This is a summary, written by members of the CITF Secretariat, of:

Brunet-Ratnasingham E, Morin S, Randolph HE, Labrecque M, Bélair J, Lima-Barbosa R, Pagliuzza A, Marchitto L, Hultström M, Niessl J, Cloutier R, Flores AMS, Brassard N, Benlarbi M, Prévost J, Ding S, Anand SP, Sannier G, Bareke E,  Zeberg H, Lipcsey M, Frithiof R, Larsson A, Zhou S, Nakanishi T, Morrison D, Vezina D, Bourassa C, Gendron-Lepage G, Medjahed H, Point F, Richard J,  Larochelle C, Prat A, Arbour N, Durand M, Richards JB, Moon K, Chomont N,  Finzi A, Tétreault M, Barreiro L, Wolf G, Kaufmann DE. Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity. medRxiv 2023.06.14.23290814. doi:

The results and/or conclusions contained in the research do not necessarily reflect the views of all CITF members.

A CITF- and CIHR-funded study, published in preprint and not yet peer-reviewed, found that SARS-CoV-2-infected patients experiencing high, sustained interferonInterferons are proteins that are part of our natural defenses, usually in response to the entry of a virus. They have the property of inhibiting virus replication. signaling have a delayed generation of Spike-specific CD4+ T cells and RBD-specific B cells. This directly links to a delay in mounting an antibody response against the virus. In patients who also show increased inflammation, tissue damage, and plasma viral RNA exposure, it is associated with a high risk of death. The study was led by Dr. Daniel Kaufmann (Centre de recherche du Centre hospitalier de l’Université de Montréal) and Dr. Guy Wolf (Université de Montréal and Mila-Quebec AI Institute).

Key findings:

  • 782 longitudinal plasma samples from 318 hospitalized COVID-19 patients were profiled. Integrated analysis with advanced computational tools revealed four patient clusters in a discovery cohort: mechanically ventilated critically ill cases were subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors were subdivided into high and low antibody responses.
  • Only the high-fatality cluster was enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster had a distinct RBD-specific antibody expression profile.
  • People in both the critical and non-critical clusters, who had delayed antibody responses, exhibited sustained interferon signatures. This negatively correlated with (meaning that they did not have high) RBD-specific antibody levels and SARS-CoV-2-specific B and CD4+T cell frequencies.

Hospitalized COVID-19 patients with symptomatic infection and a positive SARS-CoV-2 nasopharyngeal swab (NSW) PCR were enrolled prospectively from two hospitals in Montreal, Canada (n=242, discovery cohort) and one hospital in Uppsala, Sweden (n=76, validation cohort). Blood draws were serially done throughout their hospital stay: at enrollment and at 2, 7, 14, and 30 days. Only acute samples – defined as those collected within 30 days of symptom onset (n=630 in the discovery cohort and 152 in the validation cohort) – were considered for this analysis.

The four patient clusters identified were strongly associated with the level of respiratory support received in the discovery cohort. (Moderate = no supplemental oxygen; severe = oxygen on nasal cannula; critical = non-invasive or invasive mechanical ventilation) and the fatality risk at 60 days after symptom onset. Clusters 1 and 2 had a larger number of critical patients, while clusters 3 and 4 contained mainly non-critical patients.  Cluster 1 included the most severe cases and 50% of the patients died within 60 days of symptom onset, while a minority of patients died in the other three clusters.

Overall, the data from this study suggest that while interferon pathways play key roles as intrinsic innate antiviral mechanisms and in priming of antiviral immunity, excessive interferon signaling could delay the development of virus-specific immunity in patients, which is also known as the “Interferon Paradox.”