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1.
Commun Biol ; 4(1): 1196, 2021 10 13.
Article in English | MEDLINE | ID: covidwho-1467140

ABSTRACT

Emerging mutations in SARS-CoV-2 cause several waves of COVID-19 pandemic. Here we investigate the infectivity and antigenicity of ten emerging SARS-CoV-2 variants-B.1.1.298, B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), P.2(Zeta), B.1.429(Epsilon), B.1.525(Eta), B.1.526-1(Iota), B.1.526-2(Iota), B.1.1.318-and seven corresponding single amino acid mutations in the receptor-binding domain using SARS-CoV-2 pseudovirus. The results indicate that the pseudovirus of most of the SARS-CoV-2 variants (except B.1.1.298) display slightly increased infectivity in human and monkey cell lines, especially B.1.351, B.1.525 and B.1.526 in Calu-3 cells. The K417N/T, N501Y, or E484K-carrying variants exhibit significantly increased abilities to infect mouse ACE2-overexpressing cells. The activities of furin, TMPRSS2, and cathepsin L are increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y cause significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines elicited serum is mainly caused by the E484K mutation. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants. Our study provides insights regarding therapeutic antibodies and vaccines, and highlights the importance of E484K mutation.


Subject(s)
COVID-19/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/therapy , Cell Line , HEK293 Cells , Humans , Immunization, Passive/methods , Mammals/immunology , Mice , Mutation , Pandemics , Primates/immunology , Protein Binding , Tropism/genetics
2.
Emerg Microbes Infect ; 10(1): 1881-1889, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1398037

ABSTRACT

SARS-CoV-2 has been the causative pathogen of the pandemic of COVID-19, resulting in catastrophic health issues globally. It is important to develop human-like animal models for investigating the mechanisms that SARS-CoV-2 uses to infect humans and cause COVID-19. Several studies demonstrated that the non-human primate (NHP) is permissive for SARS-CoV-2 infection to cause typical clinical symptoms including fever, cough, breathing difficulty, and other diagnostic abnormalities such as immunopathogenesis and hyperplastic lesions in the lung. These NHP models have been used for investigating the potential infection route and host immune response to SARS-CoV-2, as well as testing vaccines and drugs. This review aims to summarize the benefits and caveats of NHP models currently available for SARS-CoV-2, and to discuss key topics including model optimization, extended application, and clinical translation.


Subject(s)
COVID-19/virology , Disease Models, Animal , Primates/virology , SARS-CoV-2/physiology , Animals , Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/immunology , COVID-19/pathology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Humans , Primates/immunology , SARS-CoV-2/genetics
3.
Cell Rep Med ; 2(9): 100405, 2021 09 21.
Article in English | MEDLINE | ID: covidwho-1377862

ABSTRACT

Recently approved vaccines have shown remarkable efficacy in limiting SARS-CoV-2-associated disease. However, with the variety of vaccines, immunization strategies, and waning antibody titers, defining the correlates of immunity across a spectrum of antibody titers is urgently required. Thus, we profiled the humoral immune response in a cohort of non-human primates immunized with a recombinant SARS-CoV-2 spike glycoprotein (NVX-CoV2373) at two doses, administered as a single- or two-dose regimen. Both antigen dose and boosting significantly altered neutralization titers and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were associated with distinct levels of protection in the upper and lower respiratory tract. Moreover, NVX-CoV2373 elicited antibodies that functionally targeted emerging SARS-CoV-2 variants. Collectively, the data presented here suggest that a single dose may prevent disease via combined Fc/Fab functions but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.


Subject(s)
COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , Saponins/immunology , Animals , Antibodies, Neutralizing/drug effects , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , Dose-Response Relationship, Immunologic , Female , Immunity, Humoral/immunology , Immunogenicity, Vaccine , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fc Fragments/immunology , Macaca mulatta , Male , Nanoparticles , Primates/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus , Vaccination
4.
Nat Immunol ; 22(10): 1306-1315, 2021 10.
Article in English | MEDLINE | ID: covidwho-1366822

ABSTRACT

B.1.351 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence protection. Nonhuman primates received two doses of 30 or 100 µg of Moderna's mRNA-1273 vaccine, a single immunization of 30 µg, or no vaccine. Two doses of 100 µg of mRNA-1273 induced 50% inhibitory reciprocal serum dilution neutralizing antibody titers against live SARS-CoV-2 p.Asp614Gly and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. After challenge with B.1.351, there was ~4- to 5-log10 reduction of viral subgenomic RNA and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1-log10 reduction in nasal swabs in the 100-µg group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Primates/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Cell Line , Chlorocebus aethiops , Female , Humans , Macaca mulatta , Male , Mesocricetus , Primates/virology , RNA, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods , Vero Cells , Viral Load/methods
5.
Sci Transl Med ; 13(583)2021 03 03.
Article in English | MEDLINE | ID: covidwho-1117652

ABSTRACT

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus-associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.


Subject(s)
Hemagglutinin Glycoproteins, Influenza Virus/immunology , Influenza Vaccines/immunology , Primates/immunology , Animals , Antibodies, Viral/biosynthesis , Antibodies, Viral/chemistry , Antigen-Antibody Complex/chemistry , Broadly Neutralizing Antibodies/biosynthesis , Broadly Neutralizing Antibodies/chemistry , COVID-19 , Ferritins/chemistry , Ferritins/immunology , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Humans , Influenza Vaccines/administration & dosage , Influenza Vaccines/chemistry , Influenza, Human/immunology , Influenza, Human/virology , Macaca fascicularis , Models, Molecular , Nanoparticles/chemistry , Pandemics , Primates/virology , Protein Structure, Quaternary , SARS-CoV-2
6.
Cell Rep ; 34(10): 108837, 2021 03 09.
Article in English | MEDLINE | ID: covidwho-1095904

ABSTRACT

Passive transfer of convalescent plasma or serum is a time-honored strategy for treating infectious diseases. Human convalescent plasma containing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently being used to treat patients with coronavirus disease 2019 where clinical efficacy trials are ongoing. Here, we assess therapeutic passive transfer in groups of SARS-CoV-2-infected African green monkeys with convalescent sera containing either high or low anti-SARS-CoV-2 neutralizing antibody titers. Differences in viral load and pathology are minimal between monkeys that receive the lower titer convalescent sera and untreated controls. However, lower levels of SARS-CoV-2 in respiratory compartments, reduced severity of virus-associated lung pathology, and reductions in coagulopathy and inflammatory processes are observed in monkeys that receive high titer sera versus untreated controls. Our data indicate that convalescent plasma therapy in humans may be an effective strategy provided that donor sera contain high anti-SARS-CoV-2 neutralizing titers given in early stages of the disease.


Subject(s)
COVID-19/therapy , COVID-19/veterinary , Primate Diseases/therapy , Primate Diseases/virology , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , COVID-19/virology , Chlorocebus aethiops/immunology , Female , Immunization, Passive/methods , Immunization, Passive/veterinary , Male , Primate Diseases/immunology , Primates/immunology , Viral Load
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