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2.
Science ; 375(6576): 43-50, 2022 Jan 07.
Article in English | MEDLINE | ID: covidwho-1649486

ABSTRACT

In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These immune markers were measured at the time of second vaccination and 4 weeks later, with values reported in standardized World Health Organization international units. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. Vaccine recipients with postvaccination 50% neutralization titers 10, 100, and 1000 had estimated vaccine efficacies of 78% (95% confidence interval, 54 to 89%), 91% (87 to 94%), and 96% (94 to 98%), respectively. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines.


Subject(s)
2019-nCoV Vaccine mRNA-1273/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , SARS-CoV-2/immunology , Vaccine Efficacy , Adolescent , Adult , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Clinical Trials, Phase III as Topic , Female , Humans , Immunogenicity, Vaccine , Male , Middle Aged , Randomized Controlled Trials as Topic , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/immunology , Young Adult
3.
Sci Rep ; 11(1): 23921, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1585804

ABSTRACT

Vaccine-induced neutralizing antibodies (nAbs) are key biomarkers considered to be associated with vaccine efficacy. In United States government-sponsored phase 3 efficacy trials of COVID-19 vaccines, nAbs are measured by two different validated pseudovirus-based SARS-CoV-2 neutralization assays, with each trial using one of the two assays. Here we describe and compare the nAb titers obtained in the two assays. We observe that one assay consistently yielded higher nAb titers than the other when both assays were performed on the World Health Organization's anti-SARS-CoV-2 immunoglobulin International Standard, COVID-19 convalescent sera, and mRNA-1273 vaccinee sera. To overcome the challenge this difference in readout poses in comparing/combining data from the two assays, we evaluate three calibration approaches and show that readouts from the two assays can be calibrated to a common scale. These results may aid decision-making based on data from these assays for the evaluation and licensure of new or adapted COVID-19 vaccines.


Subject(s)
Antibodies, Neutralizing/blood , COVID-19/immunology , Neutralization Tests/standards , SARS-CoV-2/immunology , /immunology , Antibodies, Viral/blood , COVID-19/blood , Clinical Decision-Making , Clinical Trials as Topic , Diagnostic Tests, Routine , Humans , Neutralization Tests/methods , World Health Organization
4.
Nat Commun ; 12(1): 6097, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1475295

ABSTRACT

Effective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/drug therapy , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Monoclonal/pharmacokinetics , Antiviral Agents/pharmacokinetics , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Lung/metabolism , Lung/virology , Macaca fascicularis , Male , Mesocricetus , Mice , Mice, Transgenic , SARS-CoV-2/isolation & purification , Tissue Distribution , Viral Load
5.
Science ; 373(6561): eabj0299, 2021 Sep 17.
Article in English | MEDLINE | ID: covidwho-1334532

ABSTRACT

Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. Here, nonhuman primates (NHPs) received either no vaccine or doses ranging from 0.3 to 100 µg of the mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. mRNA-1273 vaccination elicited circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs after SARS-CoV-2 challenge in vaccinated animals and most strongly correlated with levels of anti­S antibody and neutralizing activity. Lower antibody levels were needed for reduction of viral replication in the lower airway than in the upper airway. Passive transfer of mRNA-1273­induced immunoglobulin G to naïve hamsters was sufficient to mediate protection. Thus, mRNA-1273 vaccine­induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 in NHPs.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Affinity , Bronchoalveolar Lavage Fluid/immunology , Bronchoalveolar Lavage Fluid/virology , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/virology , Female , Immunization Schedule , Immunization, Passive , Immunization, Secondary , Immunoglobulin G/immunology , Immunologic Memory , Lung/immunology , Lung/virology , Macaca mulatta , Male , Mesocricetus , Nasal Mucosa/immunology , Nasal Mucosa/virology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Vaccine Potency , Virus Replication
6.
Cell Host Microbe ; 29(4): 529-539.e3, 2021 04 14.
Article in English | MEDLINE | ID: covidwho-1309188

ABSTRACT

All current vaccines for COVID-19 utilize ancestral SARS-CoV-2 spike with the goal of generating protective neutralizing antibodies. The recent emergence and rapid spread of several SARS-CoV-2 variants carrying multiple spike mutations raise concerns about possible immune escape. One variant, first identified in the United Kingdom (B.1.1.7, also called 20I/501Y.V1), contains eight spike mutations with potential to impact antibody therapy, vaccine efficacy, and risk of reinfection. Here, we show that B.1.1.7 remains sensitive to neutralization, albeit at moderately reduced levels (∼sim;2-fold), by serum samples from convalescent individuals and recipients of an mRNA vaccine (mRNA-1273, Moderna) and a protein nanoparticle vaccine (NVX-CoV2373, Novavax). A subset of monoclonal antibodies to the receptor binding domain (RBD) of spike are less effective against the variant, while others are largely unaffected. These findings indicate that variant B.1.1.7 is unlikely to be a major concern for current vaccines or for an increased risk of reinfection.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , 2019-nCoV Vaccine mRNA-1273 , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/immunology , Female , Humans , Male , Middle Aged , Mutation , Neutralization Tests , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Young Adult
7.
Cell ; 184(16): 4203-4219.e32, 2021 08 05.
Article in English | MEDLINE | ID: covidwho-1275187

ABSTRACT

SARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo, increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques.


Subject(s)
Antibodies, Neutralizing/immunology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Viral/immunology , Bronchoalveolar Lavage Fluid/chemistry , COVID-19/pathology , COVID-19/virology , Cytokines/metabolism , Female , Haplorhini , Humans , Lung/pathology , Lung/virology , Male , Mice , Mice, Inbred BALB C , Protein Domains , RNA, Guide/metabolism , Receptors, IgG/metabolism , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Viral Load , Virus Replication
8.
Cell Host Microbe ; 29(1): 23-31.e4, 2021 01 13.
Article in English | MEDLINE | ID: covidwho-956078

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein acquired a D614G mutation early in the pandemic that confers greater infectivity and is now the globally dominant form. To determine whether D614G might also mediate neutralization escape that could compromise vaccine efficacy, sera from spike-immunized mice, nonhuman primates, and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 spike. In all cases, the G614 pseudovirus was moderately more susceptible to neutralization. The G614 pseudovirus also was more susceptible to neutralization by receptor-binding domain (RBD) monoclonal antibodies and convalescent sera from people infected with either form of the virus. Negative stain electron microscopy revealed a higher percentage of the 1-RBD "up" conformation in the G614 spike, suggesting increased epitope exposure as a mechanism of enhanced vulnerability to neutralization. Based on these findings, the D614G mutation is not expected to be an obstacle for current vaccine development.


Subject(s)
COVID-19/therapy , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Animals , Antibodies, Monoclonal/immunology , Binding Sites , COVID-19/immunology , COVID-19 Vaccines/immunology , Female , HEK293 Cells , Humans , Immunization, Passive/methods , Macaca mulatta , Male , Mice, Inbred BALB C , Middle Aged , Neutralization Tests , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Young Adult
9.
Cell ; 182(4): 812-827.e19, 2020 08 20.
Article in English | MEDLINE | ID: covidwho-628613

ABSTRACT

A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic. Dynamic tracking of variant frequencies revealed a recurrent pattern of G614 increase at multiple geographic levels: national, regional, and municipal. The shift occurred even in local epidemics where the original D614 form was well established prior to introduction of the G614 variant. The consistency of this pattern was highly statistically significant, suggesting that the G614 variant may have a fitness advantage. We found that the G614 variant grows to a higher titer as pseudotyped virions. In infected individuals, G614 is associated with lower RT-PCR cycle thresholds, suggestive of higher upper respiratory tract viral loads, but not with increased disease severity. These findings illuminate changes important for a mechanistic understanding of the virus and support continuing surveillance of Spike mutations to aid with development of immunological interventions.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/genetics , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Epidemiological Monitoring , Genetic Fitness , Genetic Variation , Geographic Information Systems , Hospitalization , Humans , Pandemics , Phylogeny , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Respiratory System/virology , SARS-CoV-2 , Severity of Illness Index , Viral Load
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