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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336803

ABSTRACT

Neutralizing antibodies (NAbs) can prevent and treat infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, continuously emerging variants, such as Omicron, have significantly reduced the potency of most known NAbs. The selection of NAbs with broad neutralizing activities and the identification of conserved critical epitopes are still urgently needed. Here, we identified an extremely potent antibody (55A8) by single B-cell sorting from convalescent SARS-CoV-2-infected patients that recognized the receptor-binding domain (RBD) in the SARS-CoV-2 spike (S) protein. 55A8 could bind to wild-type SARS-CoV-2, Omicron BA.1 and Omicron BA.2 simultaneously with 58G6, a NAb previously identified by our group. Importantly, an antibody cocktail containing 55A8 and 58G6 (2-cocktail) showed synergetic neutralizing activity with a half-maximal inhibitory concentration (IC 50 ) in the picomolar range in vitro and prophylactic efficacy in hamsters challenged with Omicron (BA.1) through intranasal delivery at an extraordinarily low dosage (25 μg of each antibody daily) at 3 days post-infection. Structural analysis by cryo-electron microscopy (cryo-EM) revealed that 55A8 is a Class III NAb that recognizes a highly conserved epitope. It could block angiotensin-converting enzyme 2 (ACE2) binding to the RBD in the S protein trimer via steric hindrance. The epitopes in the RBD recognized by 55A8 and 58G6 were found to be different and complementary, which could explain the synergetic mechanism of these two NAbs. Our findings not only provide a potential antibody cocktail for clinical use against infection with current SARS-CoV-2 strains and future variants but also identify critical epitope information for the development of better antiviral agents.

2.
Structure ; 30(5): 707-720.e5, 2022 05 05.
Article in English | MEDLINE | ID: covidwho-1829569

ABSTRACT

Because of the evolutionary variants of SARS-CoV-2, development of broad-spectrum neutralizing antibodies resilient to virus escape is urgently needed. We identified a group of high-affinity nanobodies from camels immunized with receptor-binding domain (RBD) of SARS-CoV-2 spike protein and resolved the structures of two non-competing nanobodies (NB1A7 and NB1B11) in complex with RBD using X-ray crystallography. The structures show that NB1A7 targets the highly conserved cryptic epitope shared by SARS-CoV-2 variants and some other coronaviruses and blocks ACE2 receptor attachment of the spike protein, and NB1B11 epitope overlaps with the contacting surface of ACE2 and is different from the binding site of NB1A7. These two nanobodies were covalently linked into multivalent and bi-paratopic formats, which significantly improved the avidity and neutralization potency and may further inhibit viral escape. The results contribute to the structure-guided design of antibodies against future variants of SARS-CoV-2 virus to combat coronavirus epidemics and pandemics.


Subject(s)
COVID-19 , Single-Domain Antibodies , Angiotensin-Converting Enzyme 2 , Antibodies, Neutralizing , Broadly Neutralizing Antibodies , Epitopes/metabolism , Humans , Protein Binding , SARS-CoV-2/genetics , Single-Domain Antibodies/chemistry , Single-Domain Antibodies/genetics , Spike Glycoprotein, Coronavirus/chemistry
3.
Chem Commun (Camb) ; 58(24): 3925-3928, 2022 Mar 22.
Article in English | MEDLINE | ID: covidwho-1730326

ABSTRACT

Adjuvants are important components in vaccines to increase the immunogenicity of proteins and induce optimal immunity. In this study, we designed a novel ternary adjuvant system Alum + c-GAMP + poly(I:C) with STING agonist 3,3'-c-GAMP (c-GAMP) and TLR3 agonist poly(I:C) co-adsorbed on the conventional adjuvant aluminum gel (Alum), and further constructed an S1 protein vaccine. Two doses of vaccination with the ternary adjuvant vaccine were sufficient to induce a balanced Th1/Th2 immune response and robust humoral and cellular immunity. Additionally, the ternary adjuvant group had effective neutralizing activity against live virus SARS-CoV-2 and pseudovirus of all variants of concern (alpha, beta, gamma, delta and omicron). These results indicate that the ternary adjuvants have a significant synergistic effect and can rapidly trigger potent immune responses; the combination of the ternary adjuvant system with S1 protein is a promising COVID-19 vaccine candidate.


Subject(s)
COVID-19 , SARS-CoV-2 , Adjuvants, Immunologic/pharmacology , Alum Compounds , Aluminum , Animals , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/pharmacology , Humans , Immunity, Cellular , Mice , Mice, Inbred BALB C , Poly I
4.
Arch Pediatr ; 29(4): 281-286, 2022 May.
Article in English | MEDLINE | ID: covidwho-1703295

ABSTRACT

AIMS: COVID-19 has led to unprecedented public health measures such as school and university closures across the world. While initial surveys show an increase in anxiety, we have little information on the subjective experience of adolescents and young adults (AYAs). The aims of this study were to understand the lived experience and needs of AYAs related to home confinement and preventive measures due to COVID-19. DEMOGRAPHICS AND SETTINGS: A total of 25 AYAs (13-24 years old) with diverse gender, age, or health conditions, living in Québec (Canada), were interviewed in May 2020, during the COVID-19 home confinement period. METHODOLOGY: Four virtual focus groups were held via a virtual video-conferencing platform (Zoom©). Thematic analysis was conducted. RESULTS: Thematic analysis revealed five main themes: (1) challenges and opportunities related to the experience of home confinement; (2) variable risk perception of COVID-19 infection; (3) development of coping strategies to maintain well-being; (4) need for information and accompaniment; (5) apprehensions related to perceptions of the future. CONCLUSION: AYAs did not feel considered in public health decisions, fostering an increase in anxiety, especially in more vulnerable AYAs living with chronic diseases.


Subject(s)
COVID-19 , Adolescent , Adult , COVID-19/epidemiology , Chronic Disease , Humans , Pandemics , Qualitative Research , SARS-CoV-2 , Young Adult
5.
J Med Chem ; 65(3): 2558-2570, 2022 02 10.
Article in English | MEDLINE | ID: covidwho-1655430

ABSTRACT

Safe and effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants are the best approach to successfully combat the COVID-19 pandemic. The receptor-binding domain (RBD) of the viral spike protein is a major target to develop candidate vaccines. α-Galactosylceramide (αGalCer), a potent invariant natural killer T cell (iNKT) agonist, was site-specifically conjugated to the N-terminus of the RBD to form an adjuvant-protein conjugate, which was anchored on the liposome surface. This is the first time that an iNKT cell agonist was conjugated to the protein antigen. Compared to the unconjugated RBD/αGalCer mixture, the αGalCer-RBD conjugate induced significantly stronger humoral and cellular responses. The conjugate vaccine also showed effective cross-neutralization to all variants of concern (B.1.1.7/alpha, B.1.351/beta, P.1/gamma, B.1.617.2/delta, and B.1.1.529/omicron). These results suggest that the self-adjuvanting αGalCer-RBD has great potential to be an effective COVID-19 vaccine candidate, and this strategy might be useful for designing various subunit vaccines.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/therapy , Galactosylceramides/therapeutic use , Peptide Fragments/therapeutic use , SARS-CoV-2/immunology , Vaccines, Conjugate/therapeutic use , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/therapeutic use , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Female , Galactosylceramides/chemistry , Galactosylceramides/immunology , Immunity, Humoral/drug effects , Immunity, Innate/drug effects , Interferon-gamma/metabolism , Liposomes/chemistry , Liposomes/immunology , Liposomes/therapeutic use , Mice, Inbred BALB C , Peptide Fragments/chemistry , Peptide Fragments/immunology , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/therapeutic use , Vaccines, Conjugate/chemistry , Vaccines, Conjugate/immunology
6.
Chem Commun (Camb) ; 58(13): 2120-2123, 2022 Feb 10.
Article in English | MEDLINE | ID: covidwho-1639577

ABSTRACT

The coronavirus 2019 (COVID-19) pandemic is causing serious impacts in the world, and safe and effective vaccines and medicines are the best methods to combat the disease. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a key role in interacting with the angiotensin-converting enzyme 2 (ACE2) receptor, and is regarded as an important target of vaccines. Herein, we constructed the adjuvant-protein conjugate Pam3CSK4-RBD as a vaccine candidate, in which the N-terminal of the RBD was site-selectively oxidized by transamination and conjugated with the TLR1/2 agonist Pam3CSK4. This demonstrated that the conjugation of Pam3CSK4 significantly enhanced the anti-RBD antibody response and cellular response. In addition, sera from the Pam3CSK4-RBD immunized group efficiently inhibited the binding of the RBD to ACE2 and protected cells from SARS-CoV-2 and four variants of concern (alpha, beta, gamma and delta), indicating that this adjuvant strategy could be one of the effective means for protein vaccine development.


Subject(s)
COVID-19/prevention & control , Lipopeptides/chemistry , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Vaccines, Conjugate/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibody Formation , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , COVID-19/virology , Female , HEK293 Cells , Humans , Macrophages/cytology , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Protein Binding , Protein Domains/immunology , RAW 264.7 Cells , Recombinant Proteins/biosynthesis , Recombinant Proteins/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Conjugate/administration & dosage , Vaccines, Conjugate/chemistry
8.
Nat Commun ; 12(1): 4887, 2021 08 09.
Article in English | MEDLINE | ID: covidwho-1349665

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that is spreading rapidly, which seriously impacts global public health and economy. Thus, developing effective drugs remains urgent. We identify two potent antibodies, nCoVmab1 and nCoVmab2, targeting the SARS-CoV-2 spike protein receptor-binding domain (RBD) with high affinities from a naïve human phage-displayed Fab library. nCoVmab1 and nCoVmab2 neutralize authentic SARS-CoV-2 with picomolar and nanomolar IC50 values, respectively. No detectable defects of nCoVmab1 and nCoVmab2 are found during the preliminary druggability evaluation. nCoVmab1 could reduce viral titer and lung injury when administered prophylactically and therapeutically in human angiotensin-converting enzyme II (hACE2)-transgenic mice. Therefore, phage display platform could be efficiently used for rapid development of neutralizing monoclonal antibodies (nmabs) with clinical potential against emerging infectious diseases. In addition, we determinate epitopes in RBD of these antibodies to elucidate the neutralizing mechanism. We also convert nCoVmab1 and nCoVmab2 to their germline formats for further analysis, which reveals the contribution of somatic hypermutation (SHM) during nCoVmab1 and nCoVmab2 maturation. Our findings not only provide two highly potent nmabs against SARS-CoV-2 as prophylactic and therapeutic candidates, but also give some clues for development of anti-SARS-CoV-2 agents (e.g., drugs and vaccines) targeting the RBD.


Subject(s)
Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/drug therapy , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Binding Sites , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Chlorocebus aethiops , Epitopes/immunology , Humans , Male , Mice , Mice, Transgenic , Protein Binding , Receptors, Virus/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus , Vero Cells
10.
MedComm (2020) ; 2(1): 101-113, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1121801

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has become a serious burden on global public health. Although therapeutic drugs against COVID-19 have been used in many countries, their efficacy is still limited. We here reported nanobody (Nb) phage display libraries derived from four camels immunized with the SARS-CoV-2 spike receptor-binding domain (RBD), from which 381 Nbs were identified to recognize SARS-CoV-2-RBD. Furthermore, seven Nbs were shown to block interaction of human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2-RBD variants and two Nbs blocked the interaction of human ACE2 with bat-SL-CoV-WIV1-RBD and SARS-CoV-1-RBD. Among these candidates, Nb11-59 exhibited the highest activity against authentic SARS-CoV-2 with 50% neutralizing dose (ND50) of 0.55 µg/ml. Nb11-59 can be produced on large scale in Pichia pastoris, with 20 g/L titer and 99.36% purity. It also showed good stability profile, and nebulization did not impact its stability. Overall, Nb11-59 might be a promising prophylactic and therapeutic molecule against COVID-19, especially through inhalation delivery.

11.
Children (Basel) ; 7(12)2020 Dec 21.
Article in English | MEDLINE | ID: covidwho-1024534

ABSTRACT

To explore factors influencing adolescents and young adults' (AYAs) risk perception of COVID-19 and adherence to public health measures, we conducted a cross-sectional online survey of AYAs (14-22 years old) from Quebec (Canada) recruited through school and community partners in April 2020 during the first wave of the COVID-19 pandemic. The study included 3037 participants (mean age = 17.7 years, 74.6% female). AYAs had higher mean (standard deviation (SD)) risk perception of COVID-19 for their relatives (8.2 (1.9)) than for themselves (5.6 (2.6)) (p < 0.001). Factors associated with higher risk perception included higher disease knowledge (adjusted odds ratio (aOR) 1.06, 95% CI 1.01-1.11), presence of chronic disease (aOR 2.31, 95%CI 1.82-2.93) and use of immunosuppressants (aOR 2.53, 95%CI 1.67-3.87). AYAs with a higher risk perception (aOR 1.06, 95%CI 1.02-1.10) those wishing to help flatten the disease curve (aOR 1.18, 95%CI 1.12-1.25) or to protect their family/friends (aOR 1.14, 95%CI 1.05-1.24) were more likely to engage in preventive behaviors. Self-perceived risk and desire to protect others were significantly associated with adherence to preventive measures among youth. These findings may help inform public health messaging to AYAs in the current and future pandemics.

12.
Children ; 7(12):311, 2020.
Article in English | ScienceDirect | ID: covidwho-984956

ABSTRACT

To explore factors influencing adolescents and young adults’(AYAs) risk perception of COVID-19 and adherence to public health measures, we conducted a cross-sectional online survey of AYAs (14–22 years old) from Quebec (Canada) recruited through school and community partners in April 2020 during the first wave of the COVID-19 pandemic. The study included 3037 participants (mean age = 17.7 years, 74.6% female). AYAs had higher mean (standard deviation (SD)) risk perception of COVID-19 for their relatives (8.2 (1.9)) than for themselves (5.6 (2.6)) (p <0.001). Factors associated with higher risk perception included higher disease knowledge (adjusted odds ratio (aOR) 1.06, 95% CI 1.01–1.11), presence of chronic disease (aOR 2.31, 95%CI 1.82–2.93) and use of immunosuppressants (aOR 2.53, 95%CI 1.67–3.87). AYAs with a higher risk perception (aOR 1.06, 95%CI 1.02–1.10) those wishing to help flatten the disease curve (aOR 1.18, 95%CI 1.12–1.25) or to protect their family/friends (aOR 1.14, 95%CI 1.05–1.24) were more likely to engage in preventive behaviors. Self-perceived risk and desire to protect others were significantly associated with adherence to preventive measures among youth. These findings may help inform public health messaging to AYAs in the current and future pandemics.

13.
Antiviral Res ; 182: 104868, 2020 10.
Article in English | MEDLINE | ID: covidwho-909531

ABSTRACT

COVID-19, which is caused by the emerging human coronavirus SARS-CoV-2, has become a global pandemic that poses a serious threat to human health. To date, no vaccines or specific antiviral drugs have been approved for the treatment of this disease in clinic. Herein, therapeutic antibodies for SARS-CoV-2 were obtained from hyperimmune equine plasma. First, a recombinant SARS-CoV-2 spike protein receptor-binding domain (RBD) was obtained in gram-level quantities through high-cell density fermentation of Chinese hamster ovary cells. Then, the binding of the RBD to the SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, was verified by several biochemical methods. The efficacy of the RBD in triggering antibody response in vivo was subsequently tested in both mice and equines, and the results showed that the RBD triggered high-titer neutralizing antibody production in vivo. Immunoglobulin F(ab')2 fragments were prepared from equine antisera via removal of the Fc region from the immunoglobulins. Finally, a neutralization test with live virus demonstrated that RBD-specific F(ab')2 inhibited SARS-CoV-2 with an EC50 of 0.07 µg/ml and an EC80 of 0.18 µg/ml, showing a potent inhibitory effect on SARS-CoV-2. These results highlight RBD-specific equine immunoglobulin F(ab')2 fragment as a candidate for the treatment of SARS-CoV-2.


Subject(s)
Antibodies, Neutralizing/immunology , Betacoronavirus/immunology , Coronavirus Infections/therapy , Coronavirus Infections/virology , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , Receptors, Immunologic/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Viral/immunology , COVID-19 , Chlorocebus aethiops , Female , HeLa Cells , Humans , Mice, Inbred BALB C , Neutralization Tests , Pandemics , Protein Binding , SARS-CoV-2 , Vero Cells
14.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-1497

ABSTRACT

Background: The coronavirus disease 2019 (COVID-19) has rapidly spread around the world. The objectives of this study were to assess the risk perception, the fe

15.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(5): 489-494, 2020 May 28.
Article in English, Chinese | MEDLINE | ID: covidwho-745338

ABSTRACT

To propose the architectural layout for the big general hospital in the face of public health emergencies, we analyzed the conditions, methods, problems and countermeasures for the reconstruction of the isolation ward from the existing medical building layout of a general hospital. The affected areas met the requirements of isolation ward in the reconstruction, and realized the corresponding partition and separation of people. But the cost of occupying the medical room should be concerned. General hospital should be alerted to potential risks of public health emergencies. The characteristics of different construction types, defects, and the function of the hospital should be considered in the construction, rebuilding, and expansion of the hospital, which shouldnot only meet the needs of the development of the hospital daily usage but also consider dealing with emergent public health events. We can adopt the reasonable layout, including setting up a firewall-like device between the channel and the floor, an ordinary ward at ordinary times, and an independent space for emergency by pulling down the gate. This strategy can not only avoid the problem of low utilization rate of the space occupied by the corresponding area in the ward for diseases spread by air and droplets, maximizing the efficiency of the medical site, but also avoid the problem of emergency response to the temporary reconstruction.


Subject(s)
Emergencies , Facility Design and Construction , Hospitals, General , Public Health , Emergency Service, Hospital , Humans
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