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


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.

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
Commun Biol ; 4(1): 1102, 2021 09 20.
Article in English | MEDLINE | ID: covidwho-1428909


Emerging variants of SARS-CoV-2 have been shown to rapidly replace original circulating strains in humans soon after they emerged. There is a lack of experimental evidence to explain how these natural occurring variants spread more efficiently than existing strains of SARS-CoV-2 in transmission. We found that the Alpha variant (B.1.1.7) increased competitive fitness over earlier parental D614G lineages in in-vitro and in-vivo systems. Using hamster transmission model, we further demonstrated that the Alpha variant is able to replicate and shed more efficiently in the nasal cavity of hamsters than other variants with low dose and short duration of exposure. The capability to initiate effective infection with low inocula may be one of the key factors leading to the rapid transmission of emerging variants of SARS-CoV-2.

COVID-19/genetics , SARS-CoV-2/genetics , Virus Replication/genetics , Animals , COVID-19/pathology , COVID-19/transmission , Cell Line/virology , Cricetinae , Disease Models, Animal , Humans , SARS-CoV-2/pathogenicity
Nat Commun ; 12(1): 2790, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1387341


SARS-CoV-2 is of zoonotic origin and contains a PRRA polybasic cleavage motif which is considered critical for efficient infection and transmission in humans. We previously reported on a panel of attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction of the spike protein. Here, we characterize pathogenicity, immunogenicity, and protective ability of a further cell-adapted SARS-CoV-2 variant, Ca-DelMut, in in vitro and in vivo systems. Ca-DelMut replicates more efficiently than wild type or parental virus in Vero E6 cells, but causes no apparent disease in hamsters, despite replicating in respiratory tissues. Unlike wild type virus, Ca-DelMut causes no obvious pathological changes and does not induce elevation of proinflammatory cytokines, but still triggers a strong neutralizing antibody and T cell response in hamsters and mice. Ca-DelMut immunized hamsters challenged with wild type SARS-CoV-2 are fully protected, with little sign of virus replication in the upper or lower respiratory tract, demonstrating sterilizing immunity.

COVID-19/diagnosis , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Virus Replication/genetics , Animals , COVID-19/immunology , COVID-19/virology , Cell Line, Tumor , Chlorocebus aethiops , Cricetinae , Cytokines/immunology , Cytokines/metabolism , Female , Host-Pathogen Interactions , Humans , Male , Mesocricetus , Mice, Inbred BALB C , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Vero Cells , Virulence/genetics , Virulence/immunology