Rapid Generation of Neutralizing Antibody Responses in COVID-19 Patients.
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ABSTRACT:
SUBMITTER: Suthar MS
PROVIDER: S-EPMC7276302 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Passive transfer of antibodies from COVID-19 convalescent patients is being used as an experimental treatment for eligible patients with SARS-CoV-2 infections. The United States Food and Drug Administration's (FDA) guidelines for convalescent plasma initially recommended target antibody titers of 160. We evaluated SARS-CoV-2 neutralizing antibodies in sera from recovered COVID-19 patients using plaque reduction neutralization tests (PRNT) at moderate (PRNT50) and high (PRNT90) stringency thresholds. We found that neutralizing activity significantly increased with time post symptom onset (PSO), reaching a peak at 31-35 days PSO. At this point, the number of sera having neutralizing titers of at least 160 was ~93% (PRNT50) and ~54% (PRNT90). Sera with high SARS-CoV-2 antibody levels (>960 ELISA titers) showed maximal activity, but not all high titer sera contained neutralizing antibody at FDA recommended levels, particularly at high stringency. These results underscore the value of serum characterization for neutralization activity.
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Project description:PurposeNeutralizing antibodies (NAbs) have been considered effective in preventing and treating viral infections. However, until now, the duration and clinical implications of antibody-mediated nature immunity in Koreans have remained unknown. Therefore, we examined NAbs levels and clinical characteristics in recovered coronavirus disease 2019 (COVID-19) patients.Materials and methodsBlood samples were collected from 143 adult patients who had been diagnosed with and had recovered from COVID-19 from February to March in 2020 at a tertiary-care university-affiliated hospital in Daegu, Korea. A plaque reduction neutralization test was conducted to analyze NAb titers. Individualized questionnaires were used to identify patient clinical information.ResultsThe median number of days from symptom onset to the blood collection date was 109.0 (104.0; 115.0). The NAb titers ranged from 10 to 2560. The median NAb titer value was 40. Of the 143 patients, 68 (47.6%) patients had NAb titers ≥80, and 31 (21.7%) patients had NAb titers ≥160. The higher the age or disease severity, the higher the NAb titer. In univariate logistic regression, statistically significant predictors of high NAb titers (≥80) were age, myalgia, nausea or vomiting, dyspnea, and disease severity (p<0.05). Multivariable logistic regression showed that age ≥50 years (p=0.013) and moderate or higher disease severity (p<0.001) were factors associated with high NAb titers (≥80). None of the patients had reinfection of COVID-19.ConclusionAll recovered patients were found to have NAbs regardless of the NAb titers maintained by natural immunity. Age and disease severity during COVID-19 infection were associated with high NAb titers.
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Project description:A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. To study the biology of afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc-gamma receptor (FcγR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from patients with COVID-19 induced inflammatory cytokine production and robust infiltration of the lung by immune cells. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by messenger RNA SARS-CoV-2 vaccines were highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. Vaccine-elicited IgG did not promote an inflammatory lung response. These results show that human IgG-FcγR interactions regulate inflammation in the lung and define distinct lung activities mediated by the IgG that are associated with protection against, or progression to, severe COVID-19.
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Project description:BackgroundLY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.MethodsIn this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.ResultsOn October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P?=?0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P?=?0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).ConclusionsMonoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).
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Project description:Our understanding of the protective immunity, particularly the long-term dynamics of neutralizing antibody (NAbs) response to SARS-CoV-2, is currently limited. We enrolled a cohort of 545 COVID-19 patients from Hubei, China, who were followed up up to 7 months, and determined the dynamics of NAbs to SARS-CoV-2 by using a surrogate virus neutralization test (sVNT). In our validation study, sVNT IC50 titers and the neutralization rate measured at a single dilution (1:20) were well correlated with FRNT titers (r = 0.85 and 0.84, respectively). The median time to seroconversion of NAbs was 5.5 days post onset of symptoms. The rate of positive sVNT was 52% in the first week, reached 100% in the third week, and remained above 97% till 6 months post onset. Quantitatively, NAbs peaked in the fourth week and only a quarter of patients had an estimated peak titer of >1000. NAbs declined with a half-time of 61 days (95% CI: 49-80 days) within the first two months, and the decay deaccelerated to a half-time of 104 days (95% CI: 86-130 days) afterward. The peak levels of NAbs were positively associated with severity of COVID-19 and age, while negatively associated with serum albumin levels. The observation that the low-moderate peak neutralizing activity and fast decay of NAbs in most naturally infected individuals called for caution in evaluating the feasibility of antibody-based therapy and vaccine durability. NAbs response positively correlated with disease severity, warning for the possibility of repeat infection in patients with mild COVID-19.
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Project description:The emergence of SARS-CoV-2 and subsequent COVID-19 pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. In this article, we review the role of SARS-CoV-2 neutralizing antibodies (nAbs) in the clinical management of COVID-19 and provide an overview of recent randomized controlled trial data evaluating nAbs in the ambulatory, hospitalized and prophylaxis settings. Two nAb cocktails (casirivimab/imdevimab and bamlanivimab/etesevimab) and one nAb monotherapy (bamlanivimab) have been granted Emergency Use Authorization by the US Food and Drug Administration for the treatment of ambulatory patients who have a high risk of progressing to severe disease, and the European Medicines Agency has similarly recommended both cocktails and bamlanivimab monotherapy for use in COVID-19 patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19. Efficacy of nAbs in hospitalized patients with COVID-19 has been varied, potentially highlighting the challenges of antiviral treatment in patients who have already progressed to severe disease. However, early data suggest a promising prophylactic role for nAbs in providing effective COVID-19 protection. We also review the risk of treatment-emergent antiviral resistant "escape" mutants and strategies to minimize their occurrence, discuss the susceptibility of newly emerging SARS-COV-2 variants to nAbs, as well as explore administration challenges and ways to improve patient access.
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Project description:COVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection. It is currently unknown as to the correlation between the magnitude of neutralizing antibody (NAb) responses and the disease severity in COVID-19 patients. In a cohort of 59 recovered patients with disease severity including severe, moderate, mild, and asymptomatic, we observed the positive correlation between serum neutralizing capacity and disease severity, in particular, the highest NAb capacity in sera from the patients with severe disease, while a lack of ability of asymptomatic patients to mount competent NAbs. Furthermore, the compositions of NAb subtypes were also different between recovered patients with severe symptoms and with mild-to-moderate symptoms. These results reveal the tremendous heterogeneity of SARS-CoV-2-specific NAb responses and their correlations to disease severity, highlighting the needs of future vaccination in COVID-19 patients recovered from asymptomatic or mild illness.
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