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Adv Sci (Weinh) ; 9(11): e2105378, 2022 04.
Article in English | MEDLINE | ID: covidwho-1680239


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.

COVID-19 , Nanoparticles , Animals , Broadly Neutralizing Antibodies , COVID-19/prevention & control , Macaca mulatta/metabolism , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccines, Conjugate
Signal Transduct Target Ther ; 6(1): 189, 2021 05 12.
Article in English | MEDLINE | ID: covidwho-1226420


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.

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
Immunity ; 53(6): 1315-1330.e9, 2020 12 15.
Article in English | MEDLINE | ID: covidwho-967948


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.

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