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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335258

ABSTRACT

The recently emerged SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.2 1 . The new variants’ receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we show that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1;while BA.4/BA.5 displays the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization evasion against the plasma of 3-dose vaccinees and, most strikingly, of vaccinated BA.1 convalescents. To delineate the underlying evasion mechanism, we determined the escaping mutation profiles 2 , epitope distribution 3 and Omicron sublineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype (WT) induced humoral memory and elicits antibodies that neutralize both WT and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes;and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure induced by Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to WT SARS-CoV-2 due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths. As for therapeutic NAbs, LY-CoV1404 (Bebtelovimab 4 ) and COV2-2130 (Cilgavimab 5 ) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

2.
Adv Sci (Weinh) ; 9(14): e2104333, 2022 05.
Article in English | MEDLINE | ID: covidwho-1782562

ABSTRACT

Coronavirus disease 2019 (COVID-19) remains a global public health threat. Hence, more effective and specific antivirals are urgently needed. Here, COVID-19 hyperimmune globulin (COVID-HIG), a passive immunotherapy, is prepared from the plasma of healthy donors vaccinated with BBIBP-CorV (Sinopharm COVID-19 vaccine). COVID-HIG shows high-affinity binding to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein, the receptor-binding domain (RBD), the N-terminal domain of the S protein, and the nucleocapsid protein; and blocks RBD binding to human angiotensin-converting enzyme 2 (hACE2). Pseudotyped and authentic virus-based assays show that COVID-HIG displays broad-spectrum neutralization effects on a wide variety of SARS-CoV-2 variants, including D614G, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529) in vitro. However, a significant reduction in the neutralization titer is detected against Beta, Delta, and Omicron variants. Additionally, assessments of the prophylactic and treatment efficacy of COVID-HIG in an Adv5-hACE2-transduced IFNAR-/- mouse model of SARS-CoV-2 infection show significantly reduced weight loss, lung viral loads, and lung pathological injury. Moreover, COVID-HIG exhibits neutralization potency similar to that of anti-SARS-CoV-2 hyperimmune globulin from pooled convalescent plasma. Overall, the results demonstrate the potential of COVID-HIG against SARS-CoV-2 infection and provide reference for subsequent clinical trials.


Subject(s)
COVID-19 Vaccines , COVID-19 , Globulins , Animals , COVID-19/therapy , Globulins/therapeutic use , Humans , Immunization, Passive , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331897

ABSTRACT

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the inactivated vaccine BBIBP-CorV. Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

4.
Cell Discov ; 8(1): 17, 2022 Feb 15.
Article in English | MEDLINE | ID: covidwho-1692628

ABSTRACT

The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen. When compared with a homo-tri-RBD vaccine candidate in the stage of phase II trial, of which all three RBDs are derived from the SARS-CoV-2 prototype strain, mutI-tri-RBD induced significantly higher neutralizing antibody titers against the Delta and Beta variants, and maintained a similar immune response against the prototype strain. Pseudo-virus neutralization assay demonstrated that mutI-tri-RBD also induced broadly strong neutralizing activities against all tested 23 SARS-CoV-2 variants. The in vivo protective capability of mutI-tri-RBD was further validated in hACE2-transgenic mice challenged by the live virus, and the results showed that mutI-tri-RBD provided potent protection not only against the SARS-CoV-2 prototype strain but also against the Delta and Beta variants.

5.
Arch Virol ; 167(2): 459-470, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1653515

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a major impact on global human health. During the spread of SARS-CoV-2, weakened host immunity and the use of vaccines with low efficacy may result in the development of more-virulent strains or strains with resistance to existing vaccines and antibodies. The prevalence of SARS-CoV-2 mutant strains differs between regions, and this variation may have an impact on the effectiveness of vaccines. In this study, an epidemiological investigation of SARS-CoV-2 in Portugal was performed, and the VSV-ΔG-G* pseudovirus system was used to construct 12 spike protein epidemic mutants, D614G, A222V+D614G, B.1.1.7, S477N+D614G, P1162R+D614G+A222V, D839Y+D614G, L176F+D614G, B.1.1.7+L216F, B.1.1.7+M740V, B.1.258, B.1.258+L1063F, and B.1.258+N751Y. The mutant pseudoviruses were used to infect four susceptible cell lines (Huh7, hACE2-293T-293T, Vero, and LLC-MK2) and 14 cell lines overexpressing ACE2 from different species. Mutant strains did not show increased infectivity or cross-species transmission. Neutralization activity against these pseudoviruses was evaluated using mouse serum and 11 monoclonal antibodies. The neutralizing activity of immunized mouse serum was not significantly reduced with the mutant strains, but the mutant strains from Portugal could evade nine of the 11 monoclonal antibodies tested. Neutralization resistance was mainly caused by the mutations S477N, N439K, and N501Y in the spike-receptor binding domain. These findings emphasize the importance of SARS-CoV-2 mutation tracking in different regions for epidemic prevention and control.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Neutralizing , Humans , Mice , Mutation , Portugal/epidemiology , Spike Glycoprotein, Coronavirus/genetics
6.
Bioorg Chem ; 116: 105309, 2021 11.
Article in English | MEDLINE | ID: covidwho-1372894

ABSTRACT

Six new polyketone metabolites, compounds (1-6) and seven known polyketone compounds (7-13) were isolated from Rhodiola tibetica endophytic fungus Alternaria sp. The structural elucidation of five new polyketone metabolites were elucidated on the basis of spectroscopic including 2D NMR and HRMS and spectrometric analysis. Inhibition rate evaluation revealed that compounds 1(EC50 = 0.02 mM), 3(EC50 = 0.3 mM), 6(EC50 = 0.07 mM), 8(EC50 = 0.1 mM) and 9(EC50 = 0.04 mM) had inhibitory effect on the SARS-CoV-2 virus.


Subject(s)
Alternaria/chemistry , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Ketones/isolation & purification , Ketones/pharmacology , Polymers/isolation & purification , Polymers/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Humans , Ketones/chemistry , Molecular Structure , Polymers/chemistry
7.
Chin Med J (Engl) ; 134(11): 1289-1298, 2021 Apr 28.
Article in English | MEDLINE | ID: covidwho-1343718

ABSTRACT

BACKGROUND: The significant morbidity and mortality resulted from the infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for urgent development of effective and safe vaccines. We report the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine, KCONVAC, in healthy adults. METHODS: Phase 1 and phase 2 randomized, double-blind, and placebo-controlled trials of KCONVAC were conducted in healthy Chinese adults aged 18 to 59 years. The participants in the phase 1 trial were randomized to receive two doses, one each on Days 0 and 14, of either KCONVAC (5 or 10 µg/dose) or placebo. The participants in the phase 2 trial were randomized to receive either KCONVAC (at 5 or 10 µg/dose) or placebo on Days 0 and 14 (0/14 regimen) or Days 0 and 28 (0/28 regimen). In the phase 1 trial, the primary safety endpoint was the proportion of participants experiencing adverse reactions/events within 28 days following the administration of each dose. In the phase 2 trial, the primary immunogenicity endpoints were neutralization antibody seroconversion and titer and anti-receptor-binding domain immunoglobulin G seroconversion at 28 days after the second dose. RESULTS: In the phase 1 trial, 60 participants were enrolled and received at least one dose of 5-µg vaccine (n = 24), 10-µg vaccine (n = 24), or placebo (n = 12). In the phase 2 trial, 500 participants were enrolled and received at least one dose of 5-µg vaccine (n = 100 for 0/14 or 0/28 regimens), 10-µg vaccine (n = 100 for each regimen), or placebo (n = 50 for each regimen). In the phase 1 trial, 13 (54%), 11 (46%), and seven (7/12) participants reported at least one adverse event (AE) after receiving 5-, 10-µg vaccine, or placebo, respectively. In the phase 2 trial, 16 (16%), 19 (19%), and nine (18%) 0/14-regimen participants reported at least one AE after receiving 5-, 10-µg vaccine, or placebo, respectively. Similar AE incidences were observed in the three 0/28-regimen treatment groups. No AEs with an intensity of grade 3+ were reported, expect for one vaccine-unrelated serious AE (foot fracture) reported in the phase 1 trial. KCONVAC induced significant antibody responses; 0/28 regimen showed a higher immune responses than that did 0/14 regimen after receiving two vaccine doses. CONCLUSIONS: Both doses of KCONVAC are well tolerated and able to induce robust immune responses in healthy adults. These results support testing 5-µg vaccine in the 0/28 regimen in an upcoming phase 3 efficacy trial. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx (No. ChiCTR2000038804, http://www.chictr.org.cn/showproj.aspx?proj=62350; No. ChiCTR2000039462, http://www.chictr.org.cn/showproj.aspx?proj=63353).


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , COVID-19 Vaccines , Double-Blind Method , Humans , Vaccines, Inactivated/adverse effects
8.
Zhongguo Bingdubing Zazhi = Chinese Journal of Viral Diseases ; - (3):209, 2021.
Article in English | ProQuest Central | ID: covidwho-1329332

ABSTRACT

Most viruses require their glycoproteins to be hydrolyzed in order to enter host cells.In some cases, the severability of viral glycoproteins is a determinant of their virulence.These viral glycoproteins can be cleaved by one or more proteases in host cells with furin as the common one.Furin further promotes viral infection by identifying specific amino acid sequences in glycoprotein precursors.Morever, furin plays a critical role in the infections of many viruses including human immunodeficiency virus, flavivirus, filamentavirus and coronavirus, and is considered as a promising drug treatment and prevention target.In this review, we summarize the biological background of furin and its hydrolysis function to viral glycoproteins.

9.
Bioorg Chem ; 115: 105196, 2021 10.
Article in English | MEDLINE | ID: covidwho-1322004

ABSTRACT

So far, there is still no specific drug against COVID-19. Taking compound 1 with anti-EBOV activity as the lead, fifty-four 12N-substituted aloperine derivatives were synthesized and evaluated for the anti-SARS-CoV-2 activities using pseudotyped virus model. Among them, 8a exhibited the most potential effects against both pseudotyped and authentic SARS-CoV-2, as well as SARS-CoV and MERS-CoV, indicating a broad-spectrum anti-coronavirus profile. The mechanism study disclosed that 8a might block a late stage of viral entry, mainly via inhibiting host cathepsin B activity rather than directly targeting cathepsin B protein. Also, 8a could significantly reduce the release of multiple inflammatory cytokines in a time- and dose-dependent manner, such as IL-6, IL-1ß, IL-8 and MCP-1, the major contributors to cytokine storm. Therefore, 8a is a promising agent with the advantages of broad-spectrum anti-coronavirus and anti-cytokine effects, thus worthy of further investigation.


Subject(s)
Antiviral Agents/pharmacology , Piperidines/pharmacology , Quinolizidines/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Cathepsin B/antagonists & inhibitors , Chlorocebus aethiops , Cytokines/metabolism , HEK293 Cells , Humans , Male , Mice , Microbial Sensitivity Tests , Molecular Structure , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Piperidines/toxicity , Quinolizidines/chemical synthesis , Quinolizidines/pharmacokinetics , Quinolizidines/toxicity , Rats, Sprague-Dawley , Structure-Activity Relationship , Vero Cells
10.
Signal Transduct Target Ther ; 6(1): 134, 2021 03 27.
Article in English | MEDLINE | ID: covidwho-1152831

ABSTRACT

To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/metabolism , Cathepsin L , Cysteine Proteinase Inhibitors/pharmacology , Drug Development , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , Adolescent , Adult , Aged , Animals , COVID-19/drug therapy , COVID-19/genetics , Cathepsin L/antagonists & inhibitors , Cathepsin L/genetics , Cathepsin L/metabolism , Female , Humans , Male , Mice , Mice, Transgenic , Middle Aged , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
11.
2020.
Preprint | CAplus | ID: ppcovidwho-5353

ABSTRACT

A review. Transmembrane serine protein 2 (TMPRSS2) is a member of serine protease family on the surface of cell membrane. It mediates the hydrolysis of spike protein of coronavirus, and is necessary for coronavirus infection in host cells. This paper summarized the research progress of TMPRSS2 in recent years, including its gene composition, protein structure, expression distribution, and mol. biol. functions. It focused on the role of TMPRSS2 in virus infection on respiratory system, especially on coronavirus infection, and summarized the research progress of drugs in targeting on TMPRSS2, hoping to provide new directions and targets for the prevention and treatment of the novel coronavirus.

12.
Cell ; 182(5): 1271-1283.e16, 2020 09 03.
Article in English | MEDLINE | ID: covidwho-666099

ABSTRACT

There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.


Subject(s)
RNA, Messenger/genetics , RNA, Viral/genetics , Vaccines, Synthetic/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/immunology , Binding Sites , COVID-19 Vaccines , Chlorocebus aethiops , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Female , HEK293 Cells , HeLa Cells , Humans , Immunogenicity, Vaccine , Injections, Intramuscular , Macaca fascicularis , Male , Mice , Mice, Inbred ICR , Nanoparticles/chemistry , RNA, Messenger/metabolism , RNA, Viral/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Th1 Cells/immunology , Vaccine Potency , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/genetics , Vero Cells , Viral Vaccines/administration & dosage , Viral Vaccines/genetics
13.
Cell Host Microbe ; 28(1): 124-133.e4, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-378130

ABSTRACT

Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought an urgent need for an animal model. Human angiotensin-converting enzyme II (ACE2) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human ACE2 (hACE2) by using CRISPR/Cas9 knockin technology. In comparison with wild-type C57BL/6 mice, both young and aged hACE2 mice sustained high viral loads in lung, trachea, and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected-aged hACE2 mice. Interestingly, intragastric inoculation of SARS-CoV-2 was seen to cause productive infection and lead to pulmonary pathological changes in hACE2 mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis and evaluating COVID-19 vaccines and therapeutics.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections , Disease Models, Animal , Mice, Inbred C57BL , Pandemics , Pneumonia, Viral , Aging , Angiotensin-Converting Enzyme 2 , Animals , Brain/virology , COVID-19 , CRISPR-Cas Systems , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/blood , Gene Knock-In Techniques , Lung/pathology , Lung/virology , Lung Diseases, Interstitial/pathology , Nose/virology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA, Viral/analysis , SARS-CoV-2 , Stomach/virology , Trachea/virology , Viral Load , Virus Replication
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