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2.
Cell Reports Medicine ; : 100743, 2022.
Article in English | ScienceDirect | ID: covidwho-2004613

ABSTRACT

Summary SARS-CoV-2 Omicron BA.2 was a dominant circulating SARS-CoV-2 variant worldwide. Recent reports hinted that BA.2 is similarly potent in antibody evasion but may be more transmissible than BA.1. The pathogenicity of BA.2 remains unclear and is of critical public health significance. Here we investigated the virological features and pathogenicity of BA.2 with in vitro and in vivo models. We show that BA.2 is further decreased on transmembrane protease, serine 2 (TMPRSS2) dependence for virus entry in comparison to BA.1 in vitro. In K18-hACE2 mice, BA.2 replicates more efficiently than BA.1 in the nasal turbinates while replicates marginally less efficiently in the lungs, leading to decreased body weight loss and improved survival. Overall, our study indicates that BA.2 is similarly attenuated in lungs when compared to BA.1 but is potentially more transmissible due to its better replication at the nasal turbinates.

3.
Int J Biol Sci ; 18(12): 4714-4730, 2022.
Article in English | MEDLINE | ID: covidwho-1954691

ABSTRACT

The Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the biggest public health challenge the world has witnessed in the past decades. SARS-CoV-2 undergoes constant mutations and new variants of concerns (VOCs) with altered transmissibility, virulence, and/or susceptibility to vaccines and therapeutics continue to emerge. Detailed analysis of host factors involved in virus replication may help to identify novel treatment targets. In this study, we dissected the metabolome derived from COVID-19 patients to identify key host factors that are required for efficient SARS-CoV-2 replication. Through a series of metabolomic analyses, in vitro, and in vivo investigations, we identified ATP citrate lyase (ACLY) as a novel host factor required for efficient replication of SARS-CoV-2 wild-type and variants, including Omicron. ACLY should be further explored as a novel intervention target for COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , ATP Citrate (pro-S)-Lyase , Humans , Pandemics , Virus Replication/genetics
4.
JCI Insight ; 7(11)2022 06 08.
Article in English | MEDLINE | ID: covidwho-1892019

ABSTRACT

SARS-CoV-2 has been confirmed in over 450 million confirmed cases since 2019. Although several vaccines have been certified by the WHO and people are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralization by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 in the K18-hACE2 mouse model. Our data demonstrate that i.v. BCG (BCG-i.v.) vaccination induces robust trained innate immune responses and provides protection against WT SARS-CoV-2, as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between BCG-i.v. vaccination and protection against SARS-CoV-2 challenge.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , BCG Vaccine , COVID-19/prevention & control , Humans , Melphalan , Mice , gamma-Globulins
5.
Acta Biomater ; 148: 133-141, 2022 08.
Article in English | MEDLINE | ID: covidwho-1885570

ABSTRACT

Microneedles can realize the intradermal and transdermal delivery of drugs. However, most conventional microneedles made of metal, polymer and ceramics are unsuitable for the delivery of mRNA drugs that are fragile and temperature-sensitive. This study explores the usage of cryomicroneedles (CryoMNs) for the intradermal delivery of mRNA molecules. Taking luciferase mRNA as an example, we first optimize the formulation of CryoMNs to maximize mRNA stability. Later, in the mouse model, we compare the delivery efficiency with the conventional subcutaneous injection for both the luciferase mRNA and COVID-19 Comirnaty mRNA vaccines, where CryoMNs delivered mRNA vaccines successfully induce specific B-cell antibody, neutralizing activity and T-cell responses. STATEMENT OF SIGNIFICANCE: mRNA vaccines are fragile and temperature-sensitive, so they are mainly delivered by intramuscular injection that often causes pain and requires clinical expertise to immunize patients. Microneedles permit convenient, fast and safe vaccination. However, existing microneedle platforms are ineffective to protect the integrity of mRNA vaccines in fabrication, storage, and administration. This work utilizes cryomicroneedles (CryoMNs) technology to intradermally deliver mRNA. In the mouse model, CryoMNs are compared with the subcutaneous injection for the delivery efficiency of both the luciferase mRNA and COVID-19 Comirnaty mRNA vaccines, where CryoMNs delivered mRNA vaccines successfully produce specific B-cell antibodies, T-cell responses, and neutralizing activity. This work is expected to provide a new delivery strategy for the emerging mRNA therapeutics.


Subject(s)
COVID-19 , Animals , COVID-19/prevention & control , Drug Delivery Systems , Injections, Intradermal , Mice , Needles , RNA, Messenger/genetics , Vaccination
6.
Front Immunol ; 13: 861050, 2022.
Article in English | MEDLINE | ID: covidwho-1785349

ABSTRACT

It has been reported that multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) including Alpha, Beta, Gamma, and Delta can reduce neutralization by antibodies, resulting in vaccine breakthrough infections. Virus-antiserum neutralization assays are typically performed to monitor potential vaccine breakthrough strains. However, experiment-based methods took several weeks whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralization titers. Based on this correlation, we obtained a computational model for the receptor-binding domain (RBD) of the spike protein to predict the fold decrease in virus-antiserum neutralization titers with high accuracy (~0.79). Our predicted results were comparable to experimental neutralization titers of variants, including Alpha, Beta, Delta, Gamma, Epsilon, Iota, Kappa, and Lambda, as well as SARS-CoV. Here, we predicted the fold of decrease of Omicron as 17.4-fold less susceptible to neutralization. We visualized all 1,521 SARS-CoV-2 lineages to indicate variants including Mu, B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs Beta, Gamma, Delta, and Omicron. Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed at http://jdlab.online.


Subject(s)
Antigens, Viral , COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Antigens, Viral/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immune Sera , Neutralization Tests , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-321467

ABSTRACT

Mice are not susceptible to wildtype SARS-CoV-2 infection. Emerging SARS-CoV-2 variants including B.1.1.7, B.1.351, P.1, and P.3 contain mutations in spike, which have been suggested to associate with an increased recognition of mouse ACE2, raising the postulation that they may have evolved to expand species tropism to rodents. Here, we investigated the capacity of B.1.1.7 and other emerging SARS-CoV-2 variants in infecting mouse (Mus musculus) and rats (Rattus norvegicus) under in vitro and in vivo settings. Our results show that B.1.1.7 and P.3, but not B.1 or wildtype SARS-CoV-2, can utilize mouse and rat ACE2 for virus entry in vitro. High infectious virus titers, abundant viral antigen expression, and pathological changes are detected in the nasal turbinate and lung of B.1.1.7-inocluated mice and rats. Together, these results reveal that the current predominant circulating SARS-CoV-2 variant, B.1.1.7, has gained the capability to expand species tropism to rodents.

8.
Viruses ; 14(2)2022 02 14.
Article in English | MEDLINE | ID: covidwho-1687056

ABSTRACT

Omicron was designated by the WHO as a VOC on 26 November 2021, only 4 days after its sequence was first submitted. However, the impact of Omicron on current antibodies and vaccines remains unknown and evaluations are still a few weeks away. We analysed the mutations in the Omicron variant against epitopes. In our database, 132 epitopes of the 120 antibodies are classified into five groups, namely NTD, RBD-1, RBD-2, RBD-3, and RBD-4. The Omicron mutations impact all epitopes in NTD, RBD-1, RBD-2, and RBD-3, with no antibody epitopes spared by these mutations. Only four out of 120 antibodies may confer full resistance to mutations in the Omicron spike, since all antibodies in these three groups contain one or more epitopes that are affected by these mutations. Of all antibodies under EUA, the neutralisation potential of Etesevimab, Bamlanivimab, Casirivimab, Imdevima, Cilgavimab, Tixagevimab, Sotrovimab, and Regdanvimab might be dampened to varying degrees. Our analysis suggests the impact of Omicron on current therapeutic antibodies by the Omicron spike mutations may also apply to current COVID-19 vaccines.


Subject(s)
Antibodies, Monoclonal/analysis , Antibodies, Viral/pharmacology , Computer Simulation , Mutation/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Antibodies, Monoclonal/classification , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/pharmacology , Databases, Factual , Epitopes/immunology , Humans , Immunoglobulin G/pharmacology , Neutralization Tests , Spike Glycoprotein, Coronavirus/immunology
9.
Nature ; 603(7902): 693-699, 2022 03.
Article in English | MEDLINE | ID: covidwho-1641975

ABSTRACT

The Omicron (B.1.1.529) variant of SARS-CoV-2 emerged in November 2021 and is rapidly spreading among the human population1. Although recent reports reveal that the Omicron variant robustly escapes vaccine-associated and therapeutic neutralization antibodies2-10, the pathogenicity of the virus remains unknown. Here we show that the replication of Omicron is substantially attenuated in human Calu3 and Caco2 cells. Further mechanistic investigations reveal that Omicron is inefficient in its use of transmembrane serine protease 2 (TMPRSS2) compared with wild-type SARS-CoV-2 (HKU-001a) and previous variants, which may explain its reduced replication in Calu3 and Caco2 cells. The replication of Omicron is markedly attenuated in both the upper and lower respiratory tracts of infected K18-hACE2 mice compared with that of the wild-type strain and Delta (B.1.617.2) variant, resulting in its substantially ameliorated lung pathology. Compared with wild-type SARS-CoV-2 and the Alpha (B.1.1.7), Beta (1.351) and Delta variants, infection by Omicron causes the lowest reduction in body weight and the lowest mortality rate. Overall, our study demonstrates that the replication and pathogenicity of the Omicron variant of SARS-CoV-2 in mice is attenuated compared with the wild-type strain and other variants.


Subject(s)
COVID-19/pathology , COVID-19/virology , SARS-CoV-2/pathogenicity , Virus Replication , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , Caco-2 Cells , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism , Virulence
10.
EBioMedicine ; 73: 103643, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1482542

ABSTRACT

BACKGROUND: Wildtype mice are not susceptible to SARS-CoV-2 infection. Emerging SARS-CoV-2 variants, including B.1.1.7, B.1.351, P.1, and P.3, contain mutations in spike that has been suggested to associate with an increased recognition of mouse ACE2, raising the postulation that these SARS-CoV-2 variants may have evolved to expand species tropism to wildtype mouse and potentially other murines. Our study evaluated this possibility with substantial public health importance. METHODS: We investigated the capacity of wildtype (WT) SARS-CoV-2 and SARS-CoV-2 variants in infecting mice (Mus musculus) and rats (Rattus norvegicus) under in vitro and in vivo settings. Susceptibility to infection was evaluated with RT-qPCR, plaque assays, immunohistological stainings, and neutralization assays. FINDINGS: Our results reveal that B.1.1.7 and other N501Y-carrying variants but not WT SARS-CoV-2 can infect wildtype mice. High viral genome copies and high infectious virus particle titres are recovered from the nasal turbinate and lung of B.1.1.7-inocluated mice for 4-to-7 days post infection. In agreement with these observations, robust expression of viral nucleocapsid protein and histopathological changes are detected from the nasal turbinate and lung of B.1.1.7-inocluated mice but not that of the WT SARS-CoV-2-inoculated mice. Similarly, B.1.1.7 readily infects wildtype rats with production of infectious virus particles. INTERPRETATION: Our study provides direct evidence that the SARS-CoV-2 variant, B.1.1.7, as well as other N501Y-carrying variants including B.1.351 and P.3, has gained the capability to expand species tropism to murines and public health measures including stringent murine control should be implemented to facilitate the control of the ongoing pandemic. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.


Subject(s)
COVID-19/pathology , SARS-CoV-2/physiology , Viral Tropism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/virology , Female , Humans , Lung/pathology , Lung/virology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neutralization Tests , Nucleocapsid Proteins/immunology , Nucleocapsid Proteins/metabolism , RNA, Viral/analysis , RNA, Viral/metabolism , Rats , Rats, Sprague-Dawley , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Turbinates/pathology , Turbinates/virology , Virus Internalization
11.
J Immunol Res ; 2021: 5531220, 2021.
Article in English | MEDLINE | ID: covidwho-1232374

ABSTRACT

The nucleocapsid protein (NP) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains immunogenic epitopes that can induce cytotoxic T lymphocyte (CTL) against viral infection. This makes the nucleocapsid protein a suitable candidate for developing a vaccine against SARS-CoV-2 infection. This article reports the intradermal delivery of NP antigen using dissolvable microneedle skin patches that could induce both significant B cell and T cell responses.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Coronavirus Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , T-Lymphocytes, Cytotoxic/immunology , Animals , B-Lymphocytes/immunology , COVID-19 Vaccines/administration & dosage , Coronavirus Nucleocapsid Proteins/administration & dosage , Enzyme-Linked Immunosorbent Assay , Injections, Intradermal/methods , Mice , Mice, Inbred BALB C , Phosphoproteins/administration & dosage , Phosphoproteins/immunology
12.
Emerg Microbes Infect ; 10(1): 874-884, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1199439

ABSTRACT

The Coronavirus Disease 2019 (COVID-19) pandemic is unlikely to abate until sufficient herd immunity is built up by either natural infection or vaccination. We previously identified ten linear immunodominant sites on the SARS-CoV-2 spike protein of which four are located within the RBD. Therefore, we designed two linkerimmunodominant site (LIS) vaccine candidates which are composed of four immunodominant sites within the RBD (RBD-ID) or all the 10 immunodominant sites within the whole spike (S-ID). They were administered by subcutaneous injection and were tested for immunogenicity and in vivo protective efficacy in a hamster model for COVID-19. We showed that the S-ID vaccine induced significantly better neutralizing antibody response than RBD-ID and alum control. As expected, hamsters vaccinated by S-ID had significantly less body weight loss, lung viral load, and histopathological changes of pneumonia. The S-ID has the potential to be an effective vaccine for protection against COVID-19.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunodominant Epitopes/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Cricetinae , Female , HEK293 Cells , Humans , Male , Mesocricetus , Mice , Mice, Inbred BALB C , Vaccination
13.
Bioeng Transl Med ; 6(1): e10202, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-985967

ABSTRACT

The S1 subunit of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein contains an immunogenic receptor-binding domain (RBD), which is a promising candidate for the development of a potential vaccine. This study demonstrated that intradermal delivery of an S-RBD vaccine using a dissolvable microneedle skin patch can induce both significant B-cell and significant T-cell responses against S-RBD. Importantly, the outcomes were comparable to that of conventional bolus injection.

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