5. Type I IFNs and COVID-19
Type I IFNs play an essential role in fighting viral infections, and deficiencies in type I IFN signaling have been associated with poor outcomes from COVID-19 in multiple studies. These cases are often associated with autoantibodies to type I IFNs. As reviewed below, type I IFNs have been used with some success in treating severe COVID-19, particularly if administered very early in the disease process. If, as argued above, the mRNA vaccines interfere with type I signaling, this could lead to increased susceptibility to COVID-19 in the two weeks following the first vaccine, before an antibody response has been initiated.
Cells infected with a virus detect the presence of virus replication through a number of pattern recognition receptors (PPRs), which serve as sentinels sensing aberrant RNA structures that often form during viral replication. These receptors respond by oligomerizing and subsequently inducing type I IFNs, ultimately upregulating a large number of proteins involved in suppressing viral proliferation [100].
A multi-author study by researchers in Paris, France, involving a cohort of 50 COVID-19 patients with varying degrees of disease severity, revealed that patients with severe disease were characterized by a highly impaired type I IFN response [101]. These patients had essentially no IFN-β and low IFN-α production and activity. This was associated with a persistent blood viral load and an exacerbated inflammatory response, characterized by high levels of tumor necrosis factor α (TNF-α) and Il-6. The authors proposed type I IFN therapy as a potential treatment option. A paper by several researchers in the United States also identified a unique and inappropriate inflammatory response in severe COVID-19 patients, characterized by low levels of both type I and type III IFNs along with elevated chemokines and elevated expression of Il-6 [102].
Type I IFNs have even been proposed as a treatment option for severe COVID-19. In a hamster model, researchers exposed hamsters to SARS-CoV-2 and induced an inflammatory response in the lungs and systemic inflammation in distal tissues. They found that intranasal administration of recombinant IFN-α resulted in a reduced viral load and alleviation of symptoms [103]. A retrospective cohort study of 446 COVID-19 patients determined that early administration of IFN-α2b was associated with reduced in-hospital mortality. However, late IFN therapy increased mortality and delayed recovery, revealing that early administration of interferon therapy is essential for a favorable response [104].
A surprising number of people have neutralizing autoantibodies against type I IFNs, although the underlying etiology of this phenomenon is not understood. A study using longitudinal profiling of over 600,000 peripheral blood mononuclear cells and transcriptome sequencing from 54 patients with COVID-19 and 26 controls found a notable lack of type I IFN-stimulated gene responses in myeloid cells from patients with critical disease [105]. Neutralizing autoantibodies against type I IFNs were found in 19% of patients with critical disease, 6% of patients with severe disease, and 0% of patients with moderate disease. Another study based in Madrid, Spain revealed that 10% of patients with severe COVID-19 disease had autoimmune antibodies to type I IFNs [106]. Finally, Stertz and Hale (2021) note that, whether due to autoantibodies or perhaps loss-of-function polymorphisms associated with interferon system genes, deficiencies in interferon production are associated with as many as 15% of all life-threatening COVID-19 cases [107].