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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336861

ABSTRACT

Summary The ongoing outbreak of SARS-CoV-2 Omicron BA.2 infections in Hong Kong, the world model city of universal masking, has resulted in a major public health crisis. In this study, we investigate public servants who had been vaccinated with two dose (82.7%) or three dose (14%) of either CoronaVac (CorV) or BNT162b2 (BNT). During the BA.2 outbreak, 29.3% vaccinees were infected. Three-dose vaccination provided protection with lower incidence rates of breakthrough infections (2×BNT 49.2% vs 3×BNT 16.6%, p <0.0001;2×CorV 48.6% vs 3×CoV 20.6%, p =0.003). The third heterologous vaccination showed the lowest incidence (2×CorV+1×BNT 6.3%). Although BA.2 conferred the highest neutralization resistance compared with variants of concern tested, the third dose vaccination-activated spike-specific memory B and Omicron cross-reactive T cell responses contributed to reduced frequencies of breakthrough infection and disease severity. Our results have implications to timely boost vaccination and immune responses likely required for vaccine-mediated protection against Omicron BA.2 pandemic.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336250

ABSTRACT

Background: The ongoing outbreak of SARS-CoV-2 Omicron BA.2 infections in Hong Kong, the world model city of universal masking, has resulted in a major public health crisis. Although the third heterologous BNT162b2 vaccination after 2-dose CoronaVac generated higher neutralizing antibody responses than the third homologous CoronaVac booster, vaccine efficacy and corelates of immune protection against the major circulating Omicron BA.2 remains to be investigated. Methods: : We investigated the vaccine efficacy against the Omicron BA.2 breakthrough infection among 481 public servants who had been received with SARS-CoV-2 vaccines including two-dose BNT162b2 (2×BNT, n=169), three-dose BNT162b2 (2×BNT, n=175), two-dose CoronaVac (2×CorV, n=37), three-dose CoronaVac (3×CorV, n=68) and third-dose BNT162b2 following 2×CorV (2×CorV+1BNT, n=32). Humoral and cellular immune responses after three-dose vaccination were characterized and correlated with clinical characteristics of BA.2 infection. Results: : During the BA.2 outbreak, 29.3% vaccinees were infected. Three-dose vaccination provided protection with lower incidence rates of breakthrough infections (2×BNT 49.2% vs 3×BNT 16.6%, p<0.0001;2×CorV 48.6% vs 3×CoV 20.6%, p=0.003). The third heterologous vaccination showed the lowest incidence (2×CorV+1×BNT 6.3%). Although BA.2 conferred the highest neutralization resistance compared with variants of concern tested, the third dose vaccination-activated spike-specific memory B and Omicron cross-reactive T cell responses contributed to reduced frequencies of breakthrough infection and disease severity. Conclusions: : Our results have implications to timely boost vaccination and immune responses likely required for vaccine-mediated protection against Omicron BA.2 pandemic.

3.
Front Immunol ; 12: 799896, 2021.
Article in English | MEDLINE | ID: covidwho-1662583

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in rapid T lymphocytopenia and functional impairment of T cells. The underlying mechanism, however, remains incompletely understood. In this study, we focused on characterizing the phenotype and kinetics of T-cell subsets with mitochondrial dysfunction (MD) by multicolor flow cytometry and investigating the association between MD and T-cell functionality. While 73.9% of study subjects displayed clinical lymphocytopenia upon hospital admission, a significant reduction of CD4 or CD8 T-cell frequency was found in all asymptomatic, symptomatic, and convalescent cases. CD4 and CD8 T cells with increased MD were found in both asymptomatic and symptomatic patients within the first week of symptom onset. Lower proportion of memory CD8 T cell with MD was found in severe patients than in mild ones at the stage of disease progression. Critically, the frequency of T cells with MD in symptomatic patients was preferentially associated with CD4 T-cell loss and CD8 T-cell hyperactivation, respectively. Patients bearing effector memory CD4 and CD8 T cells with the phenotype of high MD exhibited poorer T-cell responses upon either phorbol 12-myristate-13-acetate (PMA)/ionomycin or SARS-CoV-2 peptide stimulation than those with low MD. Our findings demonstrated an MD-associated mechanism underlying SARS-CoV-2-induced T lymphocytopenia and functional impairment during the acute phase of infection.


Subject(s)
COVID-19/complications , Lymphopenia/complications , Lymphopenia/etiology , Mitochondrial Diseases/etiology , Adult , Aged , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , COVID-19/immunology , Female , Humans , Immunologic Memory/immunology , Ionomycin/therapeutic use , Lymphopenia/immunology , Male , Middle Aged , Mitochondria/immunology , Mitochondrial Diseases/immunology , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/therapeutic use , Polymethacrylic Acids/therapeutic use
4.
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
5.
Clin Infect Dis ; 73(2): e437-e444, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-1315658

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains the furin cleavage Proline-Arginine-Arginine-Alanine (PRRA) motif in the S1/S2 region, which enhances viral pathogenicity but is absent in closely related bat and pangolin coronaviruses. Whether bat-like coronaviral variants without PRRA (∆PRRA) can establish natural infections in humans is unknown. METHODS: Here, we developed a duplex digital polymerase chain reaction assay to examine ∆PRRA variants in Vero-E6-propagated isolates, human organoids, experimentally infected hamsters, and coronavirus disease 2019 (COVID-19) patients. RESULTS: We found that SARS-CoV-2, as currently transmitting in humans, contained a quasispecies of wild-type, ∆PRRA variants and variants that have mutations upstream of the PRRA motif. Moreover, the ∆PRRA variants were readily detected despite being at a low intra-host frequency in transmitted founder viruses in hamsters and in COVID-19 patients, including in acute cases and a family cluster, with a prevalence rate of 52.9%. CONCLUSIONS: Our findings demonstrate that bat-like SARS-CoV-2ΔPRRA not only naturally exists but remains transmissible in COVID-19 patients, which has significant implications regarding the zoonotic origin and natural evolution of SARS-CoV-2.


Subject(s)
COVID-19 , Chiroptera , Alanine , Animals , Arginine , Humans , Proline , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics
6.
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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