A cluster randomized trial of interferon ß-1a for the reduction of transmission of SARS-Cov-2: protocol for the Containing Coronavirus Disease 19 trial (ConCorD-19)

Iturriaga, Carolina; Eiffler, Nat; Aniba, Rad; Ben‐Othman, Rym; Pérez-Mateluna, Guillermo; Meyer, Jessica K. V.; Fish, Eleanor N.; Kollmann, Tobias R.; Severino, Nicolás; Stick, Stephen M.; Borzutzky, Arturo; Perret, Cecilia; Castro-Rodriguez, José; García-Huidobro, Diego

doi:10.1186/s12879-021-06519-4

Cited by 5 publications

(9 citation statements)

References 14 publications

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“…This is supported by results from our study where COVID-19 patients with elevated ISG expression did not respond to ex vivo IFN stimulation, and hospitalized patients in particular showed an inflammatory gene expression pattern that was not down regulated by IFN-I. Direct testing of this hypothesis may be provided by clinical studies testing early intervention prior to appearance of symptoms 35 or targeted to patients with known risk factors 36 , or retrospective testing of pre-treatment IFN-I levels. Reflecting multiple perturbations in the IFN-I response with increasing COVID-19 severity was our striking observation that severe patients failed to secrete IFN-I proteins after stimulation with diverse viral agonists.…”

Section: Discussionsupporting

confidence: 57%

Defective type I interferon immunity is associated with increasing COVID-19 severity

Duffy

Smith

Posseme

et al. 2022

Preprint

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Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported that reduced blood type I interferon (IFN-I) in severe COVID-19 patients preceded clinical worsening. These results were supported by studies which identified genetic mutations in loci of the TLR3- or TLR7-dependent IFN-I pathways, or autoantibodies neutralizing IFNα or IFNω, as major risk factors for development of severe and critical COVID-19 pneumonia. Here, we analyzed a range of IFN-I associated responses in patient cohorts with different severities of COVID-19, showing that baseline plasma IFNα measures differed significantly according to the immunoassay used, as well as timing of sampling, the IFNα subtype measured, and the presence of autoantibodies. We then compared immune responses induced by ex vivo stimulation between non-hospitalized moderate cases (n=27) and hospitalized (n=17) adult patients that required oxygen supplementation. This showed a consistently reduced induction of IFN-I proteins in hospitalized COVID-19 patients upon stimulation, that was not associated with detectable neutralizing autoantibodies against IFNα or IFNω. We confirmed the poor induction of IFN-I in an independent patient cohort (n=33), and showed it was more pronounced with severe disease. Intracellular proteomic analysis showed that while monocyte numbers were increased in hospitalized COVID-19 patients, they did not secrete IFN-I in response to stimulation. This was further confirmed by ex vivo whole blood stimulation with IFN-I which induced a transcriptomic response associated with inflammation in hospitalized COVID-19 patients, that was not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to IFN-I based treatments in late stage COVID-19, despite the critical importance of IFN-I in early acute infection. An improved understanding of such variable responses to treatment may help to identify potential alternative therapeutic strategies.

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Section: Discussionsupporting

confidence: 57%

Defective type I interferon immunity is associated with increasing COVID-19 severity

Duffy

Smith

Posseme

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…This is supported by results from our study where COVID-19 patients with elevated ISG expression did not respond to ex vivo IFN stimulation, and hospitalized patients in particular showed an inflammatory gene expression pattern that was not downregulated by IFN-I. Direct testing of this hypothesis may be provided by clinical studies testing early intervention prior to the appearance of symptoms 33 or targeted to patients with known risk factors 34 , or retrospective testing of pre-treatment IFN-I levels. Reflecting multiple perturbations in the IFN-I response with increasing COVID-19 severity was our striking observation that severe patients failed to secrete IFN-I proteins after stimulation with diverse viral agonists.…”

Section: Discussionsupporting

confidence: 56%

Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity

et al. 2022

View full text Add to dashboard Cite

Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported reduced type I interferon in severe COVID-19 patients preceded clinical worsening. Further studies identified genetic mutations in loci of the TLR3- or TLR7-dependent interferon-I pathways, or neutralizing interferon-I autoantibodies as risk factors for development of COVID-19 pneumonia. Here we show in patient cohorts with different severities of COVID-19, that baseline plasma interferon α measures differ according to the immunoassay used, timing of sampling, the interferon α subtype measured, and the presence of autoantibodies. We also show a consistently reduced induction of interferon-I proteins in hospitalized COVID-19 patients upon immune stimulation, that is not associated with detectable neutralizing autoantibodies against interferon α or interferon ω. Intracellular proteomic analysis shows increased monocyte numbers in hospitalized COVID-19 patients but impaired interferon-I response after stimulation. We confirm this by ex vivo whole blood stimulation with interferon-I which induces transcriptomic responses associated with inflammation in hospitalized COVID-19 patients, that is not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to interferon-I based treatments in late stage COVID-19, despite the importance of interferon-I in early acute infection and may guide alternative therapeutic strategies.

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“…The Containing Coronavirus Disease-19 (ConCorD-19) trial was a prospective, cluster, randomized trial of subcutaneous (sc) administration of pegylated IFNß-1α (Plegridy, Biogen Inc, Switzerland) versus standard care (control) 29 . Each household of an index case was randomized to either the IFNß-1α treatment or the standard care control arm.…”

Section: Methodsmentioning

confidence: 99%

“…Households were contacted by telephone to determine eligibility prior to enrolment. Individuals aged between 18 and 80 years who met inclusion and exclusion criteria were deemed as ‘eligible’ contacts with households only included if there was at least one eligible contact 29 . Enrolment and the first doses of IFNß-1α - if in the intervention arm- had to be within 72 hours of the positive identification of SARS-CoV-2 by polymerase chain reaction (PCR) in index cases.…”

Section: Methodsmentioning

confidence: 99%

“…Enrolment and the first doses of IFNß-1α - if in the intervention arm- had to be within 72 hours of the positive identification of SARS-CoV-2 by polymerase chain reaction (PCR) in index cases. A household was excluded if the index case had been in complete self-quarantine from other household members during the 48 hours prior to the diagnosis of SARS-CoV-2 infection 29 . Household characteristics were captured consistent with recommendations of the World Health Organization for assessing household transmission 30 .…”

Section: Methodsmentioning

confidence: 99%

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Interferon Beta-1α ring prophylaxis to reduce household transmission of SARS-CoV-2: the Containing Coronavirus Disease-19 randomized clinical trial

Castro-Rodriguez

Fish

Kollmann

et al. 2022

Preprint

Self Cite

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Background Evidence suggests that early, robust type 1 interferon responses to SARS-CoV-2 are critical determinants for COVID-19 disease outcomes, accelerating viral clearance and limiting viral shedding. Accordingly, we undertook a ring prophylaxis study to determine whether pegylated IFNβ-1α could reduce SARS-CoV-2 household transmission. Methods A household cluster randomized controlled study of IFNβ-1α administered to non-hospitalized, symptomatic COVID-19 index cases and treatment-eligible household contacts aged 18-70 years compared to standard care, was conducted. Following randomization participants received IFNβ-1α on days 1, 6, and 11 or standard care. Viral shedding was determined by sequential salivary polymerase chain reaction measurements until day 29 in both study arms. A post-hoc at risk population was defined as households where the index case was positive at the start of the study and there was at least one treatment eligible contact in a household who tested negative for SARS-CoV-2. Frequentist and Bayesian analyses were undertaken to determine the effects of treatment on (i) reducing viral shedding in index cases and (ii) reducing viral transmission to post-exposure household contacts. Results In total, 1172 participants in 341 households underwent randomization, with 607 assigned to receive IFNβ-1α and 565 to standard care. Based on intention to treat and per protocol analyses, IFNβ-1α treatment was ineffective. However, in the at risk population, the relative risk of infection was reduced by 23% in treated individuals and that there was a 95% probability that IFNβ-1α reduced household transmission. Conclusion Ring prophylaxis with IFNβ-1α reduces the probability of SARS-CoV-2 transmission within a household.

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A cluster randomized trial of interferon ß-1a for the reduction of transmission of SARS-Cov-2: protocol for the Containing Coronavirus Disease 19 trial (ConCorD-19)

Cited by 5 publications

References 14 publications

Defective type I interferon immunity is associated with increasing COVID-19 severity

Defective type I interferon immunity is associated with increasing COVID-19 severity

Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity

Interferon Beta-1α ring prophylaxis to reduce household transmission of SARS-CoV-2: the Containing Coronavirus Disease-19 randomized clinical trial

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