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Middle East respiratory syndrome coronavirus (MERS-CoV) first emerged in 2012 and causes human infections in endemic regions. Vaccines and therapeutics in development against MERS-CoV focus on the spike (S) glycoprotein to prevent viral entry into target cells. These efforts are limited by a poor understanding of antibody responses elicited by infection. Here, we analyze S-directed antibody responses in plasma collected from MERS-CoV-infected individuals. We observe that binding and neutralizing antibodies peak 1-6 weeks after symptom onset/hospitalization, persist for at least 6 months, and neutralize human and camel MERS-CoV strains. We show that the MERS-CoV S1 subunit is immunodominant and that antibodies targeting S1, particularly the receptor-binding domain (RBD), account for most plasma neutralizing activity. Antigenic site mapping reveals that plasma antibodies frequently target RBD epitopes, whereas targeting of S2 subunit epitopes is rare. Our data reveal the humoral immune responses elicited by MERS-CoV infection, which will guide vaccine and therapeutic design.
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Middle-East respiratory syndrome coronavirus (MERS-CoV) first emerged in 2012 and causes human infections in endemic regions. Most vaccines and therapeutics in development against MERS-CoV focus on the spike (S) glycoprotein to prevent viral entry into target cells. These efforts, however, are limited by a poor understanding of antibody responses elicited by infection along with their durability, fine specificity and contribution of distinct S antigenic sites to neutralization. To address this knowledge gap, we analyzed S-directed binding and neutralizing antibody titers in plasma collected from individuals infected with MERS-CoV in 2017-2019 (prior to the COVID-19 pandemic). We observed that binding and neutralizing antibodies peak 1 to 6 weeks after symptom onset/hospitalization, persist for at least 6 months, and broadly neutralize human and camel MERS-CoV strains. We show that the MERS-CoV S1 subunit is immunodominant and that antibodies targeting S1, particularly the RBD, account for most plasma neutralizing activity. Antigenic site mapping revealed that polyclonal plasma antibodies frequently target RBD epitopes, particularly a site exposed irrespective of the S trimer conformation, whereas targeting of S2 subunit epitopes is rare, similar to SARS-CoV-2. Our data reveal in unprecedented details the humoral immune responses elicited by MERS-CoV infection, which will guide vaccine and therapeutic design.
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Background: Type I interferons (IFNs) are essential antiviral cytokines induced upon respiratory exposure to coronaviruses. Defects in type I IFN signaling can result in severe disease upon exposure to respiratory viral infection and are associated with worse clinical outcomes. Neutralizing autoantibodies (auto-Abs) to type I IFNs were reported as a risk factor for life-threatening COVID-19, but their presence has not been evaluated in patients with severe Middle East respiratory syndrome (MERS). Methods: We evaluated the prevalence of type I IFN auto-Abs in a cohort of hospitalized patients with MERS who were enrolled in a placebo-controlled clinical trial for treatment with IFN-ß1b and lopinavir-ritonavir (MIRACLE trial). Samples were tested for type I IFN auto-Abs using a multiplex particle-based assay. Results: Among the 62 enrolled patients, 15 (24.2%) were positive for immunoglobulin G auto-Abs for at least one subtype of type I IFNs. Auto-Abs positive patients were not different from auto-Abs negative patients in age, sex, or comorbidities. However, the majority (93.3%) of patients who were auto-Abs positive were critically ill and admitted to the ICU at the time of enrollment compared to 66% in the auto-Abs negative patients. The effect of treatment with IFN-ß1b and lopinavir-ritonavir did not significantly differ between the two groups. Conclusion: This study demonstrates the presence of type I IFN auto-Abs in hospitalized patients with MERS.
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COVID-19 , Interferon Tipo I , Humanos , Ritonavir/uso terapêutico , Lopinavir/uso terapêutico , Interferon beta-1b/uso terapêutico , AutoanticorposRESUMO
Animal and human data indicate variable effects of interferons in treating coronavirus infections according to inflammatory status and timing of therapy. In this sub-study of the MIRACLE trial (MERS-CoV Infection Treated with a Combination of Lopinavir-Ritonavir and Interferon ß-1b), we evaluated the heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir versus placebo among hospitalized patients with MERS on 90-day mortality, according to cytokine levels and timing of therapy. We measured plasma levels of 17 cytokines at enrollment and tested the treatment effect on 90-day mortality according to cytokine levels (higher versus lower levels using the upper tertile (67%) as a cutoff point) and time to treatment (≤ 7 days versus > 7 days of symptom onset) using interaction tests. Among 70 included patients, 32 received interferon-ß1b and lopinavir-ritonavir and 38 received placebo. Interferon-ß1b and lopinavir-ritonavir reduced mortality in patients with lower IL-2, IL-8 and IL-13 plasma concentrations but not in patients with higher levels (p-value for interaction = 0.09, 0.07, and 0.05, respectively) and with early but not late therapy (p = 0.002). There was no statistically significant heterogeneity of treatment effect according to other cytokine levels. Further work is needed to evaluate whether the assessment of inflammatory status can help in identifying patients with MERS who may benefit from interferon-ß1b and lopinavir-ritonavir. Trial registration: This is a sub-study of the MIRACLE trial (ClinicalTrials.gov number, NCT02845843).
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Infecções por Coronavirus , Ritonavir , Animais , Humanos , Antivirais/uso terapêutico , Citocinas/uso terapêutico , Interferons/uso terapêutico , Lopinavir/uso terapêutico , Ritonavir/uso terapêuticoRESUMO
INTRODUCTION: Management of COVID-19 pneumonia cases is a medical challenge. However, the situation becomes worse if the patient has coexisting morbidities or newly developed complications. The study is about managing rectus sheath haematoma (RSH) in a patient with COVID-19 pneumonia. PRESENTATION OF CASE: The patient was a 75-year-old male, presenting with bilateral COVID-19 pneumonia, with pulmonary embolism complications. Therapeutic anticoagulation by subcutaneous Clexane injection was administered. A left rectus haematoma was observed, and the patient fell and underwent haemorrhagic shock. Laparotomy was done for the evacuation of the haematoma. DISCUSSION: Contrast-enhanced computed tomography (CECT) is an essential tool for diagnosing RSH, identifying the source of bleeding, type of haematoma, and compression of the urinary system. CONCLUSION: Surgical management of RSH in COVID-19 patients is superior to interventional radiology during the rush pandemic period.
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BACKGROUND: Whether combined treatment with recombinant interferon beta-1b and lopinavir-ritonavir reduces mortality among patients hospitalized with Middle East respiratory syndrome (MERS) is unclear. METHODS: We conducted a randomized, adaptive, double-blind, placebo-controlled trial that enrolled patients at nine sites in Saudi Arabia. Hospitalized adults with laboratory-confirmed MERS were randomly assigned to receive recombinant interferon beta-1b plus lopinavir-ritonavir (intervention) or placebo for 14 days. The primary outcome was 90-day all-cause mortality, with a one-sided P-value threshold of 0.025. Prespecified subgroup analyses and safety analyses were conducted. Because of the pandemic of coronavirus disease 2019, the data and safety monitoring board requested an unplanned interim analysis and subsequently recommended the termination of enrollment and the reporting of the results. RESULTS: A total of 95 patients were enrolled; 43 patients were assigned to the intervention group and 52 to the placebo group. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. The analysis of the primary outcome, with accounting for the adaptive design, yielded a risk difference of -19 percentage points (upper boundary of the 97.5% confidence interval [CI], -3; one-sided P = 0.024). In a prespecified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Serious adverse events occurred in 4 patients (9%) in the intervention group and in 10 (19%) in the placebo group. CONCLUSIONS: A combination of recombinant interferon beta-1b and lopinavir-ritonavir led to lower mortality than placebo among patients who had been hospitalized with laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset. (Funded by the King Abdullah International Medical Research Center; MIRACLE ClinicalTrials.gov number, NCT02845843.).
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Infecções por Coronavirus/tratamento farmacológico , Interferon beta-1b/uso terapêutico , Lopinavir/uso terapêutico , Ritonavir/uso terapêutico , Administração Oral , Adulto , Idoso , Infecções por Coronavirus/mortalidade , Método Duplo-Cego , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Hospitalização , Humanos , Injeções Subcutâneas , Interferon beta-1b/efeitos adversos , Estimativa de Kaplan-Meier , Lopinavir/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ritonavir/efeitos adversos , Estatísticas não Paramétricas , Tempo para o TratamentoRESUMO
The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-ß1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-ß1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02845843. Registered on 27 July 2016.