Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
1.
Adv Sci (Weinh) ; 9(11): e2105378, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1680239

ABSTRACT

The SARS-CoV-2 Delta (B.1.617.2) strain is a variant of concern (VOC) that has become the dominant strain worldwide in 2021. Its transmission capacity is approximately twice that of the original strain, with a shorter incubation period and higher viral load during infection. Importantly, the breakthrough infections of the Delta variant have continued to emerge in the first-generation vaccine recipients. There is thus an urgent need to develop a novel vaccine with SARS-CoV-2 variants as the major target. Here, receptor binding domain (RBD)-conjugated nanoparticle vaccines targeting the Delta variant, as well as the early and Beta/Gamma strains, are developed. Under both a single-dose and a prime-boost strategy, these RBD-conjugated nanoparticle vaccines induce the abundant neutralizing antibodies (NAbs) and significantly protect hACE2 mice from infection by the authentic SARS-CoV-2 Delta strain, as well as the early and Beta strains. Furthermore, the elicitation of the robust production of broader cross-protective NAbs against almost all the notable SARS-CoV-2 variants including the Omicron variant in rhesus macaques by the third re-boost with trivalent vaccines is found. These results suggest that RBD-based monovalent or multivalent nanoparticle vaccines provide a promising second-generation vaccine strategy for SARS-CoV-2 variants.


Subject(s)
COVID-19 , Nanoparticles , Animals , Broadly Neutralizing Antibodies , COVID-19/prevention & control , Macaca mulatta/metabolism , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccines, Conjugate
2.
Cell Rep ; 38(3): 110256, 2022 01 18.
Article in English | MEDLINE | ID: covidwho-1588136

ABSTRACT

Inoculation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is ongoing worldwide. However, the emergence of SARS-CoV-2 variants could cause immune evasion. We developed a bivalent nanoparticle vaccine that displays the receptor binding domains (RBDs) of the D614G and B.1.351 strains. With a prime-boost or a single-dose strategy, this vaccine elicits a robust neutralizing antibody and full protection against infection with the authentic D614G or B.1.351 strain in human angiotensin-converting enzyme 2 transgene mice. Interestingly, 8 months after inoculation with the D614G-specific vaccine, a new boost with this bivalent vaccine potently elicits cross-neutralizing antibodies for SARS-CoV-2 variants in rhesus macaques. We suggest that the D614G/B.1.351 bivalent vaccine could be used as an initial single dose or a sequential enforcement dose to prevent infection with SARS-CoV-2 and its variants.


Subject(s)
COVID-19/prevention & control , Cross Protection , SARS-CoV-2/immunology , Vaccines, Combined/therapeutic use , Animals , CHO Cells , COVID-19 Vaccines/chemical synthesis , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Chlorocebus aethiops , Cricetulus , Cross Protection/immunology , Female , HEK293 Cells , Humans , Macaca mulatta , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Nanoparticles , Vaccination/methods , Vaccines, Combined/chemical synthesis , Vaccines, Combined/immunology , Vero Cells
4.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Article in English | MEDLINE | ID: covidwho-1238060

ABSTRACT

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class Ι (MHC-Ι) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2-infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a strategy to improve immune surveillance.


Subject(s)
Antigen Presentation , COVID-19/immunology , Down-Regulation/immunology , Histocompatibility Antigens Class I/immunology , Immune Evasion , SARS-CoV-2/immunology , Viral Proteins/immunology , Animals , Autophagy/genetics , Autophagy/immunology , COVID-19/genetics , Chlorocebus aethiops , HEK293 Cells , Histocompatibility Antigens Class I/genetics , Humans , Lysosomes/genetics , Lysosomes/immunology , Lysosomes/virology , Mice , Mice, Transgenic , SARS-CoV-2/genetics , Vero Cells , Viral Proteins/genetics
5.
Signal Transduct Target Ther ; 6(1): 189, 2021 05 12.
Article in English | MEDLINE | ID: covidwho-1226420

ABSTRACT

Since the outbreak of coronavirus disease 2019 (COVID-19), it has become a global pandemic. The spike (S) protein of etiologic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specifically recognizes human angiotensin-converting enzyme 2 (hACE2) as its receptor, which is recently identified as an interferon (IFN)-stimulated gene. Here, we find that hACE2 exists on the surface of exosomes released by different cell types, and the expression of exosomal hACE2 is increased by IFNα/ß treatment. In particular, exosomal hACE2 can specifically block the cell entry of SARS-CoV-2, subsequently inhibit the replication of SARS-CoV-2 in vitro and ex vivo. Our findings have indicated that IFN is able to upregulate a viral receptor on the exosomes which competitively block the virus entry, exhibiting a potential antiviral strategy.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Exosomes/metabolism , Interferon-alpha/pharmacology , Interferon-beta/pharmacology , SARS-CoV-2/physiology , Virus Internalization/drug effects , Virus Replication/drug effects , Angiotensin-Converting Enzyme 2/genetics , Animals , Chlorocebus aethiops , Exosomes/genetics , Exosomes/virology , HEK293 Cells , Humans , Mice , Mice, Transgenic , Vero Cells
6.
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
SELECTION OF CITATIONS
SEARCH DETAIL