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1.
Proc Natl Acad Sci U S A ; 118(38)2021 09 21.
Article in English | MEDLINE | ID: covidwho-1392996

ABSTRACT

Emergence of novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean serum neutralizing antibody titers of 14,000 to 21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within 4 d in seven of eight animals receiving 50 µg of RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only approximately twofold relative to WA1/2020. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-CoV-like Sarbecovirus vaccine development.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/virology , Macaca mulatta/immunology , Nanoparticles/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/immunology , Adjuvants, Immunologic/administration & dosage , Animals , Antibodies, Neutralizing/biosynthesis , Antibodies, Neutralizing/immunology , Antibodies, Viral/biosynthesis , Antibodies, Viral/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Ferritins/chemistry , SARS-CoV-2/metabolism , T-Lymphocytes/immunology
2.
FEBS Lett ; 595(18): 2323-2340, 2021 09.
Article in English | MEDLINE | ID: covidwho-1332924

ABSTRACT

The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has triggered a worldwide health emergency. Here, we show that ferritin-like Dps from hyperthermophilic Sulfolobus islandicus, covalently coupled with SARS-CoV-2 antigens via the SpyCatcher system, forms stable multivalent dodecameric vaccine nanoparticles that remain intact even after lyophilisation. Immunisation experiments in mice demonstrated that the SARS-CoV-2 receptor binding domain (RBD) coupled to Dps (RBD-S-Dps) elicited a higher antibody titre and an enhanced neutralising antibody response compared to monomeric RBD. A single immunisation with RBD-S-Dps completely protected hACE2-expressing mice from serious illness and led to viral clearance from the lungs upon SARS-CoV-2 infection. Our data highlight that multimerised SARS-CoV-2 subunit vaccines are a highly efficacious modality, particularly when combined with an ultra-stable scaffold.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Receptors, Virus/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Bacterial Proteins/chemistry , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/chemistry , DNA-Binding Proteins/chemistry , Ferritins/chemistry , Humans , Immunization , Mice , Nanoparticles , Protein Domains , Protein Multimerization , Spike Glycoprotein, Coronavirus/chemistry , Sulfolobus
3.
Bioconjug Chem ; 32(5): 1034-1046, 2021 05 19.
Article in English | MEDLINE | ID: covidwho-1217668

ABSTRACT

SARS-CoV-2 caused the COVID-19 pandemic that lasted for more than a year. Globally, there is an urgent need to use safe and effective vaccines for immunization to achieve comprehensive protection against SARS-CoV-2 infection. Focusing on developing a rapid vaccine platform with significant immunogenicity as well as broad and high protection efficiency, we designed a SARS-CoV-2 spike protein receptor-binding domain (RBD) displayed on self-assembled ferritin nanoparticles. In a 293i cells eukaryotic expression system, this candidate vaccine was prepared and purified. After rhesus monkeys are immunized with 20 µg of RBD-ferritin nanoparticles three times, the vaccine can elicit specific humoral immunity and T cell immune response, and the neutralizing antibodies can cross-neutralize four SARS-CoV-2 strains from different sources. In the challenge protection test, after nasal infection with 2 × 105 CCID50 SARS-CoV-2 virus, compared with unimmunized control animals, virus replication in the vaccine-immunized rhesus monkeys was significantly inhibited, and respiratory pathology observations also showed only slight pathological damage. These analyses will benefit the immunization program of the RBD-ferritin nanoparticle vaccine in the clinical trial design and the platform construction to present a specific antigen domain in the self-assembling nanoparticle in a short time to harvest stable, safe, and effective vaccine candidates for new SARS-CoV-2 isolates.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Nanoparticles/chemistry , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/immunology , Animals , Antibodies, Neutralizing/immunology , Binding Sites , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Ferritins/chemistry , Ferritins/metabolism , Immunity, Humoral , Macaca mulatta , Male , Nanoparticles/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/metabolism , Ultracentrifugation
4.
Metallomics ; 13(5)2021 05 12.
Article in English | MEDLINE | ID: covidwho-1195731

ABSTRACT

Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidation states, is important for its biological functions, its reactivity, and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases, including cancer and coronavirus disease 2019. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.


Subject(s)
COVID-19/metabolism , Ferritins/chemistry , Ferritins/metabolism , SARS-CoV-2 , Biomarkers/chemistry , Biomarkers/metabolism , Biotechnology , Ceruloplasmin/metabolism , Drug Delivery Systems , Ferritins/genetics , Ferroptosis/physiology , Glycosylation , Homeostasis , Humans , Inflammation/metabolism , Iron/metabolism , Nanotechnology , Neoplasms/diagnosis , Neoplasms/metabolism , Prognosis , Tissue Distribution
5.
Sci Transl Med ; 13(583)2021 03 03.
Article in English | MEDLINE | ID: covidwho-1117652

ABSTRACT

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus-associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.


Subject(s)
Hemagglutinin Glycoproteins, Influenza Virus/immunology , Influenza Vaccines/immunology , Primates/immunology , Animals , Antibodies, Viral/biosynthesis , Antibodies, Viral/chemistry , Antigen-Antibody Complex/chemistry , Broadly Neutralizing Antibodies/biosynthesis , Broadly Neutralizing Antibodies/chemistry , COVID-19 , Ferritins/chemistry , Ferritins/immunology , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Humans , Influenza Vaccines/administration & dosage , Influenza Vaccines/chemistry , Influenza, Human/immunology , Influenza, Human/virology , Macaca fascicularis , Models, Molecular , Nanoparticles/chemistry , Pandemics , Primates/virology , Protein Structure, Quaternary , SARS-CoV-2
7.
Chembiochem ; 22(8): 1371-1378, 2021 04 16.
Article in English | MEDLINE | ID: covidwho-985970

ABSTRACT

Infectious diseases are a continues threat to human health and the economy worldwide. The latest example is the global pandemic of COVID-19 caused by SARS-CoV-2. Antibody therapy and vaccines are promising approaches to treat the disease; however, they have bottlenecks: they might have low efficacy or narrow breadth due to the continuous emergence of new strains of the virus or antibodies could cause antibody-dependent enhancement (ADE) of infection. To address these bottlenecks, I propose the use of 24-meric ferritin for the synthesis of mosaic nanocages to deliver a cocktail of antibodies or nanobodies alone or in combination with another therapeutic, like a nucleotide analogue, to mimic the viral entry process and deceive the virus, or to develop mosaic vaccines. I argue that available data showing the effectiveness of ferritin-antibody conjugates in targeting specific cells and ferritin-haemagglutinin nanocages in developing influenza vaccines strongly support my proposals.


Subject(s)
Antiviral Agents/chemistry , Ferritins/chemistry , Nanostructures/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies/chemistry , Antibodies/therapeutic use , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Drug Carriers/chemistry , Ferritins/metabolism , Humans , Mice , SARS-CoV-2/isolation & purification , Serine Endopeptidases/chemistry , Serine Endopeptidases/metabolism , Virus Internalization/drug effects
8.
Immunity ; 53(6): 1315-1330.e9, 2020 12 15.
Article in English | MEDLINE | ID: covidwho-967948

ABSTRACT

Various vaccine strategies have been proposed in response to the global COVID-19 pandemic, each with unique strategies for eliciting immune responses. Here, we developed nanoparticle vaccines by covalently conjugating the self-assembled 24-mer ferritin to the receptor binding domain (RBD) and/or heptad repeat (HR) subunits of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) spike (S) protein. Compared to monomer vaccines, nanoparticle vaccines elicited more robust neutralizing antibodies and cellular immune responses. RBD and RBD-HR nanoparticle vaccinated hACE2 transgenic mice vaccinated with RBD and/or RBD-HR nanoparticles exhibited reduced viral load in the lungs after SARS-CoV-2 challenge. RBD-HR nanoparticle vaccines also promoted neutralizing antibodies and cellular immune responses against other coronaviruses. The nanoparticle vaccination of rhesus macaques induced neutralizing antibodies, and T and B cell responses prior to boost immunization; these responses persisted for more than three months. RBD- and HR-based nanoparticles thus present a promising vaccination approach against SARS-CoV-2 and other coronaviruses.


Subject(s)
Bacterial Proteins/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Ferritins/immunology , Helicobacter pylori/metabolism , Recombinant Fusion Proteins/immunology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Bacterial Proteins/chemistry , COVID-19 Vaccines/chemistry , Ferritins/chemistry , Humans , Macaca mulatta , Mice , Mice, Inbred BALB C , Nanoparticles/chemistry , Pandemics , Protein Binding , Spike Glycoprotein, Coronavirus/chemistry , Vaccination
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