Pegylated interferon lambda shows good efficacy against COVID-19

In a recent study published in The New England Journal of Medicine, researchers used the TOGETHER platform trial protocol to perform a phase III randomized controlled trial (RCT) to evaluate the effectiveness of pegylated interferon (IFN) lambda (λ) therapy in outpatients with coronavirus disease 2019 (COVID-19) in Canada and Brazil. They implemented this trial between June 24, 2021, and February 7, 2022. The TOGETHER platform trial evaluated 12 different therapeutic interventions against COVID-19 since its commencement in June 2020.

Study: Early Treatment with Pegylated Interferon Lambda for Covid-19. Image Credit: NIAIDStudy: Early Treatment with Pegylated Interferon Lambda for Covid-19. ​​​​​​​Image Credit: NIAID


Type III IFNs represent the first line of defense in upper respiratory tract (URT) infections, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, SARS-CoV-2 elicits weak expression of type III IFNs. Thus, COVID-19 treatment with an exogenous source, such as pegylated IFN λ, could trigger broad-spectrum antiviral immunity to help treat SARS-CoV-2 infection at an early stage.

Two phase II studies have characterized the influence of pegylated interferon lambda treatment on SARS-CoV-2 viral load. Likewise, over 20 clinical trials covering over 4,000 patients with multiple diseases, including hepatitis B, C, and D, and COVID-19, have shown the safety and side effects of pegylated interferon lambda.

About the study

In the present study, researchers screened patients attending the trial outpatient care clinics to identify adults ≥ 18 years who presented with COVID-19 within seven days of symptom onset or met the high-risk criterion for proceeding to COVID-19 (e.g., older age, type II diabetes, obesity). All patients who met the eligibility criteria provided written informed consent, and trial personnel performed a SARS-CoV-2 rapid antigen test.

Prior to randomization, trial personnel gathered each patient’s sociodemographic characteristics, pre-existing health conditions, and the World Health Organization (WHO) clinical progression scale for COVID-19. A pharmacist randomized all participants using a block randomization procedure at a trial facility, stratifying participants in age-based groups (less than or greater than 50 years) for the administration of pegylated interferon lambda (study group) or placebo.

The treating physicians and other staff involved in the trial remained blinded to the randomized assignments. The primary study outcome was hospitalization due to the progression of COVID-19 or an emergency department (ED) visit within 28 days after randomization. Likewise, they assessed secondary outcomes within 28 days after randomization, which covered SARS-CoV-2 clearance, time lapse since randomization to COVID-19-related hospitalization or death, days spent in hospital or intensive care unit (ICU) with mechanical ventilation, and adverse reactions to treatment or placebo. They recorded adverse events as they occurred and other data on prespecified days. The team performed virological assessments virtually on days three and seven after randomization using mid-turbinate nasal swabs.

The data and safety monitoring committee assessed the safety and efficacy of pegylated interferon lambda therapy vs. placebo based on set thresholds in the statistical plan. They ceased enrolling patients into the study group as soon as they met the prespecified threshold for efficacy. The researchers applied a Bayesian framework to all statistical analyses to present the supremacy of interferon over placebo concerning the primary and the safety outcomes.


Of 2,617 patients recruited in the trial, 933 and 1,018 were randomized to receive interferon treatment and placebo, respectively. The average age of the trial patients was 43 years, and 57.1% were women. Concerning primary outcome, both intention-to-treat and modified intention-to-treat populations yielded similar results.

A primary outcome event ensued in 25/931 patients in the interferon lambda group and 57/1018 of the placebo group, with a relative risk (RR) of 0.49 and 95% Bayesian credible interval (CI) in the former. For the latter, it occurred in 23/929 and 55/1018 patients in the interferon and placebo groups, respectively, with RR of 0.47; 95% Bayesian CI.

The most frequent primary-outcome event was hospitalization, which occurred in a median of five days post-randomization and comprised 74% of all events in the intention-to-treat population. The effect of interferon treatment increased among patients who had received it within three days of symptom onset. Accordingly, only 11/567 and 28/590 patients in the interferon and placebo groups experienced a primary event, with RR of 0.42; 95% Bayesian CI.


This phase III trial demonstrated that a single subcutaneous dose of pegylated interferon lambda administered within a week of the onset of symptoms reduced the risk of a primary outcome event (hospitalization) by more than 50%. It also reduced the time to COVID-19-related hospitalization or death by 41%, hazard ratio (HR) equal to 0.59, 95% Bayesian CI. Among patients who received the treatment within three days after symptom onset, it further reduced to 65%, RR equals 0.42; 95% Bayesian CI.

Intriguingly, among the patients with a baseline viral load >192 million copies per milliliter (high), interferon treatment showed its effect at day 7 only. The median log10 decline in viral loads was 8.29 in the interferon group and 5.16 in the placebo group; the same for hospitalized patients was 7.19 and 3.16 in the interferon and placebo groups, respectively.

To summarize, this large-scale trial involving most COVID-19 vaccinated outpatients with symptomatic COVID-19 showed that a single dose of pegylated interferon lambda reduced the incidence of hospitalization or an ED visit due to COVID-19 regardless of infecting SARS-CoV-2 variant. Thus, this treatment regimen could play a vital role in response to COVID-19.

Journal reference:

  • Early Treatment with Pegylated Interferon Lambda for Covid-19 G. Reis, E.A.S. Moreira Silva, D.C. Medeiros Silva, L. Thabane, V.H.S. Campos, T.S. Ferreira, C.V.Q. Santos, A.M.R. Nogueira, A.P.F.G. Almeida, L.C.M. Savassi, A.D. Figueiredo-Neto, A.C.F. Dias, A.M. Freire Júnior, C. Bitarães, A. C. Milagres, E.D. Callegari, M.I.C. Simplicio, L.B. Ribeiro, R. Oliveira, O. Harari, L.A. Wilson, J.I. Forrest, H. Ruton, S. Sprague, P. McKay, C.M. Guo, E.H. Limbrick-Oldfield, S. Kanters, G.H. Guyatt, C.R. Rayner, C. Kandel, M.J. Biondi, R. Kozak, B. Hansen, M.A. Zahoor, P. Arora, C. Hislop, I. Choong, J.J. Feld, E.J. Mills, and J.S. Glenn, for the TOGETHER Investigators*, N Engl J Med 2023, DOI: 10.1056/NEJMoa2209760,  

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