoparticles formulated with alum adjuvant that produced high titer of neutralizing antibodies [20]. Muthumani et al. [21] reported that DNA vaccine encoding MERS-CoV S protein was immunogenic in mice, camels, and rhesus macaques. Animals immunized with the DNA vaccine show reduced typical clinical symptoms including pneumonia during the infection. So far, Clover Biopharmaceuticals had announced that they have constructed a SARS-CoV-2 S protein trimer vaccine (S-Trimer) by using its patented Trimer-Tag© technology, and this vaccine will be produced via a rapid mammalian cell-culture based expression system, further preclinical safety and analysis will be launched within the next 6–8 weeks.
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