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1.
Emerg Microbes Infect ; 11(1): 1058-1071, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1752040

ABSTRACT

Safe, efficacious, and deployable vaccines are urgently needed to control COVID-19 in the large-scale vaccination campaigns. We report here the preclinical studies of an approved protein subunit vaccine against COVID-19, ZF2001, which contains tandem-repeat dimeric receptor-binding domain (RBD) protein with alum-based adjuvant. We assessed vaccine immunogenicity and efficacy in both mice and non-human primates (NHPs). ZF2001 induced high levels of RBD-binding and SARS-CoV-2 neutralizing antibody in both mice and non-human primates, and elicited balanced TH1/TH2 cellular responses in NHPs. Two doses of ZF2001 protected Ad-hACE2-transduced mice against SARS-CoV-2 infection, as detected by reduced viral RNA and relieved lung injuries. In NHPs, vaccination of either 25 µg or 50 µg ZF2001 prevented infection with SARS-CoV-2 in lung, trachea, and bronchi, with milder lung lesions. No evidence of disease enhancement was observed in both animal models. ZF2001 has been approved for emergency use in China, Uzbekistan, Indonesia, and Columbia. The high safety, immunogenicity, and protection efficacy in both mice and NHPs found in this preclinical study was consistent with the results in human clinical trials.


Subject(s)
COVID-19 Vaccines , COVID-19 , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Carrier Proteins , Humans , Immunogenicity, Vaccine , Mice , Mice, Inbred BALB C , Primates , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Vaccines, Subunit
2.
Nat Immunol ; 23(3): 423-430, 2022 03.
Article in English | MEDLINE | ID: covidwho-1713201

ABSTRACT

The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires effective therapies against coronavirus disease 2019 (COVID-19), and neutralizing antibodies are a promising therapy. A noncompeting pair of human neutralizing antibodies (B38 and H4) blocking SARS-CoV-2 binding to its receptor, ACE2, have been described previously. Here, we develop bsAb15, a bispecific monoclonal antibody (bsAb) based on B38 and H4. bsAb15 has greater neutralizing efficiency than these parental antibodies, results in less selective pressure and retains neutralizing ability to most SARS-CoV-2 variants of concern (with more potent neutralizing activity against the Delta variant). We also selected for escape mutants of the two parental mAbs, a mAb cocktail and bsAb15, demonstrating that bsAb15 can efficiently neutralize all single-mAb escape mutants. Furthermore, prophylactic and therapeutic application of bsAb15 reduced the viral titer in infected nonhuman primates and human ACE2 transgenic mice. Therefore, this bsAb is a feasible and effective strategy to treat and prevent severe COVID-19.


Subject(s)
Antibodies, Bispecific/immunology , Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Bispecific/chemistry , Antibodies, Bispecific/genetics , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/chemistry , Antibodies, Viral/genetics , COVID-19/immunology , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Cloning, Molecular , Disease Models, Animal , Dose-Response Relationship, Immunologic , Epitopes , Humans , Macaca mulatta , Mice , Neutralization Tests , Protein Engineering/methods , Structure-Activity Relationship
4.
Cell ; 182(3): 722-733.e11, 2020 08 06.
Article in English | MEDLINE | ID: covidwho-628738

ABSTRACT

Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously emerging MERS/SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs. Structure-guided design further yielded a stable version of RBD-dimer as a tandem repeat single-chain (RBD-sc-dimer) which retained the vaccine potency. We generalized this strategy to design vaccines against COVID-19 and SARS, achieving 10- to 100-fold enhancement of NAb titers. RBD-sc-dimers in pilot scale production yielded high yields, supporting their scalability for further clinical development. The framework of immunogen design can be universally applied to other beta-CoV vaccines to counter emerging threats.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Middle East Respiratory Syndrome Coronavirus/immunology , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , SARS Virus/immunology , Universal Design , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/chemistry , COVID-19 , COVID-19 Vaccines , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus Infections/virology , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Middle East Respiratory Syndrome Coronavirus/chemistry , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Protein Binding , Protein Interaction Domains and Motifs/immunology , Receptors, Virus/metabolism , SARS Virus/chemistry , SARS-CoV-2 , Sf9 Cells , Specific Pathogen-Free Organisms , Spodoptera , Transfection , Vaccination/methods , Vero Cells , Viral Vaccines
5.
Science ; 368(6496): 1274-1278, 2020 06 12.
Article in English | MEDLINE | ID: covidwho-260594

ABSTRACT

Neutralizing antibodies could potentially be used as antivirals against the coronavirus disease 2019 (COVID-19) pandemic. Here, we report isolation of four human-origin monoclonal antibodies from a convalescent patient, all of which display neutralization abilities. The antibodies B38 and H4 block binding between the spike glycoprotein receptor binding domain (RBD) of the virus and the cellular receptor angiotensin-converting enzyme 2 (ACE2). A competition assay indicated different epitopes on the RBD for these two antibodies, making them a potentially promising virus-targeting monoclonal antibody pair for avoiding immune escape in future clinical applications. Moreover, a therapeutic study in a mouse model validated that these antibodies can reduce virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity. Our results highlight the promise of antibody-based therapeutics and provide a structural basis for rational vaccine design.


Subject(s)
Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Coronavirus Infections/therapy , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/therapy , Receptors, Virus/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/immunology , Antibodies, Viral/isolation & purification , COVID-19 , Disease Models, Animal , Humans , Immunodominant Epitopes/chemistry , Immunodominant Epitopes/immunology , Lung/immunology , Lung/virology , Mice , Neutralization Tests , Pandemics , Protein Domains , Viral Load/immunology
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