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Singh S, Liu Y, Burke M, Rayaprolu V, Stein SE, Hasan SS. Production and cryo-electron microscopy structure of an internally tagged SARS-CoV-2 spike ecto-domain construct. J Struct Biol X 2025; 11:100123. [PMID: 40046771 PMCID: PMC11880631 DOI: 10.1016/j.yjsbx.2025.100123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 02/10/2025] [Accepted: 02/10/2025] [Indexed: 03/09/2025] Open
Abstract
The SARS-CoV-2 spike protein is synthesized in the endoplasmic reticulum of host cells, from where it undergoes export to the Golgi and the plasma membrane or retrieval from the Golgi to the endoplasmic reticulum. Elucidating the fundamental principles of this bidirectional secretion are pivotal to understanding virus assembly and designing the next generation of spike genetic vaccine with enhanced export properties. However, the widely used strategy of C-terminal affinity tagging of the spike cytosolic tail interferes with proper bidirectional trafficking. Hence, the structural and biophysical investigations of spike protein trafficking have been hindered by a lack of appropriate spike constructs. Here we describe a strategy for the internal tagging of the spike protein. Using sequence analyses and AlphaFold modeling, we identified a site down-stream of the signal sequence for the insertion of a twin-strep-tag, which facilitates purification of an ecto-domain construct from the extra-cellular medium of mammalian Expi293F cells. Mass spectrometry analyses show that the internal tag has minimal impact on N-glycan modifications, which are pivotal for spike-host interactions. Single particle cryo-electron microscopy reconstructions of the spike ecto-domain reveal conformational states compatible for ACE2 receptor interactions, further solidifying the feasibility of the internal tagging strategy. Collectively, these results present a substantial advance towards reagent development for the investigations of spike protein trafficking during coronavirus infection and genetic vaccination.
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Affiliation(s)
- Suruchi Singh
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore MD 21201, USA
| | - Yi Liu
- Mass Spectrometry Data Center, Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg MD 20899, USA
| | - Meghan Burke
- Mass Spectrometry Data Center, Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg MD 20899, USA
| | - Vamseedhar Rayaprolu
- Pacific Northwest Cryo-EM Center, Oregon Health and Sciences University, Portland, OR 97201, USA
| | - Stephen E. Stein
- Mass Spectrometry Data Center, Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg MD 20899, USA
| | - S. Saif Hasan
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore MD 21201, USA
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore MD 21201, USA
- Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Rockville MD 20850, USA
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2
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Tian Y, Cipollo JF. Comparison of N- and O-Glycosylation on Spike Glycoprotein 1 of SARS-CoV-1 and MERS-CoV. J Proteome Res 2025; 24:2256-2265. [PMID: 40193531 DOI: 10.1021/acs.jproteome.4c00716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
SARS-CoV-1 and MERS-CoV were the infective agents of the 2002 and 2012 coronavirus outbreaks, respectively. Here, we report a comparative liquid chromatography/mass spectrometry (LC/MS) Orbitrap N- and O-glycosylation glycoproteomics study of the recombinant S1 spike derived from these two viruses. The former was produced in HEK293 cells and the latter in both HEK293 and insect cells. Both proteins were highly glycosylated, with SARS-CoV-1 S1 having 13 and MERS-CoV S1 having 12 N-glycosites. Nearly all were occupied at 85% or more. Between 2 and 113 unique N-glycan compositions were detected at each N-glycosite across the three proteins. Complex N-glycans dominated in HEK293 cell-derived spike S1 proteins. While glycosylation differs between HEK293 and insect cells, the extent of glycan processing at glycosites was similar for the two MERS-CoV S1 forms. The HEK293-derived SARS-CoV-1 S1 N-glycans were more highly sialylated and fucosylated compared to MERS S1, while the latter had more high-mannose glycosides, particularly in the N-terminus and near the RBD. Seven and 8 O-glycosites were identified in SARS-CoV-1 S1 and MERS-CoV S1, respectively. Mapping of predicted antigenic and glycosylation sites reveals colocalization consistent with a role for glycosylation in immune system avoidance. Glycosylation patterns of these S1 proteins differ from those of other SARS-CoV-1 and MERS-CoV spike reported forms such as recombinant trimeric and virus-propagated forms, which has implications for virus research, including vaccine development, as glycosylation plays a role in spike function and epitope structure.
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Affiliation(s)
- Yuan Tian
- Food and Drug Administration, Center for Biologics Evaluation and Research, Division of Product Quality Assessment V, Parasitic and Allergenic Products, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, United States
- Food and Drug Administration, Center for Drug Evaluation and Research, Division of Product Quality Assessment, Parasitic and Allergenic Products, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, United States
| | - John F Cipollo
- Food and Drug Administration, Center for Biologics Evaluation and Research, Division of Product Quality Assessment V, Parasitic and Allergenic Products, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, United States
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3
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Liu C, Ke Z. Cryo-ET unravels the mystery of Ad5-nCoV vaccines. Structure 2025; 33:836-837. [PMID: 40315818 DOI: 10.1016/j.str.2025.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Revised: 04/06/2025] [Accepted: 04/07/2025] [Indexed: 05/04/2025]
Abstract
The Ad5-nCoV vaccine (Convidecia) against COVID-19 showed promising clinical results. However, the molecular mechanisms underlying its high immunogenicity and potential adverse reactions have remained elusive. In this issue of Structure, Dong et al.1 employed cryo-electron tomography as a powerful technique to show that abundant prefusion spike protein formation is induced by Ad5-nCoV vaccines.
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Affiliation(s)
- Chang Liu
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
| | - Zunlong Ke
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA; LaMontagne Center for Infectious Disease, The University of Texas at Austin, Austin, TX 78712, USA.
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Dong D, Song Y, Wu S, Wang B, Peng C, Zhang W, Kong W, Zhang Z, Song J, Hou LH, Li S. Molecular basis of Ad5-nCoV vaccine-induced immunogenicity. Structure 2025; 33:858-868.e5. [PMID: 40112804 DOI: 10.1016/j.str.2025.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 12/12/2024] [Accepted: 02/21/2025] [Indexed: 03/22/2025]
Abstract
Ad5-nCoV (Convidecia) is listed for emergency use against COVID-19 by the World Health Organization (WHO) and has been globally administered to millions of people. It utilizes human adenovirus 5 (Ad5) replication-incompetent vector to deliver the spike (S) protein gene from various SARS-CoV-2 strains. Despite promising clinical data, the molecular mechanism underlying its high immunogenicity and adverse reactions remain incompletely understood. Here, we primarily applied cryo-electron tomography (cryo-ET), fluorescence microscopy and mass spectrometry to analyze the Ad5-nCoV_Wu and Ad5-nCoV_O vaccine-induced S antigens. These antigens encode the unmodified SARS-CoV-2 Wuhan-Hu-1 S gene and the stabilized Omicron S gene, respectively. Our findings highlight the structural integrity, antigenicity, and dense distribution on cell membrane of the vaccine-induced S proteins. Ad5-nCoV_O induced S proteins exhibit improved stability and reduced syncytia formation among inoculated cells. Our work demonstrates that Ad5-nCoV is a prominent platform for antigen induction and cryo-ET can be a useful technique for vaccine characterization and development.
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Affiliation(s)
- Dongyang Dong
- Beijing Frontier Research Center for Biological Structure & Tsinghua-Peking Center for Life Sciences & State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yutong Song
- Beijing Frontier Research Center for Biological Structure & Tsinghua-Peking Center for Life Sciences & State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Shipo Wu
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Busen Wang
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Cheng Peng
- Beijing Frontier Research Center for Biological Structure & Tsinghua-Peking Center for Life Sciences & State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Weiping Zhang
- Beijing Frontier Research Center for Biological Structure & Tsinghua-Peking Center for Life Sciences & State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Weizheng Kong
- Beijing Frontier Research Center for Biological Structure & Tsinghua-Peking Center for Life Sciences & State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zheyuan Zhang
- Beijing Frontier Research Center for Biological Structure & Tsinghua-Peking Center for Life Sciences & State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Jingwen Song
- Beijing Frontier Research Center for Biological Structure & Tsinghua-Peking Center for Life Sciences & State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Li-Hua Hou
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Sai Li
- Beijing Frontier Research Center for Biological Structure & Tsinghua-Peking Center for Life Sciences & State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
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Akula VR, Bhate AS, Gillurkar CS, Kushwaha JS, Singh AP, Singh C, Pandey AK, K K S, Rai SK, Vadrevu KM. Effect of heterologous intranasal iNCOVACC ® vaccination as a booster to two-dose intramuscular Covid-19 vaccination series: a randomized phase 3 clinical trial. COMMUNICATIONS MEDICINE 2025; 5:133. [PMID: 40269252 PMCID: PMC12019531 DOI: 10.1038/s43856-025-00818-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 03/21/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Due to waning immunity and emerging variants, protection following primary intramuscular Covid-19 vaccinations is decreasing, so health agencies have been proposing heterologous booster vaccinations. Here, we report immunogenicity and safety evaluation of heterologous booster vaccination with an intranasal, adenovirus vectored SARS-CoV-2 vaccine (BBV154) in healthy adults, who were previously primed with two doses of either Covaxin® or Covishield™. We compare results with use of a homologous booster vaccination combination. METHODS This was a randomized, open-label phase 3 trial conducted to evaluate immunogenicity and safety of a booster dose of intranasal BBV154 vaccine or intramuscular EUA approved Covid-19 vacines in India. Healthy participants of ≥18 years age with no history of SARS-CoV-2 infection, who received two doses of Covaxin® or Covishield™ at least 6 ± 1 months earlier were enrolled. The primary outcome was the neutralising antibody titers against wild-type virus using a plaque-reduction neutralization test (PRNT50). Other outcomes measured were humoral (IgG), mucosal (IgA) and cell mediated responses. The protocol was registered #NCT05567471 and approved by National Regulatory Authority (India) #CTRI/2022/02/039992. RESULTS In this phase 3 trial, a total of 875 participants were randomized into 5 Groups in a ratio of 2:1:2:1:1 to receive either booster dose of BBV154 or Covaxin or Covishield. Based on per-protocol population, at Day 56, neutralization antibody titres were 564.1 (479·1, 664·1), 578.1 (436·9, 764·9), 655.5 (533·3, 805·8), 625.4 (474·7, 824·0), 650.1 (519·7, 813·1) for Group 1 to 5 respectively. This study was conducted, whilst the Omicron variant was prevalent. There were varying levels of severity of infection across different study sites with varied baseline antibody titers. Consequently, the average neutralization (PRNT50) antibody titers are similar across all Groups on day 56 and exhibited large differences within the Group, depending on the study site. All booster vaccinations are well tolerated and reported no serious adverse events; in particular, study participants boosted with BBV154 had significantly fewer solicited local adverse events than those primed and boosted with Covishield. CONCLUSIONS These findings demonstrate that impact of booster across different cohorts is governed by infection status of the individual and geographical diversity, thus necessitating large cohorts, well distributed studies before Covid-19 booster effects are interpreted.
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Affiliation(s)
| | | | | | | | | | | | | | - Shivaraj K K
- Vagus Super Speciality Hospital, Bangalore, Karnataka, India
| | - Sanjay K Rai
- All India Institute of Medical Sciences, New Delhi, India
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Posa A. Spike protein-related proteinopathies: A focus on the neurological side of spikeopathies. Ann Anat 2025; 260:152662. [PMID: 40254264 DOI: 10.1016/j.aanat.2025.152662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/22/2025]
Abstract
BACKGROUND The spike protein (SP) is an outward-projecting transmembrane glycoprotein on viral surfaces. SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), responsible for COVID-19 (Coronavirus Disease 2019), uses SP to infect cells that express angiotensin converting enzyme 2 (ACE2) on their membrane. Remarkably, SP has the ability to cross the blood-brain barrier (BBB) into the brain and cause cerebral damage through various pathomechanisms. To combat the COVID-19 pandemic, novel gene-based products have been used worldwide to induce human body cells to produce SP to stimulate the immune system. This artificial SP also has a harmful effect on the human nervous system. STUDY DESIGN Narrative review. OBJECTIVE This narrative review presents the crucial role of SP in neurological complaints after SARS-CoV-2 infection, but also of SP derived from novel gene-based anti-SARS-CoV-2 products (ASP). METHODS Literature searches using broad terms such as "SARS-CoV-2", "spike protein", "COVID-19", "COVID-19 pandemic", "vaccines", "COVID-19 vaccines", "post-vaccination syndrome", "post-COVID-19 vaccination syndrome" and "proteinopathy" were performed using PubMed. Google Scholar was used to search for topic-specific full-text keywords. CONCLUSIONS The toxic properties of SP presented in this review provide a good explanation for many of the neurological symptoms following SARS-CoV-2 infection and after injection of SP-producing ASP. Both SP entities (from infection and injection) interfere, among others, with ACE2 and act on different cells, tissues and organs. Both SPs are able to cross the BBB and can trigger acute and chronic neurological complaints. Such SP-associated pathologies (spikeopathies) are further neurological proteinopathies with thrombogenic, neurotoxic, neuroinflammatory and neurodegenerative potential for the human nervous system, particularly the central nervous system. The potential neurotoxicity of SP from ASP needs to be critically examined, as ASPs have been administered to millions of people worldwide.
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Affiliation(s)
- Andreas Posa
- University Clinics and Outpatient Clinics for Radiology, Neuroradiology and Neurology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, Halle 06120, Germany.
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7
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Oliveira ASF, Kearns FL, Rosenfeld MA, Casalino L, Tulli L, Berger I, Schaffitzel C, Davidson AD, Amaro RE, Mulholland AJ. Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike. eLife 2025; 13:RP97313. [PMID: 40208235 PMCID: PMC11984958 DOI: 10.7554/elife.97313] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025] Open
Abstract
The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating virus entry and mediating viral-host membrane fusion. The spike contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This site is coupled to key regions in the protein, but the impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore the allosteric effects of the FA site in the fully glycosylated spike of the SARS-CoV-2 ancestral variant. Our results identify the allosteric networks connecting the FA site to functionally important regions in the protein, including the receptor-binding motif, an antigenic supersite in the N-terminal domain, the fusion peptide region, and another allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected link between different allosteric sites. Comparison of the FA site connections from D-NEMD in the glycosylated and non-glycosylated spike revealed that glycans do not qualitatively change the internal allosteric pathways but can facilitate the transmission of the structural changes within and between subunits.
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Affiliation(s)
- A Sofia F Oliveira
- Centre for Computational Chemistry, School of Chemistry, University of BristolBristolUnited Kingdom
- School of Chemistry, University of BristolBristolUnited Kingdom
| | - Fiona L Kearns
- Department of Chemistry and Biochemistry, University of California San DiegoLa JollaUnited States
| | - Mia A Rosenfeld
- Department of Chemistry and Biochemistry, University of California San DiegoLa JollaUnited States
| | - Lorenzo Casalino
- Department of Chemistry and Biochemistry, University of California San DiegoLa JollaUnited States
| | - Lorenzo Tulli
- Centre for Computational Chemistry, School of Chemistry, University of BristolBristolUnited Kingdom
- School of Chemistry, University of BristolBristolUnited Kingdom
| | - Imre Berger
- School of Chemistry, University of BristolBristolUnited Kingdom
- School of Biochemistry, University of BristolBristolUnited Kingdom
- Max Planck Bristol Centre for Minimal Biology, School of ChemistryBristolUnited Kingdom
| | | | - Andrew D Davidson
- School of Cellular and Molecular Medicine, University of Bristol, University WalkBristolUnited Kingdom
| | - Rommie E Amaro
- Department of Molecular Biology, University of California San DiegoLa JollaUnited States
| | - Adrian J Mulholland
- Centre for Computational Chemistry, School of Chemistry, University of BristolBristolUnited Kingdom
- School of Chemistry, University of BristolBristolUnited Kingdom
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Chakraborty D, Singh R, Rajmani RS, Kumar S, Ringe RP, Varadarajan R. Stabilizing Prefusion SARS-CoV-2 Spike by Destabilizing the Postfusion Conformation. Vaccines (Basel) 2025; 13:315. [PMID: 40266205 PMCID: PMC11946859 DOI: 10.3390/vaccines13030315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/01/2025] [Accepted: 03/11/2025] [Indexed: 04/24/2025] Open
Abstract
Background/Objectives: As with many viral fusion proteins, the native conformation of SARS-CoV-2 Spike is metastable. Most COVID-19 vaccines utilize a stabilized Spike (Spike-2P) containing two proline substitutions, and subsequently, a further stabilized variant with four additional proline substitutions, Spike-6P, has been developed. In an alternative approach, we introduced two aspartic acid residues (2D) in the HR1 region of Spike at positions that are exposed and buried in the pre- and postfusion states, respectively, to destabilize the postfusion conformation. Methods: The recombinant protein constructs were expressed in a mammalian cell culture and characterized for their yield and antigenicity, and the formulations were then used to immunize hamsters. After two immunizations, the hamsters were challenged with live B.1.351 SARS-CoV-2 virus for an evaluation of the protective efficacy. Results: The introduction of the two aspartic acid mutations resulted in an approximately six-fold increase in expression, comparable to that in Spike-2P. When the 2D mutations were combined with the above four proline mutations (Spike-4P-2D), this led to a further three- to four-fold enhancement of protein expression, similar to that seen in Spike-6P. When formulated with the oil-in-water emulsion adjuvant Sepivac SWE, the 2P, 2D, 6P, and 4P-2D Spike variants all protected female hamsters against heterologous challenge with the B.1.351 SARS-CoV-2 virus and elicited high titers of neutralizing antibodies. Conclusions: We suggest that destabilization of the postfusion conformation through the introduction of charged amino acids at sites that are exposed in the pre- and buried in the postfusion conformation offers a general strategy to enhance the yield and stability of the native, prefusion conformation of viral surface proteins.
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Affiliation(s)
- Debajyoti Chakraborty
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India; (D.C.); (R.S.R.)
| | - Randhir Singh
- Mynvax Private Limited, 3rd Floor, Brigade MLR Centre, No.50, Vani Vilas Road, Basavanagudi, Bengaluru 560004, India;
| | - Raju S. Rajmani
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India; (D.C.); (R.S.R.)
| | - Sahil Kumar
- Virology Unit, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Chandigarh 160036, India; (S.K.); (R.P.R.)
| | - Rajesh P. Ringe
- Virology Unit, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Chandigarh 160036, India; (S.K.); (R.P.R.)
| | - Raghavan Varadarajan
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India; (D.C.); (R.S.R.)
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Tsuchiya H, Mizogami M. Characteristics of Oral Adverse Effects following COVID-19 Vaccination and Similarities with Oral Symptoms in COVID-19 Patients: Taste and Saliva Secretory Disorders. Med Princ Pract 2024; 34:101-120. [PMID: 39701050 PMCID: PMC11936456 DOI: 10.1159/000543182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 12/15/2024] [Indexed: 12/21/2024] Open
Abstract
Although coronavirus disease 2019 (COVID-19) vaccines exhibit diverse side effects, taste and saliva secretory disorders have remained poorly understood despite their negative impact on the overall quality of life. The present study aimed to characterize oral adverse effects following COVID-19 vaccination and assess their similarities with oral symptoms in COVID-19 patients. A literature search was conducted in databases, including PubMed, LitCovid, and Google Scholar, to retrieve relevant studies. The narrative review indicated that a certain number of vaccinated people develop ageusia, dysgeusia, hypogeusia, xerostomia, and dry mouth, while they are rare compared with COVID-19 oral symptoms. The prevalence of oral adverse effects varies by country/region and such geographical differences may be related to the type of vaccine used. Similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 vaccination adversely affects taste perception and salivary secretion in females and older subjects more frequently than in males and younger subjects. Their impairments mostly appear within 3 days of vaccination, and bitter taste is specifically impaired in some cases. Considering that oral adverse effects following COVID-19 vaccination share some characteristics with oral symptoms in COVID-19 patients, it is speculated that the spike protein derived from COVID-19 vaccination and SARS-CoV-2 infection may be pathophysiologically responsible for taste and saliva secretory disorders. This is because such spike protein has the potential to interact with ACE2 expressed on the relevant cells, produce proinflammatory cytokines, and form antiphospholipid antibodies. Our results do not deny the advantages of COVID-19 vaccination, but attention should be paid to post-vaccination oral effects in addition to COVID-19 oral symptoms. Although coronavirus disease 2019 (COVID-19) vaccines exhibit diverse side effects, taste and saliva secretory disorders have remained poorly understood despite their negative impact on the overall quality of life. The present study aimed to characterize oral adverse effects following COVID-19 vaccination and assess their similarities with oral symptoms in COVID-19 patients. A literature search was conducted in databases, including PubMed, LitCovid, and Google Scholar, to retrieve relevant studies. The narrative review indicated that a certain number of vaccinated people develop ageusia, dysgeusia, hypogeusia, xerostomia, and dry mouth, while they are rare compared with COVID-19 oral symptoms. The prevalence of oral adverse effects varies by country/region and such geographical differences may be related to the type of vaccine used. Similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 vaccination adversely affects taste perception and salivary secretion in females and older subjects more frequently than in males and younger subjects. Their impairments mostly appear within 3 days of vaccination, and bitter taste is specifically impaired in some cases. Considering that oral adverse effects following COVID-19 vaccination share some characteristics with oral symptoms in COVID-19 patients, it is speculated that the spike protein derived from COVID-19 vaccination and SARS-CoV-2 infection may be pathophysiologically responsible for taste and saliva secretory disorders. This is because such spike protein has the potential to interact with ACE2 expressed on the relevant cells, produce proinflammatory cytokines, and form antiphospholipid antibodies. Our results do not deny the advantages of COVID-19 vaccination, but attention should be paid to post-vaccination oral effects in addition to COVID-19 oral symptoms.
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Affiliation(s)
- Hironori Tsuchiya
- Department of Dental Basic Education, Asahi University School of Dentistry, Mizuho, Japan
| | - Maki Mizogami
- Department of Anesthesiology, Central Japan International Medical Center, Minokamo, Japan
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Zhou Q, Lok SM. Visualizing the virus world inside the cell by cryo-electron tomography. J Virol 2024; 98:e0108523. [PMID: 39494908 PMCID: PMC11650999 DOI: 10.1128/jvi.01085-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2024] Open
Abstract
Structural studies on purified virus have revealed intricate architectures, but there is little structural information on how viruses interact with host cells in situ. Cryo-focused ion beam (FIB) milling and cryo-electron tomography (cryo-ET) have emerged as revolutionary tools in structural biology to visualize the dynamic conformational of viral particles and their interactions with host factors within infected cells. Here, we review the state-of-the-art cryo-ET technique for in situ viral structure studies and highlight exemplary studies that showcase the remarkable capabilities of cryo-ET in capturing the dynamic virus-host interaction, advancing our understanding of viral infection and pathogenesis.
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Affiliation(s)
- Qunfei Zhou
- Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Shee-Mei Lok
- Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
- Department of Biological Sciences, Centre for BioImaging Sciences, National University of Singapore, Singapore, Singapore
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11
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Sun X, Tian T, Lian Y, Cui Z. Current Advances in Viral Nanoparticles for Biomedicine. ACS NANO 2024; 18:33827-33863. [PMID: 39648920 DOI: 10.1021/acsnano.4c13146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/10/2024]
Abstract
Viral nanoparticles (VNPs) have emerged as crucial tools in the field of biomedicine. Leveraging their biological and physicochemical properties, VNPs exhibit significant advantages in the prevention, diagnosis, and treatment of human diseases. Through techniques such as chemical bioconjugation, infusion, genetic engineering, and encapsulation, these VNPs have been endowed with multifunctional capabilities, including the display of functional peptides or proteins, encapsulation of therapeutic drugs or inorganic particles, integration with imaging agents, and conjugation with bioactive molecules. This review provides an in-depth analysis of VNPs in biomedicine, elucidating their diverse types, distinctive features, production methods, and complex design principles behind multifunctional VNPs. It highlights recent innovative research and various applications, covering their roles in imaging, drug delivery, therapeutics, gene delivery, vaccines, immunotherapy, and tissue regeneration. Additionally, the review provides an assessment of their safety and biocompatibility and discusses challenges and future opportunities in the field, underscoring the vast potential and evolving nature of VNP research.
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Affiliation(s)
- Xianxun Sun
- School of Life Sciences, Jianghan University, Wuhan 430056, China
| | - Tao Tian
- School of Life Sciences, Jianghan University, Wuhan 430056, China
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China
| | - Yindong Lian
- School of Life Sciences, Jianghan University, Wuhan 430056, China
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China
| | - Zongqiang Cui
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China
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12
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Kephart SM, Hom N, Lee KK. Visualizing intermediate stages of viral membrane fusion by cryo-electron tomography. Trends Biochem Sci 2024; 49:916-931. [PMID: 39054240 PMCID: PMC11455608 DOI: 10.1016/j.tibs.2024.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/07/2024] [Accepted: 06/18/2024] [Indexed: 07/27/2024]
Abstract
Protein-mediated membrane fusion is the dynamic process where specialized protein machinery undergoes dramatic conformational changes that drive two membrane bilayers together, leading to lipid mixing and opening of a fusion pore between previously separate membrane-bound compartments. Membrane fusion is an essential stage of enveloped virus entry that results in viral genome delivery into host cells. Recent studies applying cryo-electron microscopy techniques in a time-resolved fashion provide unprecedented glimpses into the interaction of viral fusion proteins and membranes, revealing fusion intermediate states from the initiation of fusion to release of the viral genome. In combination with complementary structural, biophysical, and computation modeling approaches, these advances are shedding new light on the mechanics and dynamics of protein-mediated membrane fusion.
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Affiliation(s)
- Sally M Kephart
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
| | - Nancy Hom
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
| | - Kelly K Lee
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA; Biological Structure Physics and Design Graduate Program, University of Washington, Seattle, WA, USA.
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13
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Park SJ, Seo J, Han KH, Lee BS, Lee C, Kim BY, Ko KC, Kim YB. Safety pharmacology of human endogenous retrovirus-enveloped baculoviral DNA vaccines against SARS-CoV-2 in Sprague-Dawley rats and beagle dogs. Vaccine X 2024; 20:100545. [PMID: 39221182 PMCID: PMC11363860 DOI: 10.1016/j.jvacx.2024.100545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 08/02/2024] [Indexed: 09/04/2024] Open
Abstract
The coronavirus disease 2019 (COVID-19) emerged as a major global health crisis, posing significant health, economic, and social challenges. Vaccine development has been a crucial response to the severe-acute-respiratory-syndrome-related coronavirus-2 pandemic owing to the critical role of immunization in controlling infectious diseases, leading to the expedited development of several effective vaccines. Although mRNA platform-based COVID-19 vaccines authorized under emergency-use authorization have been administered globally, concerns regarding the vaccines have increased owing to the occurrence of various side effects. The present study aimed to evaluate the safety of a non-replicating recombinant baculovirus expressing the human endogenous retrovirus envelope gene (AcHERV) vaccine encoding SARS-CoV-2 antigens. Owing to the limited number of existing safety pharmacology studies on AcHERV as a viral vector vaccine, we conducted neurobehavior (Modified Irwin's Test), body temperature, and respiratory function studies in rats and cardiovascular system studies in male beagle dogs, which were administered the AcHERV-COVID-19 vaccine using telemetry. The safety assessment revealed no significant toxicological alterations. However, in rats, both sexes administered with the AcHERV-COVID-19 vaccine exhibited a temporary increase in body temperature, which normalized or showed signs of recovery. In conclusion, AcHERV-COVID-19 demonstrates a sufficient safety profile that supports its potential evaluation in future clinical trials.
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Affiliation(s)
- Sang-Jin Park
- Korea Institute of Toxicology, 141 Gaejeongro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Joung‐Wook Seo
- Korea Institute of Toxicology, 141 Gaejeongro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Kang-Hyun Han
- Korea Institute of Toxicology, 141 Gaejeongro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Byoung-Seok Lee
- Korea Institute of Toxicology, 141 Gaejeongro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Chanyeong Lee
- Department of Biomedical Science and Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Bong Young Kim
- Department of Biomedical Science and Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Kyong-Cheol Ko
- Korea Preclinical Evaluation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Yong-Bum Kim
- Korea Institute of Toxicology, 141 Gaejeongro, Yuseong-gu, Daejeon 34114, Republic of Korea
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14
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Lyu CA, Shen Y, Zhang P. Zooming in and out: Exploring RNA Viral Infections with Multiscale Microscopic Methods. Viruses 2024; 16:1504. [PMID: 39339980 PMCID: PMC11437419 DOI: 10.3390/v16091504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/19/2024] [Accepted: 09/22/2024] [Indexed: 09/30/2024] Open
Abstract
RNA viruses, being submicroscopic organisms, have intriguing biological makeups and substantially impact human health. Microscopic methods have been utilized for studying RNA viruses at a variety of scales. In order of observation scale from large to small, fluorescence microscopy, cryo-soft X-ray tomography (cryo-SXT), serial cryo-focused ion beam/scanning electron microscopy (cryo-FIB/SEM) volume imaging, cryo-electron tomography (cryo-ET), and cryo-electron microscopy (cryo-EM) single-particle analysis (SPA) have been employed, enabling researchers to explore the intricate world of RNA viruses, their ultrastructure, dynamics, and interactions with host cells. These methods evolve to be combined to achieve a wide resolution range from atomic to sub-nano resolutions, making correlative microscopy an emerging trend. The developments in microscopic methods provide multi-fold and spatial information, advancing our understanding of viral infections and providing critical tools for developing novel antiviral strategies and rapid responses to emerging viral threats.
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Affiliation(s)
- Cheng-An Lyu
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK;
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7BN, UK
| | - Yao Shen
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK;
| | - Peijun Zhang
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK;
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7BN, UK
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
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15
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Riedl A, Bojková D, Tan J, Jeney Á, Larsen PK, Jeney C, Full F, Kalinke U, Ruzsics Z. Construction and Characterization of a High-Capacity Replication-Competent Murine Cytomegalovirus Vector for Gene Delivery. Vaccines (Basel) 2024; 12:791. [PMID: 39066429 PMCID: PMC11281640 DOI: 10.3390/vaccines12070791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/14/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
We investigated the basic characteristics of a new murine cytomegalovirus (MCMV) vector platform. Using BAC technology, we engineered replication-competent recombinant MCMVs with deletions of up to 26% of the wild-type genome. To this end, we targeted five gene blocks (m01-m17, m106-m109, m129-m141, m144-m158, and m159-m170). BACs featuring deletions from 18% to 26% of the wild-type genome exhibited delayed virus reconstitution, while smaller deletions (up to 16%) demonstrated reconstitution kinetics similar to those of the wild type. Utilizing an innovative methodology, we introduced large genomic DNA segments, up to 35 kbp, along with reporter genes into a newly designed vector with a potential cloning capacity of 46 kbp (Q4). Surprisingly, the insertion of diverse foreign DNAs alleviated the delayed plaque formation phenotype of Q4, and these large inserts remained stable through serial in vitro passages. With reporter-gene-expressing recombinant MCMVs, we successfully transduced not only mouse cell lines but also non-rodent mammalian cells, including those of human, monkey, bovine, and bat origin. Remarkably, even non-mammalian cell lines derived from chickens exhibited successful transduction.
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Affiliation(s)
- André Riedl
- Medical Center, Institute of Virology, University of Freiburg, 79104 Freiburg, Germany (F.F.)
- Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Denisa Bojková
- Medical Center, Institute of Virology, University of Freiburg, 79104 Freiburg, Germany (F.F.)
- Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Institute of Medical Virology, Goethe University Frankfurt, University Hospital, 60596 Frankfurt am Main, Germany
| | - Jiang Tan
- Medical Center, Institute of Virology, University of Freiburg, 79104 Freiburg, Germany (F.F.)
- Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Ábris Jeney
- Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Pia-Katharina Larsen
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Hanover Medical School and the Helmholtz Centre for Infection Research, Institute for Experimental Infection Research, 30625 Hanover, Germany
| | - Csaba Jeney
- Department of Microsystems Engineering—IMTEK, University of Freiburg, 79110 Freiburg, Germany
| | - Florian Full
- Medical Center, Institute of Virology, University of Freiburg, 79104 Freiburg, Germany (F.F.)
- Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Ulrich Kalinke
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Hanover Medical School and the Helmholtz Centre for Infection Research, Institute for Experimental Infection Research, 30625 Hanover, Germany
| | - Zsolt Ruzsics
- Medical Center, Institute of Virology, University of Freiburg, 79104 Freiburg, Germany (F.F.)
- Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
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16
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Keller J, Fernández-Busnadiego R. In situ studies of membrane biology by cryo-electron tomography. Curr Opin Cell Biol 2024; 88:102363. [PMID: 38677049 DOI: 10.1016/j.ceb.2024.102363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/26/2024] [Accepted: 04/08/2024] [Indexed: 04/29/2024]
Abstract
Cryo-electron tomography (cryo-ET) allows high resolution 3D imaging of biological samples in near-native environments. Thus, cryo-ET has become the method of choice to analyze the unperturbed organization of cellular membranes. Here, we briefly discuss current cryo-ET workflows and their application to study membrane biology in situ, under basal and pathological conditions.
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Affiliation(s)
- Jenny Keller
- University Medical Center Göttingen, Institute for Neuropathology, Göttingen, 37077, Germany; Collaborative Research Center 1190 "Compartmental Gates and Contact Sites in Cells", University of Göttingen, Göttingen, Germany.
| | - Rubén Fernández-Busnadiego
- University Medical Center Göttingen, Institute for Neuropathology, Göttingen, 37077, Germany; Collaborative Research Center 1190 "Compartmental Gates and Contact Sites in Cells", University of Göttingen, Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, 37077, Germany; Faculty of Physics, University of Göttingen, Göttingen, 37077, Germany.
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17
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Torres-Flores A, Ontiveros-Padilla LA, Madera-Sandoval RL, Tepale-Segura A, Gajón-Martínez J, Rivera-Hernández T, Ferat-Osorio EA, Cérbulo-Vázquez A, Arriaga-Pizano LA, Bonifaz L, Paz-De la Rosa G, Rojas-Martínez O, Suárez-Martínez A, Peralta-Sánchez G, Sarfati-Mizrahi D, Sun W, Chagoya-Cortés HE, Palese P, Krammer F, García-Sastre A, Lozano-Dubernard B, López-Macías C. Newcastle disease virus vector-based SARS-CoV-2 vaccine candidate AVX/COVID-12 activates T cells and is recognized by antibodies from COVID-19 patients and vaccinated individuals. Front Immunol 2024; 15:1394114. [PMID: 38873610 PMCID: PMC11169921 DOI: 10.3389/fimmu.2024.1394114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/10/2024] [Indexed: 06/15/2024] Open
Abstract
Introduction Several effective vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and implemented in the population. However, the current production capacity falls short of meeting global demand. Therefore, it is crucial to further develop novel vaccine platforms that can bridge the distribution gap. AVX/COVID-12 is a vector-based vaccine that utilizes the Newcastle Disease virus (NDV) to present the SARS-CoV-2 spike protein to the immune system. Methods This study aims to analyze the antigenicity of the vaccine candidate by examining antibody binding and T-cell activation in individuals infected with SARS-CoV-2 or variants of concern (VOCs), as well as in healthy volunteers who received coronavirus disease 2019 (COVID-19) vaccinations. Results Our findings indicate that the vaccine effectively binds antibodies and activates T-cells in individuals who received 2 or 3 doses of BNT162b2 or AZ/ChAdOx-1-S vaccines. Furthermore, the stimulation of T-cells from patients and vaccine recipients with AVX/COVID-12 resulted in their proliferation and secretion of interferon-gamma (IFN-γ) in both CD4+ and CD8+ T-cells. Discussion The AVX/COVID-12 vectored vaccine candidate demonstrates the ability to stimulate robust cellular responses and is recognized by antibodies primed by the spike protein present in SARS-CoV-2 viruses that infected patients, as well as in the mRNA BNT162b2 and AZ/ChAdOx-1-S vaccines. These results support the inclusion of the AVX/COVID-12 vaccine as a booster in vaccination programs aimed at addressing COVID-19 caused by SARS-CoV-2 and its VOCs.
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Affiliation(s)
- Alejandro Torres-Flores
- UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Unidad de Investigación Médica en Inmunoquímica, Ciudad de México, Mexico
- Posgrado en Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Luis Alberto Ontiveros-Padilla
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ruth Lizzeth Madera-Sandoval
- UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Unidad de Investigación Médica en Inmunoquímica, Ciudad de México, Mexico
- Departamento de Biología Molecular y Validación de Técnicas, Instituto de Diagnóstico y Referencia Epidemiológicos (InDRE) “Dr, Manuel Martínez Báez”, Secretaría de Salud, Ciudad de México, Mexico
| | - Araceli Tepale-Segura
- UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Unidad de Investigación Médica en Inmunoquímica, Ciudad de México, Mexico
| | - Julián Gajón-Martínez
- UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Unidad de Investigación Médica en Inmunoquímica, Ciudad de México, Mexico
| | - Tania Rivera-Hernández
- UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Unidad de Investigación Médica en Inmunoquímica, Ciudad de México, Mexico
- Investigadores por México, Consejo Nacional de Humanidades, Ciencias y Tecnologías (CONAHCYT), Ciudad de México, Mexico
| | - Eduardo Antonio Ferat-Osorio
- División de Investigación en Salud, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Cuauhtémoc, Ciudad de México, Mexico
| | - Arturo Cérbulo-Vázquez
- Servicio de Medicina Genómica. Hospital General de México “Dr. Eduardo Liceaga”, Ciudad de México, Mexico
| | - Lourdes Andrea Arriaga-Pizano
- UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Unidad de Investigación Médica en Inmunoquímica, Ciudad de México, Mexico
| | - Laura Bonifaz
- UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Unidad de Investigación Médica en Inmunoquímica, Ciudad de México, Mexico
- Coordinación de Investigación en Salud, Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, Mexico
| | | | | | | | | | | | - Weina Sun
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | | | - Peter Palese
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Florian Krammer
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Adolfo García-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | | | - Constantino López-Macías
- UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Unidad de Investigación Médica en Inmunoquímica, Ciudad de México, Mexico
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18
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Reiter L, Greffrath J, Zidel B, Ostrowski M, Gommerman J, Madhi SA, Tran R, Martin-Orozco N, Panicker RKG, Cooper C, Pastrak A. Comparable safety and non-inferior immunogenicity of the SARS-CoV-2 mRNA vaccine candidate PTX-COVID19-B and BNT162b2 in a phase 2 randomized, observer-blinded study. Sci Rep 2024; 14:5365. [PMID: 38438427 PMCID: PMC10912344 DOI: 10.1038/s41598-024-55320-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 02/22/2024] [Indexed: 03/06/2024] Open
Abstract
In the aftermath of the COVID-19 pandemic, the evolution of the SARS-CoV-2 into a seasonal pathogen along with the emergence of new variants, underscores the need for dynamic and adaptable responses, emphasizing the importance of sustained vaccination strategies. This observer-blind, double-dummy, randomized immunobridging phase 2 study (NCT05175742) aimed to compare the immunogenicity induced by two doses of 40 μg PTX-COVID19-B vaccine candidate administered 28 days apart, with the response induced by two doses of 30 µg Pfizer-BioNTech COVID-19 vaccine (BNT162b2), administered 21 days apart, in Nucleocapsid-protein seronegative adults 18-64 years of age. Both vaccines were administrated via intramuscular injection in the deltoid muscle. Two weeks after the second dose, the neutralizing antibody (NAb) geometric mean titer ratio and seroconversion rate met the non-inferiority criteria, successfully achieving the primary immunogenicity endpoints of the study. PTX-COVID19-B demonstrated similar safety and tolerability profile to BNT162b2 vaccine. The lowest NAb response was observed in subjects with low-to-undetectable NAb at baseline or no reported breakthrough infection. Conversely, participants who experienced breakthrough infections during the study exhibited higher NAb titers. This study also shows induction of cell-mediated immune (CMI) responses by PTX-COVID19-B. In conclusion, the vaccine candidate PTX-COVID19-B demonstrated favourable safety profile along with immunogenicity similar to the active comparator BNT162b2 vaccine.
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Affiliation(s)
- Lawrence Reiter
- Providence Therapeutics Holdings Inc., 120-8832 Blackfoot Trail SE, Calgary, AB, T2J 3J1, Canada
| | - Johann Greffrath
- South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Bian Zidel
- Malton Medical Center, 6870 Goreway Dr., Mississauga, ON, L4V 1P1, Canada
| | - Mario Ostrowski
- Department of Medicine, Immunology, University of Toronto, Medical Sciences Building, Rm 6271. 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Jennifer Gommerman
- Department of Immunology, Temerty Faculty of Medicine, 1 King's College Circle, Rm. 7233, Toronto, ON, M5S 1A8, Canada
| | - Shabir A Madhi
- South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Richard Tran
- Providence Therapeutics Holdings Inc., 120-8832 Blackfoot Trail SE, Calgary, AB, T2J 3J1, Canada
| | - Natalia Martin-Orozco
- Providence Therapeutics Holdings Inc., 120-8832 Blackfoot Trail SE, Calgary, AB, T2J 3J1, Canada
| | | | - Curtis Cooper
- The Ottawa Hospital Viral Hepatitis Program, Division of Infectious Diseases, Department of Medicine, The Ottawa Hospital, University of Ottawa, 75 Laurier Ave. East, Ottawa, ON, K1N 6N5, Canada
| | - Aleksandra Pastrak
- Providence Therapeutics Holdings Inc., 120-8832 Blackfoot Trail SE, Calgary, AB, T2J 3J1, Canada.
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19
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Maity S, Acharya A. Many Roles of Carbohydrates: A Computational Spotlight on the Coronavirus S Protein Binding. ACS APPLIED BIO MATERIALS 2024; 7:646-656. [PMID: 36947738 PMCID: PMC10880061 DOI: 10.1021/acsabm.2c01064] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/08/2023] [Indexed: 03/24/2023]
Abstract
Glycosylation is one of the post-translational modifications with more than 50% of human proteins being glycosylated. The exact nature and chemical composition of glycans are inaccessible to X-ray or cryo-electron microscopy imaging techniques. Therefore, computational modeling studies and molecular dynamics must be used as a "computational microscope". The spike (S) protein of SARS-CoV-2 is heavily glycosylated, and a few glycans play a more functional role "beyond shielding". In this mini-review, we discuss computational investigations of the roles of specific S-protein and ACE2 glycans in the overall ACE2-S protein binding. We highlight different functions of specific glycans demonstrated in myriad computational models and simulations in the context of the SARS-CoV-2 virus binding to the receptor. We also discuss interactions between glycocalyx and the S protein, which may be utilized to design prophylactic polysaccharide-based therapeutics targeting the S protein. In addition, we underline the recent emergence of coronavirus variants and their impact on the S protein and its glycans.
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Affiliation(s)
- Suman Maity
- Department
of Chemistry, Syracuse University, Syracuse, New York 13244, United States
| | - Atanu Acharya
- Department
of Chemistry, Syracuse University, Syracuse, New York 13244, United States
- BioInspired
Syracuse, Syracuse University, Syracuse, New York 13244, United States
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20
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Muñoz-Alía MÁ, Nace RA, Balakrishnan B, Zhang L, Packiriswamy N, Singh G, Warang P, Mena I, Narjari R, Vandergaast R, Peng KW, García-Sastre A, Schotsaert M, Russell SJ. Surface-modified measles vaccines encoding oligomeric, prefusion-stabilized SARS-CoV-2 spike glycoproteins boost neutralizing antibody responses to Omicron and historical variants, independent of measles seropositivity. mBio 2024; 15:e0292823. [PMID: 38193729 PMCID: PMC10865805 DOI: 10.1128/mbio.02928-23] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 12/04/2023] [Indexed: 01/10/2024] Open
Abstract
Serum titers of SARS-CoV-2-neutralizing antibodies (nAbs) correlate well with protection from symptomatic COVID-19 but decay rapidly in the months following vaccination or infection. In contrast, measles-protective nAb titers are lifelong after measles vaccination, possibly due to persistence of the live-attenuated virus in lymphoid tissues. We, therefore, sought to generate a live recombinant measles vaccine capable of driving high SARS-CoV-2 nAb responses. Since previous clinical testing of a live measles vaccine encoding a SARS-CoV-2 spike glycoprotein resulted in suboptimal anti-spike antibody titers, our new vectors were designed to encode prefusion-stabilized SARS-CoV-2 spike glycoproteins, trimerized via an inserted peptide domain, and displayed on a dodecahedral miniferritin scaffold. Additionally, to circumvent the blunting of vaccine efficacy by preformed anti-measles antibodies, we extensively modified the measles surface glycoproteins. Comprehensive in vivo mouse testing demonstrated the potent induction of high titer nAbs in measles-immune mice and confirmed the significant contributions to overall potency afforded by prefusion stabilization, trimerization, and miniferritin display of the SARS-CoV-2 spike glycoprotein. In animals primed and boosted with a measles virus (MeV) vaccine encoding the ancestral SARS-CoV-2 spike, high-titer nAb responses against ancestral virus strains were only weakly cross-reactive with the Omicron variant. However, in primed animals that were boosted with a MeV vaccine encoding the Omicron BA.1 spike, antibody titers to both ancestral and Omicron strains were robustly elevated, and the passive transfer of serum from these animals protected K18-ACE2 mice from infection and morbidity after exposure to BA.1 and WA1/2020 strains. Our results demonstrate that by engineering the antigen, we can develop potent measles-based vaccine candidates against SARS-CoV-2.IMPORTANCEAlthough the live-attenuated measles virus (MeV) is one of the safest and most efficacious human vaccines, a measles-vectored COVID-19 vaccine candidate expressing the SARS-CoV-2 spike failed to elicit neutralizing antibody (nAb) responses in a phase-1 clinical trial, especially in measles-immune individuals. Here, we constructed a comprehensive panel of MeV-based COVID-19 vaccine candidates using a MeV with extensive modifications on the envelope glycoproteins (MeV-MR). We show that artificial trimerization of the spike is critical for the induction of nAbs and that their magnitude can be significantly augmented when the spike protein is synchronously fused to a dodecahedral scaffold. Furthermore, preexisting measles immunity did not abolish heterologous immunity elicited by our vector. Our results highlight the importance of antigen optimization in the development of spike-based COVID-19 vaccines and therapies.
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Affiliation(s)
- Miguel Á. Muñoz-Alía
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Vyriad Inc, Rochester, Minnesota, USA
| | - Rebecca A. Nace
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Lianwen Zhang
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Gagandeep Singh
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Prajakta Warang
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ignacio Mena
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | | | | | - Kah-Whye Peng
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Vyriad Inc, Rochester, Minnesota, USA
- Imanis Life Sciences, Rochester, Minnesota, USA
| | - Adolfo García-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Michael Schotsaert
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Stephen J. Russell
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Vyriad Inc, Rochester, Minnesota, USA
- Imanis Life Sciences, Rochester, Minnesota, USA
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
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21
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Jung W, Yuan D, Kellman B, Gonzalez IGDS, Clemens R, Milan EP, Sprinz E, Cerbino Neto J, Smolenov I, Alter G, McNamara RP, Costa Clemens SA. Boosting with adjuvanted SCB-2019 elicits superior Fcγ-receptor engagement driven by IgG3 to SARS-CoV-2 spike. NPJ Vaccines 2024; 9:7. [PMID: 38182593 PMCID: PMC10770118 DOI: 10.1038/s41541-023-00791-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 12/08/2023] [Indexed: 01/07/2024] Open
Abstract
With the continued emergence of variants of concern, the global threat of COVID-19 persists, particularly in low- and middle-income countries with limited vaccine access. Protein-based vaccines, such as SCB-2019, can be produced on a large scale at a low cost while antigen design and adjuvant use can modulate efficacy and safety. While effective humoral immunity against SARS-CoV-2 variants has been shown to depend on both neutralization and Fc-mediated immunity, data on the effectiveness of protein-based vaccines with enhanced Fc-mediated immunity is limited. Here, we assess the humoral profile, including antibody isotypes, subclasses, and Fc receptor binding generated by a boosting with a recombinant trimer-tag protein vaccine SCB-2019. Individuals who were primed with 2 doses of the ChAdOx1 vaccine were equally divided into 4 groups and boosted with following formulations: Group 1: 9 μg SCB-2019 and Alhydrogel; Group 2: 9 μg SCB-2019, CpG 1018, and Alhydrogel; Group 3: 30 μg SCB-2019, CpG 1018, and Alhydrogel; Group 4: ChAdOx1. Group 3 showed enhanced antibody FcγR binding against wild-type and variants compared to Groups 1 and 2, showing a dose-dependent enhancement of immunity conferred by the SCB-2019 vaccine. Moreover, from day 15 after vaccination, Group 3 exhibited higher IgG3 and FcγR binding across variants of concerns, including Omicron and its subvariants, compared to the ChAdOx1-boosted individuals. Overall, this highlights the potential of SCB-2019 as a cost-efficient boosting regimen effective across variants of concerns.
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Affiliation(s)
- Wonyeong Jung
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
| | - Dansu Yuan
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
| | | | | | - Ralf Clemens
- International Vaccine Institute, Seoul, Republic of Korea
| | - Eveline Pipolo Milan
- Centro de Estudos e Pesquisa em Moléstias Infecciosas Ltda. (CEPCLIN), Natal, Brazil
| | - Eduardo Sprinz
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - José Cerbino Neto
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
| | | | - Galit Alter
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
| | - Ryan P McNamara
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
| | - Sue Ann Costa Clemens
- Oxford Vaccine Group, Department of Pediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, UK
- Siena University, Siena, Italy
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22
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Stiving AQ, Foreman DJ, VanAernum ZL, Durr E, Wang S, Vlasak J, Galli J, Kafader JO, Tsukidate T, Li X, Schuessler HA, Richardson DD. Dissecting the Heterogeneous Glycan Profiles of Recombinant Coronavirus Spike Proteins with Individual Ion Mass Spectrometry. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2024; 35:62-73. [PMID: 38032172 DOI: 10.1021/jasms.3c00309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
Abstract
Surface-embedded glycoproteins, such as the spike protein trimers of coronaviruses MERS, SARS-CoV, and SARS-CoV-2, play a key role in viral function and are the target antigen for many vaccines. However, their significant glycan heterogeneity poses an analytical challenge. Here, we utilized individual ion mass spectrometry (I2MS), a multiplexed charge detection measurement with similarities to charge detection mass spectrometry (CDMS), in which a commercially available Orbitrap analyzer is used to directly produce mass profiles of these heterogeneous coronavirus spike protein trimers under native-like conditions. Analysis by I2MS shows that glycosylation contributes to the molecular mass of each protein trimer more significantly than expected by bottom-up techniques, highlighting the importance of obtaining complementary intact mass information when characterizing glycosylation of such heterogeneous proteins. Enzymatic dissection to remove sialic acid or N-linked glycans demonstrates that I2MS can be used to better understand the glycan profile from a native viewpoint. Deglycosylation of N-glycans followed by I2MS analysis indicates that the SARS-CoV-2 spike protein trimer contains glycans that are more difficult to remove than its MERS and SARS-CoV counterparts, and these differences are correlated with solvent accessibility. I2MS technology enables characterization of protein mass and intact glycan profile and is orthogonal to traditional mass analysis methods such as size exclusion chromatography-multiangle light scattering (SEC-MALS) and field flow fractionation-multiangle light scattering (FFF-MALS). An added advantage of I2MS is low sample use, requiring 100-fold less than other methodologies. This work highlights how I2MS technology can enable efficient development of vaccines and therapeutics for pharmaceutical development.
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Affiliation(s)
- Alyssa Q Stiving
- Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States
| | - David J Foreman
- Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States
| | - Zachary L VanAernum
- Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States
| | - Eberhard Durr
- Infectious Diseases and Vaccines Discovery, Merck & Co., Inc., West Point, Pennsylvania 19486, United States
| | - Shiyi Wang
- Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States
| | - Josef Vlasak
- Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States
| | - Jennifer Galli
- Infectious Diseases and Vaccines Discovery, Merck & Co., Inc., West Point, Pennsylvania 19486, United States
| | - Jared O Kafader
- Departments of Chemistry and Molecular Biosciences, The Chemistry of Life Processes Institute, The Proteomics Center of Excellence at Northwestern University, Evanston, Illinois 60208, United States
| | - Taku Tsukidate
- Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States
| | - Xuanwen Li
- Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States
| | - Hillary A Schuessler
- Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States
| | - Douglas D Richardson
- Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States
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23
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Newby ML, Allen JD, Crispin M. Influence of glycosylation on the immunogenicity and antigenicity of viral immunogens. Biotechnol Adv 2024; 70:108283. [PMID: 37972669 PMCID: PMC10867814 DOI: 10.1016/j.biotechadv.2023.108283] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 10/04/2023] [Accepted: 11/09/2023] [Indexed: 11/19/2023]
Abstract
A key aspect of successful viral vaccine design is the elicitation of neutralizing antibodies targeting viral attachment and fusion glycoproteins that embellish viral particles. This observation has catalyzed the development of numerous viral glycoprotein mimetics as vaccines. Glycans can dominate the surface of viral glycoproteins and as such, the viral glycome can influence the antigenicity and immunogenicity of a candidate vaccine. In one extreme, glycans can form an integral part of epitopes targeted by neutralizing antibodies and are therefore considered to be an important feature of key immunogens within an immunization regimen. In the other extreme, the existence of peptide and bacterially expressed protein vaccines shows that viral glycosylation can be dispensable in some cases. However, native-like glycosylation can indicate native-like protein folding and the presence of conformational epitopes. Furthermore, going beyond native glycan mimicry, in either occupancy of glycosylation sites or the glycan processing state, may offer opportunities for enhancing the immunogenicity and associated protection elicited by an immunogen. Here, we review key determinants of viral glycosylation and how recombinant immunogens can recapitulate these signatures across a range of enveloped viruses, including HIV-1, Ebola virus, SARS-CoV-2, Influenza and Lassa virus. The emerging understanding of immunogen glycosylation and its control will help guide the development of future vaccines in both recombinant protein- and nucleic acid-based vaccine technologies.
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Affiliation(s)
- Maddy L Newby
- School of Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK
| | - Joel D Allen
- School of Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
| | - Max Crispin
- School of Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
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24
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Pencheva M, Bozhkova M, Kalchev Y, Petrov S, Baldzhieva A, Kalfova T, Dichev V, Keskinova D, Genova S, Atanasova M, Murdzheva M. The Serum ACE2, CTSL, AngII, and TNFα Levels after COVID-19 and mRNA Vaccines: The Molecular Basis. Biomedicines 2023; 11:3160. [PMID: 38137381 PMCID: PMC10741205 DOI: 10.3390/biomedicines11123160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/16/2023] [Accepted: 11/23/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND The SARS-CoV-2 virus as well as the COVID-19 mRNA vaccines cause an increased production of proinflammatory cytokines. AIM We investigated the relationship between ACE2, CTSL, AngII, TNFα and the serum levels of IL-6, IL-10, IL-33, IL-28A, CD40L, total IgM, IgG, IgA and absolute count of T- and B-lymphocytes in COVID-19 patients, vaccinees and healthy individuals. METHODS We measured the serum levels ACE2, AngII, CTSL, TNFα and humoral biomarkers (CD40L, IL-28A, IL-10, IL-33) by the ELISA method. Immunophenotyping of lymphocyte subpopulations was performed by flow cytometry. Total serum immunoglobulins were analyzed by the turbidimetry method. RESULTS The results established an increase in the total serum levels for ACE2, CTSL, AngII and TNFα by severely ill patients and vaccinated persons. The correlation analysis described a positive relationship between ACE2 and proinflammatory cytokines IL-33 (r = 0.539) and CD40L (r = 0.520), a positive relationship between AngII and CD40L (r = 0.504), as well as between AngII and IL-33 (r = 0.416), and a positive relationship between CTSL, total IgA (r = 0.437) and IL-28A (r = 0.592). Correlation analysis confirmed only two of the positive relationships between TNFα and IL-28A (r = 0.491) and CD40L (r = 0.458). CONCLUSIONS In summary, the findings presented in this study unveil a complex web of interactions within the immune system in response to SARS-CoV-2 infection and vaccination.
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Affiliation(s)
- Mina Pencheva
- Department of Medical Physics and Biophysics, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
| | - Martina Bozhkova
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Yordan Kalchev
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Steliyan Petrov
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Alexandra Baldzhieva
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Teodora Kalfova
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Valentin Dichev
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
- Department of Medical Biology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
| | - Donka Keskinova
- Department of Applied and Institutional Sociology, Faculty of Philosophy and History, University of Plovdiv “Paisii Hilendarski”, 4000 Plovdiv, Bulgaria;
| | - Silvia Genova
- Department of General and Clinical Pathology, Medical Faculty, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Mariya Atanasova
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Laboratory of Virology, UMBAL “St. George” EAD, 4002 Plovdiv, Bulgaria
| | - Mariana Murdzheva
- Department of Medical Microbiology and Immunology, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.B.); (Y.K.); (S.P.); (A.B.); (T.K.); (M.A.); (M.M.)
- Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria;
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25
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Kaltbeitzel J, Wich PR. Protein-based Nanoparticles: From Drug Delivery to Imaging, Nanocatalysis and Protein Therapy. Angew Chem Int Ed Engl 2023; 62:e202216097. [PMID: 36917017 DOI: 10.1002/anie.202216097] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 03/12/2023] [Accepted: 03/13/2023] [Indexed: 03/16/2023]
Abstract
Proteins and enzymes are versatile biomaterials for a wide range of medical applications due to their high specificity for receptors and substrates, high degradability, low toxicity, and overall good biocompatibility. Protein nanoparticles are formed by the arrangement of several native or modified proteins into nanometer-sized assemblies. In this review, we will focus on artificial nanoparticle systems, where proteins are the main structural element and not just an encapsulated payload. While under natural conditions, only certain proteins form defined aggregates and nanoparticles, chemical modifications or a change in the physical environment can further extend the pool of available building blocks. This allows the assembly of many globular proteins and even enzymes. These advances in preparation methods led to the emergence of new generations of nanosystems that extend beyond transport vehicles to diverse applications, from multifunctional drug delivery to imaging, nanocatalysis and protein therapy.
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Affiliation(s)
- Jonas Kaltbeitzel
- School of Chemical Engineering, University of New South Wales, Sydney, NSW 2052, Australia
- Australian Centre for NanoMedicine, University of New South Wales, Sydney, NSW 2052, Australia
| | - Peter R Wich
- School of Chemical Engineering, University of New South Wales, Sydney, NSW 2052, Australia
- Australian Centre for NanoMedicine, University of New South Wales, Sydney, NSW 2052, Australia
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26
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Ni T, Mendonça L, Zhu Y, Howe A, Radecke J, Shah PM, Sheng Y, Krebs AS, Duyvesteyn HM, Allen E, Lambe T, Bisset C, Spencer A, Morris S, Stuart DI, Gilbert S, Zhang P. ChAdOx1 COVID vaccines express RBD open prefusion SARS-CoV-2 spikes on the cell surface. iScience 2023; 26:107882. [PMID: 37766989 PMCID: PMC10520439 DOI: 10.1016/j.isci.2023.107882] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 07/18/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been proven to be an effective means of decreasing COVID-19 mortality, hospitalization rates, and transmission. One of the vaccines deployed worldwide is ChAdOx1 nCoV-19, which uses an adenovirus vector to drive the expression of the original SARS-CoV-2 spike on the surface of transduced cells. Using cryo-electron tomography and subtomogram averaging, we determined the native structures of the vaccine product expressed on cell surfaces in situ. We show that ChAdOx1-vectored vaccines expressing the Beta SARS-CoV-2 variant produce abundant native prefusion spikes predominantly in one-RBD-up conformation. Furthermore, the ChAdOx1-vectored HexaPro-stabilized spike yields higher cell surface expression, enhanced RBD exposure, and reduced shedding of S1 compared to the wild type. We demonstrate in situ structure determination as a powerful means for studying antigen design options in future vaccine development against emerging novel SARS-CoV-2 variants and broadly against other infectious viruses.
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Affiliation(s)
- Tao Ni
- Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Luiza Mendonça
- Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Yanan Zhu
- Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Andrew Howe
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
| | - Julika Radecke
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
| | - Pranav M. Shah
- Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7BN, UK
| | - Yuewen Sheng
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
| | - Anna-Sophia Krebs
- Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Helen M.E. Duyvesteyn
- Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Elizabeth Allen
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Teresa Lambe
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
- NIHR Oxford Biomedical Research Centre, Oxford OX3 7BN, UK
| | - Cameron Bisset
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Alexandra Spencer
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Susan Morris
- Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford, OX3 7TY, UK
| | - David I. Stuart
- Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7BN, UK
- Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford, OX3 7TY, UK
| | - Sarah Gilbert
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
- NIHR Oxford Biomedical Research Centre, Oxford OX3 7BN, UK
- Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford, OX3 7TY, UK
| | - Peijun Zhang
- Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7BN, UK
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27
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Graham M, Zhang P. Cryo-electron tomography to study viral infection. Biochem Soc Trans 2023; 51:1701-1711. [PMID: 37560901 PMCID: PMC10578967 DOI: 10.1042/bst20230103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/19/2023] [Accepted: 07/31/2023] [Indexed: 08/11/2023]
Abstract
Developments in cryo-electron microscopy (cryo-EM) have been interwoven with the study of viruses ever since its first applications to biological systems. Following the success of single particle cryo-EM in the last decade, cryo-electron tomography (cryo-ET) is now rapidly maturing as a technology and catalysing great advancement in structural virology as its application broadens. In this review, we provide an overview of the use of cryo-ET to study viral infection biology, discussing the key workflows and strategies used in the field. We highlight the vast body of studies performed on purified viruses and virus-like particles (VLPs), as well as discussing how cryo-ET can characterise host-virus interactions and membrane fusion events. We further discuss the importance of in situ cellular imaging in revealing previously unattainable details of infection and highlight the need for validation of high-resolution findings from purified ex situ systems. We give perspectives for future developments to achieve the full potential of cryo-ET to characterise the molecular processes of viral infection.
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Affiliation(s)
- Miles Graham
- Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, U.K
| | - Peijun Zhang
- Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, U.K
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, U.K
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7BN, U.K
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28
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Martínez-Mármol R, Giordano-Santini R, Kaulich E, Cho AN, Przybyla M, Riyadh MA, Robinson E, Chew KY, Amor R, Meunier FA, Balistreri G, Short KR, Ke YD, Ittner LM, Hilliard MA. SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity. SCIENCE ADVANCES 2023; 9:eadg2248. [PMID: 37285437 PMCID: PMC10246911 DOI: 10.1126/sciadv.adg2248] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 05/01/2023] [Indexed: 06/09/2023]
Abstract
Numerous viruses use specialized surface molecules called fusogens to enter host cells. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the brain and are associated with severe neurological symptoms through poorly understood mechanisms. We show that SARS-CoV-2 infection induces fusion between neurons and between neurons and glia in mouse and human brain organoids. We reveal that this is caused by the viral fusogen, as it is fully mimicked by the expression of the SARS-CoV-2 spike (S) protein or the unrelated fusogen p15 from the baboon orthoreovirus. We demonstrate that neuronal fusion is a progressive event, leads to the formation of multicellular syncytia, and causes the spread of large molecules and organelles. Last, using Ca2+ imaging, we show that fusion severely compromises neuronal activity. These results provide mechanistic insights into how SARS-CoV-2 and other viruses affect the nervous system, alter its function, and cause neuropathology.
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Affiliation(s)
- Ramón Martínez-Mármol
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Rosina Giordano-Santini
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Eva Kaulich
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Ann-Na Cho
- Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia
| | - Magdalena Przybyla
- Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia
| | - Md Asrafuzzaman Riyadh
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Emilija Robinson
- Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia
| | - Keng Yih Chew
- School of Chemistry and Molecular Biosciences, Faculty of Science, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Rumelo Amor
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Frédéric A. Meunier
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Giuseppe Balistreri
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
- Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki FIN-00014, Finland
| | - Kirsty R. Short
- School of Chemistry and Molecular Biosciences, Faculty of Science, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Yazi D. Ke
- Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia
| | - Lars M. Ittner
- Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia
| | - Massimo A. Hilliard
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
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29
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Halma MTJ, Plothe C, Marik P, Lawrie TA. Strategies for the Management of Spike Protein-Related Pathology. Microorganisms 2023; 11:1308. [PMID: 37317282 PMCID: PMC10222799 DOI: 10.3390/microorganisms11051308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/04/2023] [Accepted: 05/10/2023] [Indexed: 06/16/2023] Open
Abstract
In the wake of the COVID-19 crisis, a need has arisen to prevent and treat two related conditions, COVID-19 vaccine injury and long COVID-19, both of which can trace at least part of their aetiology to the spike protein, which can cause harm through several mechanisms. One significant mechanism of harm is vascular, and it is mediated by the spike protein, a common element of the COVID-19 illness, and it is related to receiving a COVID-19 vaccine. Given the significant number of people experiencing these two related conditions, it is imperative to develop treatment protocols, as well as to consider the diversity of people experiencing long COVID-19 and vaccine injury. This review summarizes the known treatment options for long COVID-19 and vaccine injury, their mechanisms, and their evidentiary basis.
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Affiliation(s)
| | - Christof Plothe
- Center for Biophysical Osteopathy, Am Wegweiser 27, 55232 Alzey, Germany
| | - Paul Marik
- Front Line COVID-19 Critical Care Alliance (FLCCC), 2001 L St. NW Suite 500, Washington, DC 20036, USA;
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Buso G, Agabiti-Rosei C, Muiesan ML. The relationship between COVID-19 vaccines and increased blood pressure: A word of caution. Eur J Intern Med 2023; 111:27-29. [PMID: 36914539 PMCID: PMC9986138 DOI: 10.1016/j.ejim.2023.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Affiliation(s)
- Giacomo Buso
- Department of Clinical and Experimental Sciences, University of Brescia, Italy; University of Lausanne, CH-1015 Lausanne, Switzerland
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Rzymski P. Guillain-Barré syndrome and COVID-19 vaccines: focus on adenoviral vectors. Front Immunol 2023; 14:1183258. [PMID: 37180147 PMCID: PMC10169623 DOI: 10.3389/fimmu.2023.1183258] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
COVID-19 vaccination is a life-saving intervention. However, it does not come up without a risk of rare adverse events, which frequency varies between vaccines developed using different technological platforms. The increased risk of Guillain-Barré syndrome (GBS) has been reported for selected adenoviral vector vaccines but not for other vaccine types, including more widely used mRNA preparations. Therefore, it is unlikely that GBS results from the cross-reactivity of antibodies against the SARS-CoV-2 spike protein generated after the COVID-19 vaccination. This paper outlines two hypotheses according to which increased risk of GBS following adenoviral vaccination is due to (1) generation of anti-vector antibodies that may cross-react with proteins involved in biological processes related to myelin and axons, or (2) neuroinvasion of selected adenovirus vectors to the peripheral nervous system, infection of neurons and subsequent inflammation and neuropathies. The rationale behind these hypotheses is outlined, advocating further epidemiological and experimental research to verify them. This is particularly important given the ongoing interest in using adenoviruses in developing vaccines against various infectious diseases and cancer immunotherapeutics.
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Affiliation(s)
- Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, Poznan, Poland
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Jiang M, Väisänen E, Kolehmainen P, Huttunen M, Ylä-Herttuala S, Meri S, Österlund P, Julkunen I. COVID-19 adenovirus vector vaccine induces higher interferon and pro-inflammatory responses than mRNA vaccines in human PBMCs, macrophages and moDCs. Vaccine 2023:S0264-410X(23)00463-2. [PMID: 37142461 PMCID: PMC10126225 DOI: 10.1016/j.vaccine.2023.04.049] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/05/2023] [Accepted: 04/18/2023] [Indexed: 05/06/2023]
Abstract
BACKGROUND During the COVID-19 pandemic multiple vaccines were rapidly developed and widely used throughout the world. At present there is very little information on COVID-19 vaccine interactions with primary human immune cells such as peripheral blood mononuclear cells (PBMCs), monocyte-derived macrophages and dendritic cells (moDCs). METHODS Human PBMCs, macrophages and moDCs were stimulated with different COVID-19 vaccines, and the expression of interferon (IFN-λ1, IFN-α1), pro-inflammatory (IL-1β, IL-6, IL-8, IL-18, CXCL-4, CXCL-10, TNF-α) and Th1-type cytokine mRNAs (IL-2, IFN-γ) were analyzed by qPCR. In addition, the expression of vaccine induced spike (S) protein and antiviral molecules were studied in primary immune cells and in A549 lung epithelial cells. RESULTS Adenovirus vector (Ad-vector) vaccine AZD1222 induced high levels of IFN-λ1, IFN-α1, CXCL-10, IL-6, and TNF-α mRNAs in PBMCs at early time points of stimulation while the expression of IFN-γ and IL-2 mRNA took place at later times. AZD1222 also induced IFN-λ1, CXCL-10 and IL-6 mRNA expression in monocyte-derived macrophages and DCs in a dose-dependent fashion. AZD1222 also activated the phosphorylation of IRF3 and induced MxA expression. BNT162b2 and mRNA-1273 mRNA vaccines failed to induce or induced very weak cytokine gene expression in all cell models. None of the vaccines enhanced the expression of CXCL-4. AZD1222 and mRNA-1273 vaccines induced high expression of S protein in all studied cells. CONCLUSIONS Ad-vector vaccine induces higher IFN and pro-inflammatory responses than the mRNA vaccines in human immune cells. This data shows that AZD1222 readily activates IFN and pro-inflammatory cytokine gene expression in PBMCs, macrophages and DCs, but fails to further enhance CXCL-4 mRNA expression.
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Affiliation(s)
- Miao Jiang
- Expert Microbiology Unit, Department of Health Security, Finnish Institute for Health and Welfare, 00300 Helsinki, Finland; Infection and Immunity, Institute of Biomedicine, University of Turku, 20520 Turku, Finland.
| | - Elina Väisänen
- Expert Microbiology Unit, Department of Health Security, Finnish Institute for Health and Welfare, 00300 Helsinki, Finland; Infection and Immunity, Institute of Biomedicine, University of Turku, 20520 Turku, Finland.
| | - Pekka Kolehmainen
- Infection and Immunity, Institute of Biomedicine, University of Turku, 20520 Turku, Finland.
| | - Moona Huttunen
- Infection and Immunity, Institute of Biomedicine, University of Turku, 20520 Turku, Finland.
| | - Seppo Ylä-Herttuala
- A.I.Virtanen Institute, Department of Molecular Medicine, University of Eastern Finland, 70210 Kuopio, Finland.
| | - Seppo Meri
- Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, and HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.
| | - Pamela Österlund
- Expert Microbiology Unit, Department of Health Security, Finnish Institute for Health and Welfare, 00300 Helsinki, Finland.
| | - Ilkka Julkunen
- Infection and Immunity, Institute of Biomedicine, University of Turku, 20520 Turku, Finland; Turku University Hospital, Clinical Microbiology, 20520 Turku, Finland.
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Prompetchara E, Ketloy C, Alameh MG, Tharakhet K, Kaewpang P, Yostrerat N, Pitakpolrat P, Buranapraditkun S, Manopwisedjaroen S, Thitithanyanont A, Jongkaewwattana A, Hunsawong T, Im-Erbsin R, Reed M, Wijagkanalan W, Patarakul K, Techawiwattanaboon T, Palaga T, Lam K, Heyes J, Weissman D, Ruxrungtham K. Immunogenicity and protective efficacy of SARS-CoV-2 mRNA vaccine encoding secreted non-stabilized spike in female mice. Nat Commun 2023; 14:2309. [PMID: 37085495 PMCID: PMC10120480 DOI: 10.1038/s41467-023-37795-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 03/24/2023] [Indexed: 04/23/2023] Open
Abstract
Establishment of an mRNA vaccine platform in low- and middle-income countries (LMICs) is important to enhance vaccine accessibility and ensure future pandemic preparedness. Here, we describe the preclinical studies of "ChulaCov19", a SARS-CoV-2 mRNA encoding prefusion-unstabilized ectodomain spike protein encapsulated in lipid nanoparticles (LNP). In female BALB/c mice, ChulaCov19 at 0.2, 1, 10, and 30 μg elicits robust neutralizing antibody (NAb) and T cell responses in a dose-dependent relationship. The geometric mean titers (GMTs) of NAb against wild-type (WT, Wuhan-Hu1) virus are 1,280, 11,762, 54,047, and 62,084, respectively. Higher doses induce better cross-NAb against Delta (B.1.617.2) and Omicron (BA.1 and BA.4/5) variants. This elicited immunogenicity is significantly higher than those induced by homologous CoronaVac or AZD1222 vaccination. In a heterologous prime-boost study, ChulaCov19 booster dose generates a 7-fold increase of NAb against Wuhan-Hu1 WT virus and also significantly increases NAb response against Omicron (BA.1 and BA.4/5) when compared to homologous CoronaVac or AZD1222 vaccination. Challenge studies show that ChulaCov19 protects human-ACE-2-expressing female mice from COVID-19 symptoms, prevents viremia and significantly reduces tissue viral load. Moreover, anamnestic NAb response is undetectable in challenge animals. ChulaCov19 is therefore a promising mRNA vaccine candidate either as a primary or boost vaccination and has entered clinical development.
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Affiliation(s)
- Eakachai Prompetchara
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Integrated Frontier Biotechnology for Emerging Disease, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Chutitorn Ketloy
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
- Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
- Integrated Frontier Biotechnology for Emerging Disease, Chulalongkorn University, Bangkok, 10330, Thailand.
| | - Mohamad-Gabriel Alameh
- Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Kittipan Tharakhet
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Papatsara Kaewpang
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Nongnaphat Yostrerat
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Patrawadee Pitakpolrat
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Supranee Buranapraditkun
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Thai Pediatric Gastroenterology, Hepatology and Immunology (TPGHAI) Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | | | - Arunee Thitithanyanont
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
| | - Anan Jongkaewwattana
- Virology and Cell Technology Research Team, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathumthani, 12120, Thailand
| | - Taweewan Hunsawong
- Department of Virology, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, 10400, Thailand
| | - Rawiwan Im-Erbsin
- Department of Veterinary Medicine, USAMD-AFRIMS, Bangkok, 10400, Thailand
| | - Matthew Reed
- Department of Veterinary Medicine, USAMD-AFRIMS, Bangkok, 10400, Thailand
| | | | - Kanitha Patarakul
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Integrated Frontier Biotechnology for Emerging Disease, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Teerasit Techawiwattanaboon
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Tanapat Palaga
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Kieu Lam
- Genevant Sciences Corporation, Vancouver, BC, V5T 4T5, Canada
| | - James Heyes
- Genevant Sciences Corporation, Vancouver, BC, V5T 4T5, Canada
| | - Drew Weissman
- Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Kiat Ruxrungtham
- Center of Excellence in Vaccine Research and Development (Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Integrated Frontier Biotechnology for Emerging Disease, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Medicine, and School of Global Health, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
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Schinas G, Polyzou E, Dimakopoulou V, Tsoupra S, Gogos C, Akinosoglou K. Immune-mediated liver injury following COVID-19 vaccination. World J Virol 2023; 12:100-108. [PMID: 37033146 PMCID: PMC10075055 DOI: 10.5501/wjv.v12.i2.100] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/23/2022] [Accepted: 01/23/2023] [Indexed: 03/21/2023] Open
Abstract
Liver injury secondary to vaccination is a rare adverse event that has recently come under attention thanks to the continuous pharmacovigilance following the widespread implementation of coronavirus disease 2019 (COVID-19) vaccination protocols. All three most widely distributed severe acute respiratory syndrome coronavirus 2 vaccine formulations, e.g., BNT162b2, mRNA-1273, and ChAdOx1-S, can induce liver injury that may involve immune-mediated pathways and result in autoimmune hepatitis-like presentation that may require therapeutic intervention in the form of corticosteroid administration. Various mechanisms have been proposed in an attempt to highlight immune checkpoint inhibition and thus establish causality with vaccination. The autoimmune features of such a reaction also prompt an in-depth investigation of the newly employed vaccine technologies. Novel vaccine delivery platforms, e.g., mRNA-containing lipid nanoparticles and adenoviral vectors, contribute to the inflammatory background that leads to an exaggerated immune response, while patterns of molecular mimicry between the spike (S) protein and prominent liver antigens may account for the autoimmune presentation. Immune mediators triggered by vaccination or vaccine ingredients per se, including autoreactive antibodies, cytokines, and cytotoxic T-cell populations, may inflict hepatocellular damage through well-established pathways. We aim to review available data associated with immune-mediated liver injury associated with COVID-19 vaccination and elucidate potential mechanisms underlying its pathogenesis.
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Affiliation(s)
- Georgios Schinas
- Department of Medicine, University of Patras, Patras 26504, Greece
| | - Eleni Polyzou
- Department of Internal Medicine, University of Patras, Patras 26504, Greece
| | | | - Stamatia Tsoupra
- Department of Internal Medicine, University of Patras, Patras 26504, Greece
| | - Charalambos Gogos
- Department of Internal Medicine, University of Patras, Patras 26504, Greece
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Lu C, Zhang Y, Liu X, Hou F, Cai R, Yu Z, Liu F, Yang G, Ding J, Xu J, Hua X, Cheng X, Pan X, Liu L, Lin K, Wang Z, Li X, Lu J, Zhang Q, Li Y, Hu C, Fan H, Liu X, Wang H, Jia R, Xu F, Wang X, Huang H, Zhao R, Li J, Cheng H, Jia W, Yang X. Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine. Antiviral Res 2023; 212:105556. [PMID: 36871919 PMCID: PMC9985518 DOI: 10.1016/j.antiviral.2023.105556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 02/12/2023] [Accepted: 02/13/2023] [Indexed: 03/07/2023]
Abstract
The coronavirus SARS-CoV-2 has mutated quickly and caused significant global damage. This study characterizes two mRNA vaccines ZSVG-02 (Delta) and ZSVG-02-O (Omicron BA.1), and associating heterologous prime-boost strategy following the prime of a most widely administrated inactivated whole-virus vaccine (BBIBP-CorV). The ZSVG-02-O induces neutralizing antibodies that effectively cross-react with Omicron subvariants. In naïve animals, ZSVG-02 or ZSVG-02-O induce humoral responses skewed to the vaccine's targeting strains, but cellular immune responses cross-react to all variants of concern (VOCs) tested. Following heterologous prime-boost regimes, animals present comparable neutralizing antibody levels and superior protection against Delta and Omicron BA.1variants. Single-boost only generated ancestral and omicron dual-responsive antibodies, probably by "recall" and "reshape" the prime immunity. New Omicron-specific antibody populations, however, appeared only following the second boost with ZSVG-02-O. Overall, our results support a heterologous boost with ZSVG-02-O, providing the best protection against current VOCs in inactivated virus vaccine-primed populations.
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Affiliation(s)
- Changrui Lu
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China
| | | | - Xiaohu Liu
- Virogin Biotech (Shanghai) Ltd (Virogin), China
| | - Fujun Hou
- Virogin Biotech (Shanghai) Ltd (Virogin), China
| | - Rujie Cai
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China
| | - Zhibin Yu
- Virogin Biotech (Shanghai) Ltd (Virogin), China
| | - Fei Liu
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China
| | - Guohuan Yang
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China
| | - Jun Ding
- Virogin Biotech (Shanghai) Ltd (Virogin), China
| | - Jiang Xu
- Virogin Biotech (Shanghai) Ltd (Virogin), China
| | - Xianwu Hua
- Virogin Biotech (Shanghai) Ltd (Virogin), China
| | - Xinhua Cheng
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China
| | - Xinping Pan
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China
| | - Lianxiao Liu
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China
| | - Kang Lin
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China
| | - Zejun Wang
- Wuhan Institute of Biological Products Co., LTD (WIBP), China
| | - Xinguo Li
- Wuhan Institute of Biological Products Co., LTD (WIBP), China
| | - Jia Lu
- Wuhan Institute of Biological Products Co., LTD (WIBP), China
| | - Qiu Zhang
- Wuhan Institute of Biological Products Co., LTD (WIBP), China
| | - Yuwei Li
- Wuhan Institute of Biological Products Co., LTD (WIBP), China
| | - Chunxia Hu
- Wuhan Institute of Biological Products Co., LTD (WIBP), China
| | - Huifen Fan
- Wuhan Institute of Biological Products Co., LTD (WIBP), China
| | - Xiaoke Liu
- Wuhan Institute of Biological Products Co., LTD (WIBP), China
| | - Hui Wang
- Wuhan Institute of Biological Products Co., LTD (WIBP), China
| | - Rui Jia
- China National Biotec Group (CNBG), China
| | | | | | - Hongwei Huang
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China; Virogin Biotech (Shanghai) Ltd (Virogin), China
| | - Ronghua Zhao
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China; Virogin Biotech (Shanghai) Ltd (Virogin), China
| | - Jing Li
- Shuimu BioSciences Ltd, China
| | | | - William Jia
- China National Biological Group-Virogin Biotech (Shanghai) Ltd (CNBG-Virogin), China; Virogin Biotech (Shanghai) Ltd (Virogin), China.
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Newby ML, Fogarty CA, Allen JD, Butler J, Fadda E, Crispin M. Variations within the Glycan Shield of SARS-CoV-2 Impact Viral Spike Dynamics. J Mol Biol 2023; 435:167928. [PMID: 36565991 PMCID: PMC9769069 DOI: 10.1016/j.jmb.2022.167928] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/25/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
The emergence of SARS-CoV-2 variants alters the efficacy of existing immunity, whether arisen naturally or through vaccination. Understanding the structure of the viral spike assists in determining the impact of mutations on the antigenic surface. One class of mutation impacts glycosylation attachment sites, which have the capacity to influence the antigenic structure beyond the immediate site of attachment. Here, we compare the site-specific glycosylation of recombinant viral spike mimetics of B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), B.1.1.529 (Omicron). The P.1 strain exhibits two additional N-linked glycan sites compared to the other variants analyzed and we investigate the impact of these glycans by molecular dynamics. The acquired N188 site is shown to exhibit very limited glycan maturation, consistent with limited enzyme accessibility. Structural modeling and molecular dynamics reveal that N188 is located within a cavity by the receptor binding domain, which influences the dynamics of these attachment domains. These observations suggest a mechanism whereby mutations affecting viral glycosylation sites have a structural impact across the protein surface.
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Affiliation(s)
- Maddy L Newby
- School of Biological Sciences, University of Southampton, Southampton, UK. https://twitter.com/Maddy_Newby
| | - Carl A Fogarty
- Department of Chemistry and Hamilton Institute, Maynooth University, Maynooth, Kildare, Ireland. https://twitter.com/2016Carl
| | - Joel D Allen
- School of Biological Sciences, University of Southampton, Southampton, UK. https://twitter.com/JoelDalllen
| | - John Butler
- School of Biological Sciences, University of Southampton, Southampton, UK
| | - Elisa Fadda
- Department of Chemistry and Hamilton Institute, Maynooth University, Maynooth, Kildare, Ireland.
| | - Max Crispin
- School of Biological Sciences, University of Southampton, Southampton, UK.
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Ehteshaminia Y, Jalali SF, Jadidi-Niaragh F, Enderami SE, Pagheh AS, Akbari E, Kenari SA, Hassannia H. Enhancement of immunogenicity and neutralizing responses against SARS-CoV-2 spike protein using the Fc fusion fragment. Life Sci 2023; 320:121525. [PMID: 36841470 PMCID: PMC9951089 DOI: 10.1016/j.lfs.2023.121525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/18/2023] [Accepted: 02/20/2023] [Indexed: 02/27/2023]
Abstract
AIMS Vaccination has played an important role in protecting against death and the severity of COVID-19. The recombinant protein vaccine platform has a long track record of safety and efficacy. Here, we fused the SARS-CoV-2 spike S1 subunit to the Fc region of IgG and investigated immunogenicity, reactivity to human vaccinated sera, and neutralizing activity as a candidate protein vaccine. MATERIALS AND METHOD We evaluated the immunogenicity of CHO-expressed S1-Fc fusion protein and tag-free S1 protein in rabbits via the production of S1-specific polyclonal antibodies. We subsequently compared the neutralizing activities of sera from immunized rabbits and human-vaccinated individuals using a surrogate Virus Neutralization Test (sVNT). KEY FINDINGS The results indicate that S1-specific polyclonal antibodies were induced in all groups; however, antibody levels were higher in rabbits immunized with S1-Fc fusion protein than tag-free S1 protein. Moreover, the reactivity of human vaccinated sera against S1-Fc fusion protein was significantly higher than tag-free S1 protein. Lastly, the results of the virus-neutralizing activity revealed that vaccination with S1-Fc fusion protein induced the highest level of neutralizing antibody response against SARS-CoV-2. SIGNIFICANCE Our results demonstrate that the S1 protein accompanied by the Fc fragment significantly enhances the immunogenicity and neutralizing responses against SARS-CoV-2. It is hoped that this platform can be used for human vaccination.
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Affiliation(s)
- Yahya Ehteshaminia
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyedeh Farzaneh Jalali
- Department of Hematology, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Seyed Ehsan Enderami
- Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abdol Sattar Pagheh
- Infectious Diseases Research Center, Birjand University of Medical Science, Birjand, Iran
| | - Esmaeil Akbari
- Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Saeid Abedian Kenari
- Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hadi Hassannia
- Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
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Roy P, Veesler D, Rey F. Virus structures and molecular biology exchange glances. Structure 2023; 31:S0969-2126(23)00034-5. [PMID: 36841235 DOI: 10.1016/j.str.2023.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 01/20/2023] [Accepted: 01/30/2023] [Indexed: 02/27/2023]
Abstract
The definition of structure as the arrangement of and relations between the parts of something complex has always been a challenge in virology. The balance required for a virus to be sufficiently stable to allow transmission yet also be primed for disassembly on contact with a permissive cell is precarious and seemingly difficult to attain. Add to this that virus structural components often have multiple functions such as receptor binding, fusion, and cleavage, and the puzzle deepens. It also has consequences: virus yields may be compromised, vaccine shelf-life may be limited, and the ability to quickly evolve away from an intervention may be underestimated. Progress in understanding virus structure and the ways in which it might be exploited were the subject of the latest International Virus Assembly Symposium. Whole viruses, individual components, and transient intermediates were revealed at sufficiently high resolution to deduce the mechanisms concerned.
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Affiliation(s)
- Polly Roy
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
| | - David Veesler
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
| | - Felix Rey
- Structural Virology Unit Virology Department and CNRS UMR3569 Institut Pasteur, Paris, France
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Rzymski P, Szuster-Ciesielska A, Dzieciątkowski T, Gwenzi W, Fal A. mRNA vaccines: The future of prevention of viral infections? J Med Virol 2023; 95:e28572. [PMID: 36762592 DOI: 10.1002/jmv.28572] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023]
Abstract
Messenger RNA (mRNA) vaccines against COVID-19 are the first authorized biological preparations developed using this platform. During the pandemic, their administration has been proven to be a life-saving intervention. Here, we review the main advantages of using mRNA vaccines, identify further technological challenges to be met during the development of the mRNA platform, and provide an update on the clinical progress on leading mRNA vaccine candidates against different viruses that include influenza viruses, human immunodeficiency virus 1, respiratory syncytial virus, Nipah virus, Zika virus, human cytomegalovirus, and Epstein-Barr virus. The prospects and challenges of manufacturing mRNA vaccines in low-income countries are also discussed. The ongoing interest and research in mRNA technology are likely to overcome some existing challenges for this technology (e.g., related to storage conditions and immunogenicity of some components of lipid nanoparticles) and enhance the portfolio of vaccines against diseases for which classical formulations are already authorized. It may also open novel pathways of protection against infections and their consequences for which no safe and efficient immunization methods are currently available.
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Affiliation(s)
- Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, Poznań, Poland.,Integrated Science Association (ISA), Universal Scientific Education and Research Network (USERN), Poznań, Poland
| | - Agnieszka Szuster-Ciesielska
- Department of Virology and Immunology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland
| | | | - Willis Gwenzi
- Alexander von Humboldt Fellow & Guest Professor, Grassland Science and Renewable Plant Resources, Faculty of Organic Agricultural Sciences, Universität Kassel, Witzenhausen, Germany.,Alexander von Humboldt Fellow & Guest Professor, Leibniz Institute for Agricultural Engineering and Bioeconomy (ATB), Potsdam, Germany
| | - Andrzej Fal
- Collegium Medicum, Warsaw Faculty of Medicine, Cardinal Stefan Wyszynski University, Warsaw, Poland.,Department of Public Health, Wrocław Medical University, Wrocław, Poland
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40
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Teschers CS, Gilmour R. Fluorine-Directed Automated Mannoside Assembly. Angew Chem Int Ed Engl 2023; 62:e202213304. [PMID: 36331042 PMCID: PMC10108063 DOI: 10.1002/anie.202213304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 11/02/2022] [Accepted: 11/04/2022] [Indexed: 11/06/2022]
Abstract
Automated glycan assembly (AGA) on solid support has become invaluable in reconciling the biological importance of complex carbohydrates with the persistent challenges associated with reproducible synthesis. Whilst AGA platforms have transformed the construction of many natural sugars, validation in the construction of well-defined (site-selectively modified) glycomimetics is in its infancy. Motivated by the importance of fluorination in drug discovery, the biomedical prominence of 2-fluoro sugars and the remarkable selectivities observed in fluorine-directed glycosylation, fluorine-directed automated glycan assembly (FDAGA) is disclosed. This strategy leverages the fluorine atom for stereocontrolled glycosylation on solid support, thereby eliminating the reliance on O-based directing groups. The logical design of C2-fluorinated mannose building blocks, and their application in the fully (α-)stereocontrolled automated assembly of linear and branched fluorinated oligomannosides, is disclosed. This operationally simple strategy can be integrated into existing AGA and post-AGA protocols to augment the scope of programmed carbohydrate synthesis.
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Affiliation(s)
- Charlotte S. Teschers
- Organisch-Chemisches InstitutWestfälische Wilhelms-Universität MünsterCorrensstr. 3648149MünsterGermany
| | - Ryan Gilmour
- Organisch-Chemisches InstitutWestfälische Wilhelms-Universität MünsterCorrensstr. 3648149MünsterGermany
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41
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Differences in BNT126b2 and ChAdOx1 Homologous Vaccination Antibody Response among Teachers in Poznan, Poland. Vaccines (Basel) 2023; 11:vaccines11010118. [PMID: 36679962 PMCID: PMC9862687 DOI: 10.3390/vaccines11010118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/28/2022] [Accepted: 12/31/2022] [Indexed: 01/05/2023] Open
Abstract
Children are among the best vectors to spread respiratory viruses, including emerging variants of SARS-CoV-2 due to the asymptomatic or relatively mild course of infection and simultaneously high titres of pathogens in the respiratory tract. Therefore, individuals who have constant contact with children, e.g., teachers should be vaccinated against COVID-19 as essential workers within the first phases of a vaccination campaign. In Poland, primary and secondary school teachers were vaccinated with ChAdOx1 from February 2021 with a three month interval between the two doses, while lecturers at medical universities, who are simultaneously healthcare workers, received the BNT126b2 vaccine from December 2020 with three weeks between the first and second doses. The aim of this study was to compare the antibody responses at two weeks and three months after vaccination and to estimate the vaccine effectiveness against COVID-19 among infection-naïve teachers vaccinated with mRNA and a vector vaccine. We found that the anti-SARS-CoV-2 spike protein antibodies were significantly higher among the lecturers but antibody waning was slower among the schoolteachers. However, those vaccinated with ChAdOx1 complained significantly more often of vaccine side effects. In addition, during the three months after the second vaccine dose no study participants were infected with SARS-CoV-2. The BNT126b2 vaccine gave higher antibody titres in comparison with ChAdOx1 but protection against COVID-19 in both cases was similar. Moreover, we did not find any anti-SARS-CoV-2 nucleoprotein antibodies at two weeks as well as at three months after vaccination among the study participants, which shows a very high vaccine effectiveness in the occupational group with a high SARS-CoV-2-infection risk.
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42
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Muñoz-Alía MÁ, Nace RA, Balakrishnan B, Zhang L, Packiriswamy N, Singh G, Warang P, Mena I, Narjari R, Vandergaast R, García-Sastre A, Schotsaert M, Russell SJ. Surface-modified measles vaccines encoding oligomeric, fusion-stabilized SARS-CoV-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2022:2022.12.16.520799. [PMID: 36561187 PMCID: PMC9774211 DOI: 10.1101/2022.12.16.520799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/11/2023]
Abstract
Serum titers of SARS-CoV-2 neutralizing antibodies (nAb) correlate well with protection from symptomatic COVID-19, but decay rapidly in the months following vaccination or infection. In contrast, measles-protective nAb titers are life-long after measles vaccination, possibly due to persistence of the live-attenuated virus in lymphoid tissues. We therefore sought to generate a live recombinant measles vaccine capable of driving high SARS-CoV-2 nAb responses. Since previous clinical testing of a live measles vaccine encoding a SARS-CoV-2 spike glycoprotein resulted in suboptimal anti-spike antibody titers, our new vectors were designed to encode prefusion-stabilized SARS-CoV-2 spike glycoproteins, trimerized via an inserted peptide domain and displayed on a dodecahedral miniferritin scaffold. Additionally, to circumvent the blunting of vaccine efficacy by preformed anti-measles antibodies, we extensively modified the measles surface glycoproteins. Comprehensive in vivo mouse testing demonstrated potent induction of high titer nAb in measles-immune mice and confirmed the significant incremental contributions to overall potency afforded by prefusion stabilization, trimerization, and miniferritin-display of the SARS-CoV-2 spike glycoprotein, and vaccine resurfacing. In animals primed and boosted with a MeV vaccine encoding the ancestral SARS-CoV-2 spike, high titer nAb responses against ancestral virus strains were only weakly cross-reactive with the omicron variant. However, in primed animals that were boosted with a MeV vaccine encoding the omicron BA.1 spike, antibody titers to both ancestral and omicron strains were robustly elevated and the passive transfer of serum from these animals protected K18-ACE2 mice from infection and morbidity after exposure to BA.1 and WA1/2020 strains. Our results demonstrate that antigen engineering can enable the development of potent measles-based SARS-CoV-2 vaccine candidates.
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Affiliation(s)
- Miguel Á. Muñoz-Alía
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
- Vyriad Inc, Rochester, MN, USA
| | - Rebecca A. Nace
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Lianwen Zhang
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Gagandeep Singh
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Prajakta Warang
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ignacio Mena
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | - Adolfo García-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michael Schotsaert
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stephen J. Russell
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
- Vyriad Inc, Rochester, MN, USA
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Imanis Life Sciences, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
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43
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Meyer zu Natrup C, Tscherne A, Dahlke C, Ciurkiewicz M, Shin DL, Fathi A, Rohde C, Kalodimou G, Halwe S, Limpinsel L, Schwarz JH, Klug M, Esen M, Schneiderhan-Marra N, Dulovic A, Kupke A, Brosinski K, Clever S, Schünemann LM, Beythien G, Armando F, Mayer L, Weskamm ML, Jany S, Freudenstein A, Tuchel T, Baumgärtner W, Kremsner P, Fendel R, Addo MM, Becker S, Sutter G, Volz A. Stabilized recombinant SARS-CoV-2 spike antigen enhances vaccine immunogenicity and protective capacity. J Clin Invest 2022; 132:159895. [PMID: 36301637 PMCID: PMC9754005 DOI: 10.1172/jci159895] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 10/21/2022] [Indexed: 12/24/2022] Open
Abstract
The SARS-CoV-2 spike (S) glycoprotein is synthesized as a large precursor protein and must be activated by proteolytic cleavage into S1 and S2. A recombinant modified vaccinia virus Ankara (MVA) expressing native, full-length S protein (MVA-SARS-2-S) is currently under investigation as a candidate vaccine in phase I clinical studies. Initial results from immunogenicity monitoring revealed induction of S-specific antibodies binding to S2, but low-level antibody responses to the S1 domain. Follow-up investigations of native S antigen synthesis in MVA-SARS-2-S-infected cells revealed limited levels of S1 protein on the cell surface. In contrast, we found superior S1 cell surface presentation upon infection with a recombinant MVA expressing a stabilized version of SARS-CoV-2 S protein with an inactivated S1/S2 cleavage site and K986P and V987P mutations (MVA-SARS-2-ST). When comparing immunogenicity of MVA vector vaccines, mice vaccinated with MVA-SARS-2-ST mounted substantial levels of broadly reactive anti-S antibodies that effectively neutralized different SARS-CoV-2 variants. Importantly, intramuscular MVA-SARS-2-ST immunization of hamsters and mice resulted in potent immune responses upon challenge infection and protected from disease and severe lung pathology. Our results suggest that MVA-SARS-2-ST represents an improved clinical candidate vaccine and that the presence of plasma membrane-bound S1 is highly beneficial to induce protective antibody levels.
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Affiliation(s)
| | - Alina Tscherne
- Division of Virology, Department of Veterinary Sciences, LMU Munich, Munich, Germany.,German Center for Infection Research, partner site Munich, and
| | - Christine Dahlke
- partner site Hamburg-Lübeck-Borstel-Riems.,University Medical Center Hamburg-Eppendorf, Institute for Infection Research and Vaccine Development (IIRVD), Hamburg, Germany
| | - Malgorzata Ciurkiewicz
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Dai-Lun Shin
- Institute of Virology, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Anahita Fathi
- partner site Hamburg-Lübeck-Borstel-Riems.,University Medical Center Hamburg-Eppendorf, Institute for Infection Research and Vaccine Development (IIRVD), Hamburg, Germany.,University Medical Center Hamburg-Eppendorf, Division of Infectious Diseases, Hamburg, Germany
| | - Cornelius Rohde
- German Center for Infection Research, partner site Gießen-Marburg-Langen.,Institute of Virology, Philipps University Marburg, Marburg, Germany
| | - Georgia Kalodimou
- Division of Virology, Department of Veterinary Sciences, LMU Munich, Munich, Germany.,German Center for Infection Research, partner site Munich, and
| | - Sandro Halwe
- Institute of Virology, Philipps University Marburg, Marburg, Germany
| | - Leonard Limpinsel
- Division of Virology, Department of Veterinary Sciences, LMU Munich, Munich, Germany
| | - Jan H. Schwarz
- Division of Virology, Department of Veterinary Sciences, LMU Munich, Munich, Germany
| | - Martha Klug
- German Center for Infection Research, partner site Tübingen.,Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
| | - Meral Esen
- German Center for Infection Research, partner site Tübingen.,Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
| | | | - Alex Dulovic
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Alexandra Kupke
- German Center for Infection Research, partner site Gießen-Marburg-Langen.,Institute of Virology, Philipps University Marburg, Marburg, Germany
| | - Katrin Brosinski
- Division of Virology, Department of Veterinary Sciences, LMU Munich, Munich, Germany
| | - Sabrina Clever
- Institute of Virology, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Lisa-Marie Schünemann
- Institute of Virology, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Georg Beythien
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Federico Armando
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Leonie Mayer
- partner site Hamburg-Lübeck-Borstel-Riems.,University Medical Center Hamburg-Eppendorf, Institute for Infection Research and Vaccine Development (IIRVD), Hamburg, Germany.,University Medical Center Hamburg-Eppendorf, Division of Infectious Diseases, Hamburg, Germany
| | - Marie L. Weskamm
- partner site Hamburg-Lübeck-Borstel-Riems.,University Medical Center Hamburg-Eppendorf, Institute for Infection Research and Vaccine Development (IIRVD), Hamburg, Germany.,University Medical Center Hamburg-Eppendorf, Division of Infectious Diseases, Hamburg, Germany
| | - Sylvia Jany
- Division of Virology, Department of Veterinary Sciences, LMU Munich, Munich, Germany
| | - Astrid Freudenstein
- Division of Virology, Department of Veterinary Sciences, LMU Munich, Munich, Germany
| | - Tamara Tuchel
- Institute of Virology, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Wolfgang Baumgärtner
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Peter Kremsner
- German Center for Infection Research, partner site Tübingen.,Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Centre de Recherches Médicales de Lambarene, Gabon
| | - Rolf Fendel
- German Center for Infection Research, partner site Tübingen.,Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
| | - Marylyn M. Addo
- University Medical Center Hamburg-Eppendorf, Institute for Infection Research and Vaccine Development (IIRVD), Hamburg, Germany.,German Center for Infection Research, partner site Tübingen
| | - Stephan Becker
- German Center for Infection Research, partner site Gießen-Marburg-Langen.,Institute of Virology, Philipps University Marburg, Marburg, Germany
| | - Gerd Sutter
- Division of Virology, Department of Veterinary Sciences, LMU Munich, Munich, Germany.,German Center for Infection Research, partner site Munich, and
| | - Asisa Volz
- Institute of Virology, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany.,German Center for Infection Research, partner site Hanover-Braunschweig
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44
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Song S, Kim H, Jang EY, Jeon H, Diao H, Khan MRI, Lee M, Lee YJ, Nam J, Kim S, Kim Y, Sohn E, Hwang I, Choi J. SARS-CoV-2 spike trimer vaccine expressed in Nicotiana benthamiana adjuvanted with Alum elicits protective immune responses in mice. PLANT BIOTECHNOLOGY JOURNAL 2022; 20:2298-2312. [PMID: 36062974 PMCID: PMC9538723 DOI: 10.1111/pbi.13908] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/30/2022] [Accepted: 08/05/2022] [Indexed: 06/15/2023]
Abstract
The ongoing coronavirus disease 2019 (COVID-19) pandemic has spurred rapid development of vaccines as part of the public health response. However, the general strategy used to construct recombinant trimeric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) proteins in mammalian cells is not completely adaptive to molecular farming. Therefore, we generated several constructs of recombinant S proteins for high expression in Nicotiana benthamiana. Intramuscular injection of N. benthamiana-expressed Sct vaccine (NSct Vac) into Balb/c mice elicited both humoral and cellular immune responses, and booster doses increased neutralizing antibody titres. In human angiotensin-converting enzyme knock-in mice, two doses of NSct Vac induced anti-S and neutralizing antibodies, which cross-neutralized Alpha, Beta, Delta and Omicron variants. Survival rates after lethal challenge with SARS-CoV-2 were up to 80%, without significant body weight loss, and viral titres in lung tissue fell rapidly, with no infectious virus detectable at 7-day post-infection. Thus, plant-derived NSct Vac could be a candidate COVID-19 vaccine.
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Affiliation(s)
- Shi‐Jian Song
- Department of Life SciencePohang University of Science and TechnologyPohangKorea
| | - Heeyeon Kim
- Division of Acute Viral Disease, Center for Emerging Virus ResearchNational Institute of Infectious Diseases, Korea National Institute of HealthCheongjuKorea
| | - Eun Young Jang
- Division of Vaccine Research, Vaccine Research CenterNational Institute of Infectious Diseases, Korea National Institute of HealthCheongjuKorea
| | - Hyungmin Jeon
- Department of Life SciencePohang University of Science and TechnologyPohangKorea
| | - Hai‐Ping Diao
- Department of Life SciencePohang University of Science and TechnologyPohangKorea
| | - Md Rezaul Islam Khan
- Department of Life SciencePohang University of Science and TechnologyPohangKorea
| | - Mi‐Seon Lee
- Division of Infectious Diseases InspectionJeju Special Self‐Governing Province Institute of Environment ResearchJejuKorea
| | - Young Jae Lee
- Division of Vaccine Research, Vaccine Research CenterNational Institute of Infectious Diseases, Korea National Institute of HealthCheongjuKorea
| | - Jeong‐hyun Nam
- Division of Vaccine Research, Vaccine Research CenterNational Institute of Infectious Diseases, Korea National Institute of HealthCheongjuKorea
| | - Seong‐Ryeol Kim
- Division of Acute Viral Disease, Center for Emerging Virus ResearchNational Institute of Infectious Diseases, Korea National Institute of HealthCheongjuKorea
| | - Young‐Jin Kim
- Department of Life SciencePohang University of Science and TechnologyPohangKorea
| | - Eun‐Ju Sohn
- BioApplications Inc.Pohang Technopark ComplexPohangSouth Korea
| | - Inhwan Hwang
- Department of Life SciencePohang University of Science and TechnologyPohangKorea
| | - Jang‐Hoon Choi
- Division of Acute Viral Disease, Center for Emerging Virus ResearchNational Institute of Infectious Diseases, Korea National Institute of HealthCheongjuKorea
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45
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Cable J, Fauci A, Dowling WE, Günther S, Bente DA, Yadav PD, Madoff LC, Wang L, Arora RK, Van Kerkhove M, Chu MC, Jaenisch T, Epstein JH, Frost SDW, Bausch DG, Hensley LE, Bergeron É, Sitaras I, Gunn MD, Geisbert TW, Muñoz‐Fontela C, Krammer F, de Wit E, Nordenfelt P, Saphire EO, Gilbert SC, Corbett KS, Branco LM, Baize S, van Doremalen N, Krieger MA, Clemens SAC, Hesselink R, Hartman D. Lessons from the pandemic: Responding to emerging zoonotic viral diseases-a Keystone Symposia report. Ann N Y Acad Sci 2022; 1518:209-225. [PMID: 36183296 PMCID: PMC9538336 DOI: 10.1111/nyas.14898] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The COVID-19 pandemic caught the world largely unprepared, including scientific and policy communities. On April 10-13, 2022, researchers across academia, industry, government, and nonprofit organizations met at the Keystone symposium "Lessons from the Pandemic: Responding to Emerging Zoonotic Viral Diseases" to discuss the successes and challenges of the COVID-19 pandemic and what lessons can be applied moving forward. Speakers focused on experiences not only from the COVID-19 pandemic but also from outbreaks of other pathogens, including the Ebola virus, Lassa virus, and Nipah virus. A general consensus was that investments made during the COVID-19 pandemic in infrastructure, collaborations, laboratory and manufacturing capacity, diagnostics, clinical trial networks, and regulatory enhancements-notably, in low-to-middle income countries-must be maintained and strengthened to enable quick, concerted responses to future threats, especially to zoonotic pathogens.
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Affiliation(s)
| | - Anthony Fauci
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID)National Institutes of Health (NIH)BethesdaMarylandUSA
| | | | - Stephan Günther
- Bernhard Nocht Institute for Tropical Medicine and German Center for Infection ResearchHamburgGermany
| | - Dennis A. Bente
- University of Texas Medical BranchGalveston National LaboratoryGalvestonTexasUSA
- Division of Biology and Biological EngineeringCalifornia Institute of TechnologyPasadenaCaliforniaUSA
| | - Pragya Dhruv Yadav
- Indian Council of Medical Research‐National Institute of VirologyPuneIndia
| | - Lawrence C. Madoff
- Department of MedicineUniversity of Massachusetts Chan School of MedicineWorcesterMassachusettsUSA
| | | | - Rahul K. Arora
- Department of Community Health SciencesUniversity of CalgaryCalgaryAlbertaCanada
- Institute of Biomedical EngineeringUniversity of OxfordOxfordUK
| | | | - May C. Chu
- Colorado School of Public HealthAnschutz Medical CampusAuroraColoradoUSA
| | - Thomas Jaenisch
- Colorado School of Public HealthAnschutz Medical CampusAuroraColoradoUSA
| | | | | | | | - Lisa E. Hensley
- Partnership for Research on Vaccines and Infectious Diseases in Liberia (PREVAIL)MonroviaLiberia
- Division of Clinical ResearchNational Institute of Allergy and Infectious DiseasesBethesdaMarylandUSA
| | - Éric Bergeron
- Viral Special Pathogens Branch, Division of High‐Consequence Pathogens and PathologyCenters for Disease Control and PreventionAtlantaGeorgiaUSA
| | - Ioannis Sitaras
- W. Harry Feinstone Department of Molecular Microbiology and ImmunologyJohns Hopkins Bloomberg School of Public HealthBaltimoreMarylandUSA
| | - Michael D. Gunn
- Department of MedicineDuke University Medical CenterDurhamNorth CarolinaUSA
| | - Thomas W. Geisbert
- University of ManitobaWinnipegManitobaCanada
- Galveston National Laboratory and Department of Microbiology and ImmunologyUniversity of Texas Medical BranchGalvestonTexasUSA
| | - César Muñoz‐Fontela
- Bernhard Nocht Institute for Tropical Medicine and German Center for Infection ResearchHamburgGermany
| | - Florian Krammer
- Department of Microbiology and Department of PathologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Emmie de Wit
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthHamiltonMontanaUSA
| | - Pontus Nordenfelt
- Department of Clinical Sciences Lund, Infection Medicine, Faculty of MedicineLund UniversityLundSweden
| | - Erica Ollmann Saphire
- Center for Infectious Disease and Vaccine ResearchLa Jolla Institute for ImmunologyLa JollaCaliforniaUSA
| | - Sarah C. Gilbert
- Pandemic Sciences Institute, Nuffield Department of MedicineUniversity of OxfordOxfordUK
| | - Kizzmekia S. Corbett
- Department of Immunology and Infectious DiseasesHarvard T.H. Chan School of Public HealthBostonMassachusettsUSA
| | | | - Sylvain Baize
- Unité de Biologie des Infections Virales EmergentesInstitut PasteurLyonFrance
- Centre International de Recherche en Infectiologie (CIRI)LyonFrance
- INSERM, Ecole Normale Supérieure de LyonUniversité de LyonLyonFrance
| | - Neeltje van Doremalen
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthHamiltonMontanaUSA
| | - Marco A. Krieger
- Laboratory for Applied Science and Technology in Health, Carlos Chagas InstituteOswaldo Cruz Foundation ‐ ParanáCuritibaBrazil
- Integrated Translational Program in Chagas Disease from Fiocruz (Fio‐Chagas)Oswaldo Cruz Foundation ‐ Rio de JaneiroRio de JaneiroBrazil
| | - Sue Ann Costa Clemens
- Oxford Vaccine GroupOxford UniversityOxfordUK
- Institute for Global HealthUniversity of SienaSienaItaly
| | - Renske Hesselink
- Coalition for Epidemic Preparedness Innovations (CEPI)OsloNorway
| | - Dan Hartman
- Bill & Melinda Gates FoundationSeattleWashingtonUSA
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46
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Gemmati D, Longo G, Gallo I, Silva JA, Secchiero P, Zauli G, Hanau S, Passaro A, Pellegatti P, Pizzicotti S, Serino ML, Singh AV, Tisato V. Host genetics impact on SARS-CoV-2 vaccine-induced immunoglobulin levels and dynamics: The role of TP53, ABO, APOE, ACE2, HLA-A, and CRP genes. Front Genet 2022; 13:1028081. [PMID: 36531241 PMCID: PMC9748098 DOI: 10.3389/fgene.2022.1028081] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/18/2022] [Indexed: 08/26/2023] Open
Abstract
Background: Development and worldwide availability of safe and effective vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to fight severe symptoms of coronavirus disease 2019 (COVID-19) and block the pandemic have been a great achievement and stimulated researchers on understanding the efficacy and duration of different vaccine types. Methods: We investigated the levels of anti-SARS-CoV-2 antibodies (IgG) and neutralizing antibodies (NAbs) in 195 healthy adult subjects belonging to the staff of the University-Hospital of Ferrara (Italy) starting from 15 days up to 190 days (about 6 months) after the second dose of the BNT162b2 (Pfizer-BioNTech) mRNA-based vaccine (n = 128) or ChAdOx1 (AstraZeneca) adenovirus-based vaccine (n = 67) using a combined approach of serological and genomics investigations. Results: A strong correlation between IgG and NAb levels was detected during the 190 days of follow-up (r 2 = 0.807; p < 0.0001) and was confirmed during the first 90 days (T1) after vaccination (r 2 = 0.789; p = 0.0001) and 91-190 days (T2) after vaccination (r 2 = 0.764; p = 0.0001) for both vaccine types (r 2 = 0.842; p = 0.0001 and r 2 = 0.780; p = 0.0001 for mRNA- and adenovirus-based vaccine, respectively). In addition to age (p < 0.01), sex (p = 0.03), and type of vaccine (p < 0.0001), which partially accounted for the remarkable individual differences observed in the antibody levels and dynamics, interesting genetic determinants appeared as significant modifiers of both IgG and NAb responses among the selected genes investigated (TP53, rs1042522; APOE, rs7412/rs429358; ABO, rs657152; ACE2, rs2285666; HLA-A rs2571381/rs2499; CRP, rs2808635/rs876538; LZTFL1, rs35044562; OAS3, rs10735079; SLC6A20, rs11385942; CFH, rs1061170; and ACE1, ins/del, rs4646994). In detail, regression analysis and mean antibody level comparison yielded appreciable differences after genotype stratification (P1 and P2, respectively, for IgG and NAb distribution) in the whole cohort and/or in the mRNA-based vaccine in the following genes: TP53, rs1042522 (P1 = 0.03; P2 = 0.04); ABO, rs657152 (P1 = 0.01; P2 = 0.03); APOE, rs7412/rs429358 (P1 = 0.0018; P2 = 0.0002); ACE2, rs2285666 (P1 = 0.014; P2 = 0.009); HLA-A, rs2571381/rs2499 (P1 = 0.02; P2 = 0.03); and CRP, rs2808635/rs876538 (P1 = 0.01 and P2 = 0.09). Conclusion: High- or low-responsive subjects can be identified among healthy adult vaccinated subjects after targeted genetic screening. This suggests that favorable genetic backgrounds may support the progression of an effective vaccine-induced immune response, though no definite conclusions can be drawn on the real effectiveness ascribed to a specific vaccine or to the different extent of a genotype-driven humoral response. The interplay between data from the polygenic predictive markers and serological screening stratified by demogeographic information can help to recognize the individual humoral response, accounting for ethnic and geographical differences, in both COVID-19 and anti-SARS-CoV-2 vaccinations.
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Affiliation(s)
- Donato Gemmati
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Centre Haemostasis & Thrombosis, University of Ferrara, Ferrara, Italy
- University Centre for Gender Medicine Studies, University of Ferrara, Ferrara, Italy
| | - Giovanna Longo
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Centre Haemostasis & Thrombosis, University of Ferrara, Ferrara, Italy
| | - Ines Gallo
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Centre Haemostasis & Thrombosis, University of Ferrara, Ferrara, Italy
| | - Juliana Araujo Silva
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Centre Haemostasis & Thrombosis, University of Ferrara, Ferrara, Italy
| | - Paola Secchiero
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Giorgio Zauli
- Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Stefania Hanau
- Department of Neuroscience & Rehabilitation, University of Ferrara, Ferrara, Italy
| | - Angelina Passaro
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | | | | | | | - Ajay Vikram Singh
- Department of Chemical & Product Safety, German Federal Institute for Risk Assessment, Berlin, Germany
| | - Veronica Tisato
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- University Centre for Gender Medicine Studies, University of Ferrara, Ferrara, Italy
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Chua JX, Durrant LG, Chok YL, Lai OM. Susceptibility to SARS-CoV-2 omicron following ChAdOx1 nCoV-19 and BNT162b2 versus CoronaVac vaccination. iScience 2022; 25:105379. [PMID: 36277260 PMCID: PMC9575314 DOI: 10.1016/j.isci.2022.105379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 09/29/2022] [Accepted: 10/13/2022] [Indexed: 11/24/2022] Open
Abstract
The emergence of SARS-CoV-2 variants raises concerns of reduced COVID-19 vaccine efficacy. We investigated the humoral immunity in uninfected and previously infected ChAdOx1 nCoV-19, BNT162b2 and CoronaVac vaccinees, who have received complete regimes of vaccines by means of a SARS-CoV-2 surrogate virus blocking test. The ChAdOx1 nCoV-19 (p = 0.0013) and BNT162b2 (p = 0.0005) vaccines induced significant higher blocking activity with longer durability against the Spike (S) protein receptor binding domain (RBD) of wild type SARS-CoV-2 than the CoronaVac vaccine in uninfected vaccinees. Prior infection improved protection in the CoronaVac vaccinees. Subsequent investigation on the breadth of SARS-CoV-2 vaccine-induced antibody blocking responses, revealed that all vaccine platforms cross-protected uninfected vaccinees against all variant of concerns, except Omicron. Prior infection protected the ChAdOx1 nCoV-19 and BNT162b2 vaccinees against Omicron but not CoronaVac vaccinees. Our study suggests that vaccines that induce broader sterilizing immunity are essential to fight against fast-emerging variants.
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Affiliation(s)
- Jia Xin Chua
- MymAb Biologics Pvt. Ltd., Department of Pre-clinical Sciences, University Tunku Abdul Rahman, Selangor, Malaysia
| | - Lindy Gillian Durrant
- MymAb Biologics Pvt. Ltd., Department of Pre-clinical Sciences, University Tunku Abdul Rahman, Selangor, Malaysia
- Academic Department of Clinical Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, City Hospital Campus, Nottingham NG7 2RD, UK
| | - Yin Ling Chok
- MymAb Biologics Pvt. Ltd., Department of Pre-clinical Sciences, University Tunku Abdul Rahman, Selangor, Malaysia
| | - Oi Ming Lai
- Department of Bioprocess Technology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor 43400 UPM, Malaysia
- Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor 43400 UPM, Malaysia
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Rueda-Fernández M, Melguizo-Rodríguez L, Costela-Ruiz VJ, González-Acedo A, Ramos-Torrecillas J, Illescas-Montes R. The current status of COVID-19 vaccines. A scoping review. Drug Discov Today 2022; 27:103336. [PMID: 35995361 PMCID: PMC9389839 DOI: 10.1016/j.drudis.2022.08.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/11/2022] [Accepted: 08/09/2022] [Indexed: 12/12/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new disease that has led to a worldwide pandemic, resulting in millions of deaths and a high economic burden. Here, we analyze the current status of preventive vaccines authorized by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Published clinical trials have shown the effectiveness of mRNA (BNT162b2 and Spikevax), adenovirus vector-based (Ad26.COV2.S and ChAdOx1 nCoV-19), and recombinant protein S (NVX-CoV2373) vaccines to be between 52.9% and 100%. The most-frequent adverse effects include local pain, fatigue, headache, or chills. Serious events are associated with Ad26.COV2.S and ChAdOx1 nCoV-19 vaccines.
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Affiliation(s)
- Manuel Rueda-Fernández
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Avda. Ilustración 60, 18016 Granada, Spain; Institute of Biosanitary Research, Ibs.Granada, C/ Doctor Azpitarte 4, 4a Planta, 18012 Granada, Spain
| | - Lucía Melguizo-Rodríguez
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Avda. Ilustración 60, 18016 Granada, Spain; Institute of Biosanitary Research, Ibs.Granada, C/ Doctor Azpitarte 4, 4a Planta, 18012 Granada, Spain
| | - Víctor J Costela-Ruiz
- Institute of Biosanitary Research, Ibs.Granada, C/ Doctor Azpitarte 4, 4a Planta, 18012 Granada, Spain; Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences of Ceuta, University of Granada, C/ Cortadura del Valle, Sn, 51001 Ceuta, Spain
| | - Anabel González-Acedo
- Institute of Biosanitary Research, Ibs.Granada, C/ Doctor Azpitarte 4, 4a Planta, 18012 Granada, Spain; Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences of Melilla, University of Granada, C/ Santander, 1, 52005 Melilla, Spain
| | - Javier Ramos-Torrecillas
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Avda. Ilustración 60, 18016 Granada, Spain; Institute of Biosanitary Research, Ibs.Granada, C/ Doctor Azpitarte 4, 4a Planta, 18012 Granada, Spain.
| | - Rebeca Illescas-Montes
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Avda. Ilustración 60, 18016 Granada, Spain; Institute of Biosanitary Research, Ibs.Granada, C/ Doctor Azpitarte 4, 4a Planta, 18012 Granada, Spain
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49
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Srinivasa Rao ASR, Krantz SG. Mathematical analysis and topology of SARS-CoV-2, bonding with cells and unbonding. JOURNAL OF MATHEMATICAL ANALYSIS AND APPLICATIONS 2022; 514:125664. [PMID: 34538930 PMCID: PMC8438870 DOI: 10.1016/j.jmaa.2021.125664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Indexed: 06/13/2023]
Abstract
We consider the structure of the novel coronavirus (SARS-Cov-2) in terms of the number of spikes that are critical in bonding with the cells in the host. Bonding formation is considered for selection criteria with and without any treatments. Functional mappings from the discrete space of spikes and cells and their analysis are performed. We found that careful mathematical constructions help in understanding the treatment impacts, and the role of vaccines within a host. Smale's famous 2-D horseshoe examples inspired us to create 3-D visualizations and understand the topological diffusion of spikes from one human organ to another organ. The pharma industry will benefit from such an analysis for designing efficient treatment and vaccine strategies.
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Affiliation(s)
- Arni S R Srinivasa Rao
- Laboratory for Theory and Mathematical Modeling, Medical College of Georgia, Department of Mathematics, Augusta University, GA, USA
| | - Steven G Krantz
- Department of Mathematics, Washington University in St. Louis, MO, USA
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50
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Chi WY, Li YD, Huang HC, Chan TEH, Chow SY, Su JH, Ferrall L, Hung CF, Wu TC. COVID-19 vaccine update: vaccine effectiveness, SARS-CoV-2 variants, boosters, adverse effects, and immune correlates of protection. J Biomed Sci 2022; 29:82. [PMID: 36243868 PMCID: PMC9569411 DOI: 10.1186/s12929-022-00853-8] [Citation(s) in RCA: 127] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 09/01/2022] [Indexed: 12/23/2022] Open
Abstract
Coronavirus Disease 2019 (COVID-19) has been the most severe public health challenge in this century. Two years after its emergence, the rapid development and deployment of effective COVID-19 vaccines have successfully controlled this pandemic and greatly reduced the risk of severe illness and death associated with COVID-19. However, due to its ability to rapidly evolve, the SARS-CoV-2 virus may never be eradicated, and there are many important new topics to work on if we need to live with this virus for a long time. To this end, we hope to provide essential knowledge for researchers who work on the improvement of future COVID-19 vaccines. In this review, we provided an up-to-date summary for current COVID-19 vaccines, discussed the biological basis and clinical impact of SARS-CoV-2 variants and subvariants, and analyzed the effectiveness of various vaccine booster regimens against different SARS-CoV-2 strains. Additionally, we reviewed potential mechanisms of vaccine-induced severe adverse events, summarized current studies regarding immune correlates of protection, and finally, discussed the development of next-generation vaccines.
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Affiliation(s)
- Wei-Yu Chi
- Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Medicine, New York, NY, USA
| | - Yen-Der Li
- Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA
| | - Hsin-Che Huang
- Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Timothy En Haw Chan
- International Max Planck Research School for Immunobiology, Epigenetics and Metabolism (IMPRS-IEM), Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- Department of Urology, Medical Center, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Sih-Yao Chow
- Downstream Process Science, EirGenix Inc., Zhubei, Hsinchu, Taiwan R.O.C
| | - Jun-Han Su
- Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA
| | - Louise Ferrall
- Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
| | - Chien-Fu Hung
- Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University, Baltimore, MD, USA
- Department of Obstetrics and Gynecology, Johns Hopkins University, Baltimore, MD, USA
| | - T-C Wu
- Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
- Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
- Department of Obstetrics and Gynecology, Johns Hopkins University, Baltimore, MD, USA.
- Department of Microbiology and Immunology, Johns Hopkins University, Baltimore, MD, USA.
- The Johns Hopkins Medical Institutions, CRB II Room 309, 1550 Orleans St, MD, 21231, Baltimore, USA.
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