Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta-1b in MIRACLE clinical trial

Abstract

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-β1b 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-β1b 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.

Keywords: ICU; MERS; MIRACLE trial; Type I IFNs; auto‐abs.

FIGURE 1

Multiplex particle‐based assay for autoantibodies (auto‐Abs) against interferon (IFN)‐α2, IFN‐β, and IFN‐ω in hospitalized patients with Middle East respiratory syndrome (MERS) (n = 62). Samples with fluorescence intensity (FI) of >800 for IFN‐α2 and IFN‐ω or >600 for IFN‐β were considered positive for auto‐Abs. Data are mean ± SEM.

FIGURE 2

(A) Distribution of the number of positive samples for patients with immunoglobulin G autoantibodies (auto‐Abs) for more than one subtype of type I interferons (IFNs) (IFN‐α2, IFN‐ω, and IFN‐β) and (IFN‐α2 and IFN‐ω) and patients with immunoglobulin G auto‐Abs for only one subtype of type I IFNs. (B) Distribution of auto‐Ab titers of patients with positive auto‐Abs samples and mortality.

FIGURE 3

Increased MERS pseudotyped viral particles' (MERSpp) infection, despite the presence of interferon (IFN)‐α2, in the presence of plasma with autoantibodies (auto‐Abs) targeting IFN‐α2. MERSpp infection measured 48 h after infection in Huh7.5 cells treated with IFN‐α2 in the presence of plasma from patients with auto‐Abs or without auto‐Abs. Samples from patients with positive auto‐Abs for IFN‐α2 (n = 9) and samples from patients with negative auto‐Abs for type I IFNs (n = 4). Asterisks represent statistical significance p ≤ 0.05 (Mann–Whitney test).