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1.
Immunotherapy advances ; 2021.
Article in English | EuropePMC | ID: covidwho-1624261

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2 has been spreading worldwide since December 2019, resulting in the ongoing COVID-19 pandemic with 237 million infections and 4.8 million deaths by 11 October 2021. While there are great efforts of global vaccination, ending this pandemic has been challenged by issues of exceptionally high viral transmissibility, re-infection, vaccine-breakthrough infection, and immune escape variants of concerns. Besides the record-breaking speed of vaccine research and development, antiviral drugs including SARS-CoV-2-specific human neutralizing antibodies (HuNAbs) have been actively explored for passive immunization. In support of HuNAb-based immunotherapy, passive immunization using convalescent patients’ plasma have generated promising evidence on clinical benefits for both mild and severe COVID-19 patients. Since the source of convalescent plasma is limited, the discovery of broadly reactive HuNAbs may have significant impacts on the fight against the COVID-19 pandemic. In this review, therefore, we discuss the current technologies of gene cloning, modes of action, in vitro and in vivo potency and breadth, and clinical development for potent SARS-CoV-2-specific HuNAbs.

2.
EBioMedicine ; 75: 103762, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1587929

ABSTRACT

BACKGROUND: Vaccines in emergency use are efficacious against COVID-19, yet vaccine-induced prevention against nasal SARS-CoV-2 infection remains suboptimal. METHODS: Since mucosal immunity is critical for nasal prevention, we investigated the efficacy of an intramuscular PD1-based receptor-binding domain (RBD) DNA vaccine (PD1-RBD-DNA) and intranasal live attenuated influenza-based vaccines (LAIV-CA4-RBD and LAIV-HK68-RBD) against SARS-CoV-2. FINDINGS: Substantially higher systemic and mucosal immune responses, including bronchoalveolar lavage IgA/IgG and lung polyfunctional memory CD8 T cells, were induced by the heterologous PD1-RBD-DNA/LAIV-HK68-RBD as compared with other regimens. When vaccinated animals were challenged at the memory phase, prevention of robust SARS-CoV-2 infection in nasal turbinate was achieved primarily by the heterologous regimen besides consistent protection in lungs. The regimen-induced antibodies cross-neutralized variants of concerns. Furthermore, LAIV-CA4-RBD could boost the BioNTech vaccine for improved mucosal immunity. INTERPRETATION: Our results demonstrated that intranasal influenza-based boost vaccination induces mucosal and systemic immunity for effective SARS-CoV-2 prevention in both upper and lower respiratory systems. FUNDING: This study was supported by the Research Grants Council Collaborative Research Fund, General Research Fund and Health and Medical Research Fund in Hong Kong; Outbreak Response to Novel Coronavirus (COVID-19) by the Coalition for Epidemic Preparedness Innovations; Shenzhen Science and Technology Program and matching fund from Shenzhen Immuno Cure BioTech Limited; the Health@InnoHK, Innovation and Technology Commission of Hong Kong; National Program on Key Research Project of China; donations from the Friends of Hope Education Fund; the Theme-Based Research Scheme.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , Immunization, Secondary , Influenza Vaccines , SARS-CoV-2 , Vaccines, DNA , Administration, Intranasal , Animals , COVID-19/genetics , COVID-19/immunology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Disease Models, Animal , Dogs , Female , HEK293 Cells , Humans , Immunity, Mucosal , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Madin Darby Canine Kidney Cells , Male , Mice , Mice, Inbred BALB C , Mice, Transgenic , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Vaccines, Attenuated/genetics , Vaccines, Attenuated/immunology , Vaccines, DNA/genetics , Vaccines, DNA/immunology , Vero Cells
3.
Nat Commun ; 12(1): 134, 2021 01 08.
Article in English | MEDLINE | ID: covidwho-1387323

ABSTRACT

Understanding the factors that contribute to efficient SARS-CoV-2 infection of human cells may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we analyze host and viral determinants essential for efficient SARS-CoV-2 infection in both human lung epithelial cells and ex vivo human lung tissues. We identify heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Next, we show that sialic acids present on ACE2 prevent efficient spike/ACE2-interaction. While SARS-CoV infection is substantially limited by the sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissues, infection by SARS-CoV-2 is limited to a lesser extent. We further demonstrate that the furin-like cleavage site in SARS-CoV-2 spike is required for efficient virus replication in human lung but not intestinal tissues. These findings provide insights on the efficient SARS-CoV-2 infection of human lungs.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , COVID-19/transmission , Sialic Acids/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment , Animals , Caco-2 Cells , Cell Line, Tumor , Chlorocebus aethiops , Cricetinae , Furin/metabolism , HEK293 Cells , Heparitin Sulfate/metabolism , Humans , Intestinal Mucosa/metabolism , Intestines/virology , Lung/pathology , Lung/virology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/pathology , Vero Cells , Virus Internalization , Virus Replication/physiology
4.
Cell Host Microbe ; 29(4): 551-563.e5, 2021 04 14.
Article in English | MEDLINE | ID: covidwho-1101147

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a burst in the upper respiratory portal for high transmissibility. To determine human neutralizing antibodies (HuNAbs) for entry protection, we tested three potent HuNAbs (IC50 range, 0.0007-0.35 µg/mL) against live SARS-CoV-2 infection in the golden Syrian hamster model. These HuNAbs inhibit SARS-CoV-2 infection by competing with human angiotensin converting enzyme-2 for binding to the viral receptor binding domain (RBD). Prophylactic intraperitoneal or intranasal injection of individual HuNAb or DNA vaccination significantly reduces infection in the lungs but not in the nasal turbinates of hamsters intranasally challenged with SARS-CoV-2. Although postchallenge HuNAb therapy suppresses viral loads and lung damage, robust infection is observed in nasal turbinates treated within 1-3 days. Our findings demonstrate that systemic HuNAb suppresses SARS-CoV-2 replication and injury in lungs; however, robust viral infection in nasal turbinate may outcompete the antibody with significant implications to subprotection, reinfection, and vaccine.


Subject(s)
Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/therapy , SARS-CoV-2/immunology , Turbinates/virology , Angiotensin-Converting Enzyme 2/physiology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , Cricetinae , Female , HEK293 Cells , Humans , Male , Mesocricetus , Viral Load
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