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1.
Front Immunol ; 12: 809244, 2021.
Article in English | MEDLINE | ID: covidwho-1635518

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new beta coronavirus that emerged at the end of 2019 in the Hubei province of China. SARS-CoV-2 causes coronavirus disease 2019 (COVID-19) and was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. Herd or community immunity has been proposed as a strategy to protect the vulnerable, and can be established through immunity from past infection or vaccination. Whether SARS-CoV-2 infection results in the development of a reservoir of resilient memory cells is under investigation. Vaccines have been developed at an unprecedented rate and 7 408 870 760 vaccine doses have been administered worldwide. Recently emerged SARS-CoV-2 variants are more transmissible with a reduced sensitivity to immune mechanisms. This is due to the presence of amino acid substitutions in the spike protein, which confer a selective advantage. The emergence of variants therefore poses a risk for vaccine effectiveness and long-term immunity, and it is crucial therefore to determine the effectiveness of vaccines against currently circulating variants. Here we review both SARS-CoV-2-induced host immune activation and vaccine-induced immune responses, highlighting the responses of immune memory cells that are key indicators of host immunity. We further discuss how variants emerge and the currently circulating variants of concern (VOC), with particular focus on implications for vaccine effectiveness. Finally, we describe new antibody treatments and future vaccine approaches that will be important as we navigate through the COVID-19 pandemic.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Immunologic Memory , Pandemics/prevention & control , SARS-CoV-2/immunology , COVID-19/genetics , COVID-19 Vaccines/genetics , COVID-19 Vaccines/therapeutic use , Humans , SARS-CoV-2/genetics
2.
Signal Transduct Target Ther ; 7(1): 7, 2022 01 04.
Article in English | MEDLINE | ID: covidwho-1606287

ABSTRACT

Activation-induced cytidine deaminase (AID) initiates class-switch recombination and somatic hypermutation (SHM) in antibody genes. Protein expression and activity are tightly controlled by various mechanisms. However, it remains unknown whether a signal from the extracellular environment directly affects the AID activity in the nucleus where it works. Here, we demonstrated that a deubiquitinase USP10, which specifically stabilizes nuclear AID protein, can translocate into the nucleus after AKT-mediated phosphorylation at its T674 within the NLS domain. Interestingly, the signals from BCR and TLR1/2 synergistically promoted this phosphorylation. The deficiency of USP10 in B cells significantly decreased AID protein levels, subsequently reducing neutralizing antibody production after immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or human immunodeficiency virus type 1 (HIV-1) nanoparticle vaccines. Collectively, we demonstrated that USP10 functions as an integrator for both BCR and TLR signals and directly regulates nuclear AID activity. Its manipulation could be used for the development of vaccines and adjuvants.


Subject(s)
AIDS Vaccines/immunology , B-Cell Activating Factor/immunology , COVID-19 Vaccines/immunology , Cytidine Deaminase/immunology , HIV-1/immunology , Nanoparticles , SARS-CoV-2/immunology , Signal Transduction/immunology , Ubiquitin Thiolesterase/immunology , Ubiquitination/immunology , AIDS Vaccines/genetics , Animals , B-Cell Activating Factor/genetics , COVID-19 Vaccines/genetics , Cytidine Deaminase/genetics , HEK293 Cells , HIV-1/genetics , Humans , Mice , Mice, Knockout , SARS-CoV-2/genetics , Signal Transduction/genetics , Ubiquitin Thiolesterase/genetics
3.
Eur Rev Med Pharmacol Sci ; 25(24): 8019-8022, 2021 12.
Article in English | MEDLINE | ID: covidwho-1605687

ABSTRACT

Recently a new variant of SARS-CoV-2 was reported from South Africa. World Health Organization (WHO) named this mutant as a variant of concern - Omicron (B.1.1.529) on 26th November 2021. This variant exhibited more than thirty amino acid mutations in the spike protein. This mutation rate is exceeding the other variants by approximately 5-11 times in the receptor-binding motif of the spike protein. Omicron (B.1.1.529) variant might have enhanced transmissibility and immune evasion. This new variant can reinfect individuals previously infected with other SARS-CoV-2 variants. Scientists expressed their concern about the efficacy of already existing COVID-19 vaccines against Omicron (B.1.1.529) infections. Some of the crucial mutations that are detected in the receptor-binding domain of the Omicron variant have been shared by previously evolved SARS-CoV-2 variants. Based on the Omicron mutation profile in the receptor-binding domain and motif, it might have collectively enhanced or intermediary infectivity relative to its previous variants. Due to extensive mutations in the spike protein, the Omicron variant might evade the immunity in the vaccinated individuals.


Subject(s)
COVID-19/epidemiology , Reinfection/epidemiology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , COVID-19/immunology , COVID-19/transmission , COVID-19/virology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Humans , Immune Evasion/genetics , Immunogenicity, Vaccine , Mutation , Reinfection/immunology , Reinfection/transmission , Reinfection/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Vaccine Potency
4.
PLoS Pathog ; 17(12): e1010092, 2021 12.
Article in English | MEDLINE | ID: covidwho-1581718

ABSTRACT

The development of safe and effective vaccines to prevent SARS-CoV-2 infections remains an urgent priority worldwide. We have used a recombinant vesicular stomatitis virus (rVSV)-based prime-boost immunization strategy to develop an effective COVID-19 vaccine candidate. We have constructed VSV genomes carrying exogenous genes resulting in the production of avirulent rVSV carrying the full-length spike protein (SF), the S1 subunit, or the receptor-binding domain (RBD) plus envelope (E) protein of SARS-CoV-2. Adding the honeybee melittin signal peptide (msp) to the N-terminus enhanced the protein expression, and adding the VSV G protein transmembrane domain and the cytoplasmic tail (Gtc) enhanced protein incorporation into pseudotype VSV. All rVSVs expressed three different forms of SARS-CoV-2 spike proteins, but chimeras with VSV-Gtc demonstrated the highest rVSV-associated expression. In immunized mice, rVSV with chimeric S protein-Gtc derivatives induced the highest level of potent neutralizing antibodies and T cell responses, and rVSV harboring the full-length msp-SF-Gtc proved to be the superior immunogen. More importantly, rVSV-msp-SF-Gtc vaccinated animals were completely protected from a subsequent SARS-CoV-2 challenge. Overall, we have developed an efficient strategy to induce a protective response in SARS-CoV-2 challenged immunized mice. Vaccination with our rVSV-based vector may be an effective solution in the global fight against COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Vesicular stomatitis Indiana virus/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/genetics , Chlorocebus aethiops , Humans , Immunization , Mice , Mice, Inbred C57BL , Mice, Transgenic , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Viral Proteins/genetics , Viral Proteins/immunology
5.
Front Immunol ; 12: 795741, 2021.
Article in English | MEDLINE | ID: covidwho-1581316

ABSTRACT

Glycan-masking the vaccine antigen by mutating the undesired antigenic sites with an additional N-linked glycosylation motif can refocus B-cell responses to desired epitopes, without affecting the antigen's overall-folded structure. This study examined the impact of glycan-masking mutants of the N-terminal domain (NTD) and receptor-binding domain (RBD) of SARS-CoV-2, and found that the antigenic design of the S protein increases the neutralizing antibody titers against the Wuhan-Hu-1 ancestral strain and the recently emerged SARS-CoV-2 variants Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2). Our results demonstrated that the use of glycan-masking Ad-S-R158N/Y160T in the NTD elicited a 2.8-fold, 6.5-fold, and 4.6-fold increase in the IC-50 NT titer against the Alpha (B.1.1.7), Beta (B.1.351) and Delta (B.1.617.2) variants, respectively. Glycan-masking of Ad-S-D428N in the RBD resulted in a 3.0-fold and 2.0-fold increase in the IC-50 neutralization titer against the Alpha (B.1.1.7) and Beta (B.1.351) variants, respectively. The use of glycan-masking in Ad-S-R158N/Y160T and Ad-S-D428N antigen design may help develop universal COVID-19 vaccines against current and future emerging SARS-CoV-2 variants.


Subject(s)
Antigens, Viral/immunology , COVID-19/immunology , Epitopes/immunology , Protein Interaction Domains and Motifs/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adenoviridae/genetics , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Disease Models, Animal , Dose-Response Relationship, Immunologic , Female , Genetic Engineering , Genetic Vectors/genetics , Humans , Immunization , Mice , Neutralization Tests , Polysaccharides , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship
6.
Biomed Pharmacother ; 146: 112550, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1588217

ABSTRACT

Coronavirus is a family of viruses that can cause diseases such as the common cold, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). The universal outbreak of coronavirus disease 2019 (COVID-19) caused by SARS coronaviruses 2 (SARS-CoV-2) has become a global pandemic. The ß-Coronaviruses, which caused SARS-CoV-2 (COVID-19), have spread in more than 213 countries, infected over 81 million people, and caused more than 1.79 million deaths. COVID-19 symptoms vary from mild fever, flu to severe pneumonia in severely ill patients. Difficult breathing, acute respiratory distress syndrome (ARDS), acute kidney disease, liver damage, and multi-organ failure ultimately lead to death. Researchers are working on different pre-clinical and clinical trials to prevent this deadly pandemic by developing new vaccines. Along with vaccines, therapeutic intervention is an integral part of healthcare response to address the ongoing threat posed by COVID-19. Despite the global efforts to understand and fight against COVID-19, many challenges need to be addressed. This article summarizes the current pandemic, different strains of SARS-CoV-2, etiology, complexities, surviving medications of COVID-19, and so far, vaccination for the treatment of COVID-19.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/genetics , Genetic Variation/genetics , SARS-CoV-2/genetics , Vaccination/trends , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/genetics , Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19 Vaccines/genetics , Disease Outbreaks/prevention & control , Humans , Medicine, Chinese Traditional/trends , Vaccination/methods
7.
Biomed Pharmacother ; 146: 112527, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1559074

ABSTRACT

Coronavirus disease 2019 (COVID-19) has a devastating impact on global populations triggered by a highly infectious viral sickness, produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The third major cause of mortality in the United States, following heart disease and cancer in 2020, was undoubtedly COVID-19. The centers for disease control and prevention (CDC) and the world health organization (WHO) separately developed a categorization system for differentiating new strains of SARS-CoV-2 into variants of concern (VoCs) and variants of interest (VoIs) with the continuing development of various strains SARS-CoV-2. By December 2021, five of the SARS-CoV-2 VoCs were discovered from the onset of the pandemic depending on the latest epidemiologic report by the WHO: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). Mutations in the receptor-binding domain (RBD) and n-terminal domain (NTD) have been found throughout all five identified VoCs. All strains other than the delta mutant are often found with the N501Y mutation situated on the RBD, resulting in higher binding between the spike protein and angiotensin-converting enzyme 2 (ACE2) receptors, enhanced viral adhesion, and following the entrance to host cells. The introduction of these new strains of SRAS-CoV-2 is likely to overcome the remarkable achievements gained in restricting this viral disease to the point where it is presented with remarkable vaccine developments against COVID-19 and strong worldwide mass immunization initiatives. Throughout this literature review, the effectiveness of current COVID-19 vaccines for managing and prohibiting SARS-CoV-2 strains is thoroughly described.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Genetic Vectors/administration & dosage , SARS-CoV-2/drug effects , Vaccines, Synthetic/administration & dosage , /administration & dosage , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/genetics , COVID-19/metabolism , COVID-19 Vaccines/genetics , COVID-19 Vaccines/metabolism , Genetic Variation/genetics , Genetic Vectors/genetics , Genetic Vectors/metabolism , Humans , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Treatment Outcome , Vaccines, Synthetic/genetics , Vaccines, Synthetic/metabolism , /metabolism
9.
Nat Commun ; 12(1): 6222, 2021 10 28.
Article in English | MEDLINE | ID: covidwho-1493103

ABSTRACT

The importance of breastmilk in postnatal life lies in the strong association between breastfeeding and the reduction in the risk of infection and infection-related infant mortality. However, data regarding the induction and dynamics of breastmilk antibodies following administration of the Pfizer-BioNTech BNT162b2 COVID-19 mRNA vaccine is scarce, as pregnant and lactating women were not included in the initial vaccine clinical trials. Here, we investigate the dynamics of the vaccine-specific antibody response in breastmilk and serum in a prospective cohort of ten lactating women who received two doses of the mRNA vaccine. We show that the antibody response is rapid and highly synchronized between breastmilk and serum, reaching stabilization 14 days after the second dose. The response in breastmilk includes both IgG and IgA with neutralization capacity.


Subject(s)
Breast Feeding , COVID-19 Vaccines/genetics , RNA, Messenger/blood , Adult , Animals , Antibody Formation/genetics , Antibody Formation/physiology , Female , Humans , Milk/chemistry , RNA, Messenger/analysis , Vaccines, Synthetic/therapeutic use
10.
Proc Natl Acad Sci U S A ; 118(45)2021 11 09.
Article in English | MEDLINE | ID: covidwho-1475573

ABSTRACT

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other pathogens with pandemic potential requires safe, protective, inexpensive, and easily accessible vaccines that can be developed and manufactured rapidly at a large scale. DNA vaccines can achieve these criteria, but induction of strong immune responses has often required bulky, expensive electroporation devices. Here, we report an ultra-low-cost (<1 USD), handheld (<50 g) electroporation system utilizing a microneedle electrode array ("ePatch") for DNA vaccination against SARS-CoV-2. The low cost and small size are achieved by combining a thumb-operated piezoelectric pulser derived from a common household stove lighter that emits microsecond, bipolar, oscillatory electric pulses and a microneedle electrode array that targets delivery of high electric field strength pulses to the skin's epidermis. Antibody responses against SARS-CoV-2 induced by this electroporation system in mice were strong and enabled at least 10-fold dose sparing compared to conventional intramuscular or intradermal injection of the DNA vaccine. Vaccination was well tolerated with mild, transient effects on the skin. This ePatch system is easily portable, without any battery or other power source supply, offering an attractive, inexpensive approach for rapid and accessible DNA vaccination to combat COVID-19, as well as other epidemics.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/immunology , COVID-19/prevention & control , Electroporation/instrumentation , SARS-CoV-2 , Vaccines, DNA/administration & dosage , Animals , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Costs and Cost Analysis , Electroporation/economics , Electroporation/methods , Equipment Design , Female , Genes, Reporter , Humans , Mice , Mice, Inbred BALB C , Microelectrodes , Needles , Pandemics/prevention & control , Proof of Concept Study , Rats , Rats, Wistar , Skin/immunology , Skin/metabolism , Transfection , Vaccination/economics , Vaccination/instrumentation , Vaccination/methods , Vaccines, DNA/genetics , Vaccines, DNA/immunology
12.
Biochemistry (Mosc) ; 86(10): 1275-1287, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1476404

ABSTRACT

A new platform for creating anti-coronavirus epitope vaccines has been developed. Two loop-like epitopes with lengths of 22 and 42 amino acid residues were selected from the receptor-binding motif of the Spike protein from the SARS-CoV-2 virus that participate in a large number of protein-protein interactions in the complexes with ACE2 and neutralizing antibodies. Two types of hybrid proteins, including one of the two selected epitopes, were constructed. To fix conformation of the selected epitopes, an approach using protein scaffolds was used. The homologue of Rop protein from the Escherichia coli ColE1 plasmid containing helix-turn-helix motif was used as an epitope scaffold for the convergence of C- and N-termini of the loop-like epitopes. Loop epitopes were inserted into the turn region. The conformation was additionally fixed by a disulfide bond formed between the cysteine residues present within the epitopes. For the purpose of multimerization, either aldolase from Thermotoga maritima, which forms a trimer in solution, or alpha-helical trimerizer of the Spike protein from SARS-CoV-2, was attached to the epitopes incorporated into the Rop-like protein. To enable purification on the heparin-containing sorbents, a short fragment from the heparin-binding hemagglutinin of Mycobacterium tuberculosis was inserted at the C-terminus of the hybrid proteins. All the obtained proteins demonstrated high level of immunogenicity after triplicate parenteral administration to mice. Sera from the mice immunized with both aldolase-based hybrid proteins and the Spike protein SARS-CoV-2 trimerizer-based protein with a longer epitope interacted with both the inactivated SARS-CoV-2 virus and the Spike protein receptor-binding domain at high titers.


Subject(s)
COVID-19 Vaccines , COVID-19 , Epitopes , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Animals , COVID-19/genetics , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , COVID-19 Vaccines/isolation & purification , COVID-19 Vaccines/pharmacology , Epitopes/genetics , Epitopes/immunology , Epitopes/isolation & purification , Epitopes/pharmacology , Female , Humans , Mice , Mice, Inbred BALB C , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Recombinant Proteins/isolation & purification , Recombinant Proteins/pharmacology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/isolation & purification , Spike Glycoprotein, Coronavirus/pharmacology
13.
Protein Expr Purif ; 190: 106003, 2022 02.
Article in English | MEDLINE | ID: covidwho-1474960

ABSTRACT

SARS-CoV-2 protein subunit vaccines are currently being evaluated by multiple manufacturers to address the global vaccine equity gap, and need for low-cost, easy to scale, safe, and effective COVID-19 vaccines. In this paper, we report on the generation of the receptor-binding domain RBD203-N1 yeast expression construct, which produces a recombinant protein capable of eliciting a robust immune response and protection in mice against SARS-CoV-2 challenge infections. The RBD203-N1 antigen was expressed in the yeast Pichia pastoris X33. After fermentation at the 5 L scale, the protein was purified by hydrophobic interaction chromatography followed by anion exchange chromatography. The purified protein was characterized biophysically and biochemically, and after its formulation, the immunogenicity was evaluated in mice. Sera were evaluated for their efficacy using a SARS-CoV-2 pseudovirus assay. The RBD203-N1 protein was expressed with a yield of 492.9 ± 3.0 mg/L of fermentation supernatant. A two-step purification process produced a >96% pure protein with a recovery rate of 55 ± 3% (total yield of purified protein: 270.5 ± 13.2 mg/L fermentation supernatant). The protein was characterized to be a homogeneous monomer that showed a well-defined secondary structure, was thermally stable, antigenic, and when adjuvanted on Alhydrogel in the presence of CpG it was immunogenic and induced high levels of neutralizing antibodies against SARS-CoV-2 pseudovirus. The characteristics of the RBD203-N1 protein-based vaccine show that this candidate is another well suited RBD-based construct for technology transfer to manufacturing entities and feasibility of transition into the clinic to evaluate its immunogenicity and safety in humans.


Subject(s)
COVID-19 Vaccines , Gene Expression , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Animals , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/genetics , COVID-19 Vaccines/pharmacology , Humans , Mice , Protein Domains , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacology , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Saccharomyces cerevisiae/chemistry , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/pharmacology
14.
Nucleic Acid Ther ; 31(5): 321-323, 2021 10.
Article in English | MEDLINE | ID: covidwho-1467290

ABSTRACT

The utilization of the mRNA-based Pfizer-BioNTech and Moderna coronavirus disease 2019 (COVID-19) vaccines represents the culmination of many years of nonviral nucleic acid delivery, but more importantly, they signify a massive clinical scientific success. Scientists working in the area of nucleic acid delivery using lipid nanoparticles will undoubtedly be energized by the success of these vaccines and begin to collect much needed data in the realm of nonviral-based RNA and DNA delivery, specifically, the use of lipid nanoparticles, the immune response, safety, and efficacy. It is easily conceivable that in the future we can utilize these data to help streamline our approach for the delivery of DNA for gene therapy and regulatory RNAs for therapeutic and regenerative medicine (ie, wound repair) applications.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , DNA/pharmacokinetics , Gene Transfer Techniques , RNA, Messenger/pharmacokinetics , Biotechnology/trends , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/biosynthesis , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/genetics , DNA/chemistry , Data Mining , Dependovirus/genetics , Dependovirus/immunology , Humans , Liposomes/chemistry , Liposomes/pharmacokinetics , Nanoparticles/administration & dosage , Nanoparticles/chemistry , RNA, Messenger/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
15.
J Exp Med ; 218(12)2021 12 06.
Article in English | MEDLINE | ID: covidwho-1462245

ABSTRACT

Broadly protective vaccines against SARS-related coronaviruses that may cause future outbreaks are urgently needed. The SARS-CoV-2 spike receptor-binding domain (RBD) comprises two regions, the core-RBD and the receptor-binding motif (RBM); the former is structurally conserved between SARS-CoV-2 and SARS-CoV. Here, in order to elicit humoral responses to the more conserved core-RBD, we introduced N-linked glycans onto RBM surfaces of the SARS-CoV-2 RBD and used them as immunogens in a mouse model. We found that glycan addition elicited higher proportions of the core-RBD-specific germinal center (GC) B cells and antibody responses, thereby manifesting significant neutralizing activity for SARS-CoV, SARS-CoV-2, and the bat WIV1-CoV. These results have implications for the design of SARS-like virus vaccines.


Subject(s)
Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , Polysaccharides/immunology , SARS Virus/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Amino Acid Motifs , Animals , COVID-19/genetics , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Female , Humans , Male , Mice , Mice, Inbred BALB C , Polysaccharides/genetics , Protein Domains , SARS Virus/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
16.
J Pediatr ; 238: 26-32.e1, 2021 11.
Article in English | MEDLINE | ID: covidwho-1461628

ABSTRACT

OBJECTIVES: To characterize the clinical course and outcomes of children 12-18 years of age who developed probable myopericarditis after vaccination with the Pfizer-BioNTech (BNT162b2) coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccine. STUDY DESIGN: A cross-sectional study of 25 children, aged 12-18 years, diagnosed with probable myopericarditis after COVID-19 mRNA vaccination as per the Centers for Disease Control and Prevention criteria for myopericarditis at 8 US centers between May 10, 2021, and June 20, 2021. We retrospectively collected the following data: demographics, severe acute respiratory syndrome coronavirus 2 virus detection or serologic testing, clinical manifestations, laboratory test results, imaging study results, treatment, and time to resolutions of symptoms. RESULTS: Most (88%) cases followed the second dose of vaccine, and chest pain (100%) was the most common presenting symptom. Patients came to medical attention a median of 2 days (range, <1-20 days) after receipt of Pfizer mRNA COVID-19 vaccination. All adolescents had an elevated plasma troponin concentration. Echocardiographic abnormalities were infrequent, and 92% showed normal cardiac function at presentation. However, cardiac magnetic resonance imaging, obtained in 16 patients (64%), revealed that 15 (94%) had late gadolinium enhancement consistent with myopericarditis. Most were treated with ibuprofen or an equivalent nonsteroidal anti-inflammatory drug for symptomatic relief. One patient was given a corticosteroid orally after the initial administration of ibuprofen or an nonsteroidal anti-inflammatory drug; 2 patients also received intravenous immune globulin. Symptom resolution was observed within 7 days in all patients. CONCLUSIONS: Our data suggest that symptoms owing to myopericarditis after the mRNA COVID-19 vaccination tend to be mild and transient. Approximately two-thirds of patients underwent cardiac magnetic resonance imaging, which revealed evidence of myocardial inflammation despite a lack of echocardiographic abnormalities.


Subject(s)
COVID-19 Vaccines/genetics , COVID-19/prevention & control , Magnetic Resonance Imaging, Cine/methods , Myocarditis/etiology , SARS-CoV-2/immunology , Vaccination/adverse effects , Vaccines, Synthetic/adverse effects , Adolescent , COVID-19/epidemiology , COVID-19/genetics , COVID-19 Vaccines/adverse effects , Child , Cross-Sectional Studies , Female , Humans , Incidence , Male , Myocarditis/diagnosis , Myocarditis/epidemiology , Pandemics , Retrospective Studies , United States/epidemiology
17.
Immunogenetics ; 73(6): 459-477, 2021 12.
Article in English | MEDLINE | ID: covidwho-1427234

ABSTRACT

Since 2019, the world was involved with SARS-CoV-2 and consequently, with the announcement by the World Health Organization that COVID-19 was a pandemic, scientific were an effort to obtain the best approach to combat this global dilemma. The best way to prevent the pandemic from spreading further is to use a vaccine against COVID-19. Here, we report the design of a recombinant multi-epitope vaccine against the four proteins spike or crown (S), membrane (M), nucleocapsid (N), and envelope (E) of SARS-CoV-2 using immunoinformatics tools. We evaluated the most antigenic epitopes that bind to HLA class 1 subtypes, along with HLA class 2, as well as B cell epitopes. Beta-defensin 3 and PADRE sequence were used as adjuvants in the structure of the vaccine. KK, GPGPG, and AAY linkers were used to fuse the selected epitopes. The nucleotide sequence was cloned into pET26b(+) vector using restriction enzymes XhoI and NdeI, and HisTag sequence was considered in the C-terminal of the construct. The results showed that the proposed candidate vaccine is a 70.87 kDa protein with high antigenicity and immunogenicity as well as non-allergenic and non-toxic. A total of 95% of the selected epitopes have conservancy with similar sequences. Molecular docking showed a strong binding between the vaccine structure and tool-like receptor (TLR) 7/8. The docking, molecular dynamics, and MM/PBSA analysis showed that the vaccine established a stable interaction with both structures of TLR7 and TLR8. Simulation of immune stimulation by this vaccine showed that it evokes immune responses related to humoral and cellular immunity.


Subject(s)
COVID-19 Vaccines/immunology , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Amino Acid Sequence , Base Sequence , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/metabolism , Computational Biology , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/genetics , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/genetics , HLA Antigens/immunology , Humans , Immunogenicity, Vaccine , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Weight , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Toll-Like Receptor 7/chemistry , Toll-Like Receptor 8/chemistry , Vaccines, Subunit/genetics , Vaccines, Subunit/immunology , Vaccines, Subunit/metabolism , Vaccinology , Viral Proteins/chemistry , Viral Proteins/genetics , Viral Proteins/immunology
18.
Clin Appl Thromb Hemost ; 27: 10760296211040110, 2021.
Article in English | MEDLINE | ID: covidwho-1430348

ABSTRACT

Since the outbreak of Covid-19 in December, 2019, scientists worldwide have been committed to developing COVID-19 vaccines. Only when most people have immunity to SARS-CoV-2, COVID-19 can reduce even wholly overcome. So far, nine kinds of COVID-19 vaccines have passed the phase III clinical trials and have approved for use. At the same time, adverse reactions after COVID-19 vaccination have also reported. This paper focuses on the adverse effects of thrombosis and thrombocytopenia caused by the COVID-19 vaccine, especially the adenovirus-vector vaccine from AstraZeneca and Pfizer, and discusses its mechanism and possible countermeasures.


Subject(s)
Adenoviridae/genetics , COVID-19 Vaccines/adverse effects , Genetic Vectors , Thrombocytopenia/chemically induced , Thrombosis/chemically induced , Vaccination/adverse effects , Antibodies/blood , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Humans , Platelet Factor 4/immunology , Risk Assessment , Risk Factors , Thrombocytopenia/blood , Thrombocytopenia/immunology , Thrombosis/blood , Thrombosis/immunology
19.
PLoS One ; 16(9): e0257191, 2021.
Article in English | MEDLINE | ID: covidwho-1412845

ABSTRACT

COVID-19 in humans is caused by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that belongs to the beta family of coronaviruses. SARS-CoV-2 causes severe respiratory illness in 10-15% of infected individuals and mortality in 2-3%. Vaccines are urgently needed to prevent infection and to contain viral spread. Although several mRNA- and adenovirus-based vaccines are highly effective, their dependence on the "cold chain" transportation makes global vaccination a difficult task. In this context, a stable lyophilized vaccine may present certain advantages. Accordingly, establishing additional vaccine platforms remains vital to tackle SARS-CoV-2 and any future variants that may arise. Vaccinia virus (VACV) has been used to eradicate smallpox disease, and several attenuated viral strains with enhanced safety for human applications have been developed. We have generated two candidate SARS-CoV-2 vaccines based on two vaccinia viral strains, MVA and v-NY, that express full-length SARS-CoV-2 spike protein. Whereas MVA is growth-restricted in mammalian cells, the v-NY strain is replication-competent. We demonstrate that both candidate recombinant vaccines induce high titers of neutralizing antibodies in C57BL/6 mice vaccinated according to prime-boost regimens. Furthermore, our vaccination regimens generated TH1-biased immune responses in mice. Most importantly, prime-boost vaccination of a Syrian hamster infection model with MVA-S and v-NY-S protected the hamsters against SARS-CoV-2 infection, supporting that these two vaccines are promising candidates for future development. Finally, our vaccination regimens generated neutralizing antibodies that partially cross-neutralized SARS-CoV-2 variants of concern.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/immunology , Vaccinia virus/genetics , Animals , Antibodies, Neutralizing/analysis , Antibodies, Neutralizing/immunology , COVID-19/virology , COVID-19 Vaccines/genetics , Female , Immunization, Secondary , Lung/pathology , Male , Mesocricetus , Mice , Mice, Inbred C57BL , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry
20.
Biosci Rep ; 41(9)2021 09 30.
Article in English | MEDLINE | ID: covidwho-1406416

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic of the Coronavirus disease in late 2019 (COVID-19). Vaccine development efforts have predominantly been aimed at 'Extra-viral' Spike (S) protein as vaccine vehicles, but there are concerns regarding 'viral immune escape' since multiple mutations may enable the mutated virus strains to escape from immunity against S protein. The 'Intra-viral' Nucleocapsid (N-protein) is relatively conserved among mutant strains of coronaviruses during spread and evolution. Herein, we demonstrate novel vaccine candidates against SARS-CoV-2 by using the whole conserved N-protein or its fragment/peptides. Using ELISA assay, we showed that high titers of specific anti-N antibodies (IgG, IgG1, IgG2a, IgM) were maintained for a reasonably long duration (> 5 months), suggesting that N-protein is an excellent immunogen to stimulate host immune system and robust B-cell activation. We synthesized three peptides located at the conserved regions of N-protein among CoVs. One peptide showed as a good immunogen for vaccination as well. Cytokine arrays on post-vaccination mouse sera showed progressive up-regulation of various cytokines such as IFN-γ and CCL5, suggesting that TH1 associated responses are also stimulated. Furthermore, vaccinated mice exhibited an elevated memory T cells population. Here, we propose an unconventional vaccine strategy targeting the conserved N-protein as an alternative vaccine target for coronaviruses. Moreover, we generated a mouse monoclonal antibody specifically against an epitope shared between SARS-CoV and SARS-CoV-2, and we are currently developing the First-in-Class humanized anti-N-protein antibody to potentially treat patients infected by various CoVs in the future.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Coronavirus Nucleocapsid Proteins/immunology , Animals , Antibodies, Monoclonal, Murine-Derived , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/genetics , Coronavirus Nucleocapsid Proteins/genetics , Epitopes/immunology , Humans , Immune Evasion , Immunogenicity, Vaccine , Mice , Models, Animal , Pandemics/prevention & control , SARS Virus/genetics , SARS Virus/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Sequence Homology, Amino Acid , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/genetics , Vaccines, Subunit/immunology
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