Background
Interferon resistance has been implicated in SARS-CoV-2 escape from innate immune responses, but interferon’s specific impact on viral evolution is unknown. SNG001 is an inhaled interferon-β1a treatment for COVID-19 which was evaluated in the ACTIV-2/A5401 randomized placebo-controlled trial. Although SNG001 did not accelerate viral decay, there was a trend towards fewer hospitalizations in the treated group. Sequence analysis of samples collected in ACTIV-2 provide a rare opportunity to investigate SARS-CoV-2 evolution and diversity in response to exogenous interferon treatment.
Methods
The study population included 220 adult outpatients with COVID-19 enrolled in ACTIV-2/A5401 and randomized to receive either SNG001 (n=110) or placebo (n=110). Participants collected nasal swabs on days 0, 3, 7, 14, and 28 for SARS-CoV-2 viral load (VL) testing. Whole genome sequencing was performed on specimens with VLs ≥2 log10 copies/mL. Viral sequences were analyzed for diversity using average pairwise distance (APD) and for the emergence of amino acid polymorphisms by gene and treatment arm. Results were analyzed using Wilcoxon Rank Sum Tests.
Results
Overall, 187 participants (SNG001 n=99; placebo n=88) had a quantifiable baseline VL which could be used to generate a variant call. The Alpha, Delta, and other variants comprised 28%, 40%, and 32% of infections, respectively. The viral diversity analyses included 136 participants with quantifiable baseline VL and ≥1 follow up timepoint (SNG001 n=75, 180 timepoints; placebo n = 61, 150 timepoints). There was lower amino acid diversity in the inhaled interferon recipients (SNG001 vs placebo, median APD 7.03×10-5 vs 10.40×10-5, p=0.056). Individuals receiving SNG001 had significantly lower numbers of emerging mutations than the placebo group for the ORF1a (SNG001 vs placebo, median 1.51×10-4 vs 4.54×10-4 mutations per Kb, p=0.04), ORF3a (1.21×10-3 vs 2.42×10-3 per Kb, p=0.03), and Spike (5.23×10-4 vs 11.77×10-4 per Kb, p=0.04) genes. No specific emerging SARS-CoV-2 amino acid changes were enriched in the SNG001 recipients.
Conclusions
Treatment with inhaled SNG001 was associated with lower viral sequence diversity and less frequent emerging amino acid polymorphisms in SARS-CoV-2 isolated from nasal swabs. These results provide some of the first in vivo data on the virologic effects of exogenous interferon exposure in COVID-19 and provide intriguing evidence that interferon may prevent SARS-CoV-2 diversification and escape.
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