Autoantibodies against type 1 interferons increase COVID-19 death risk

The presence of autoantibodies neutralizing type 1 interferons (IFN), such as IFN-α2 or IFN-ω, strongly increase the relative risk of death (RRD) and infection fatality rate (IFR) in unvaccinated patients with COVID-19, according to a recent study.

“As SARS-CoV-2 vaccination coverage increases and mortality due to COVID-19 decreases over time, it will be important to re-evaluate the risk of fatal COVID-19 in vaccinated individuals with and without autoantibodies,” the researchers said. “It is currently unclear whether these autoantibodies impair antibody responses to vaccines, and whether a vaccine-triggered antibody response can overcome type I IFN deficiency in response to large or even medium-sized viral inocula.”

The study looked at 1,261 patients who had died of COVID-19 and calculated their RRD and IFR using a general-population control cohort of 34,159 individuals, whose samples were collected before the pandemic. Analyses were stratified according to neutralizing activity and age in six classes (20–39, 40–49, 50–59, 60–69, 70–79, and ≥80 years).

Results showed that the presence of any type of either IFN-α2 or IFN-ω was indeed associated with worse survival outcomes. Interestingly, however, RRD in carriers was higher in younger patients. [Proc Natl Acad Sci USA 2022;119:e2200413119]

Among carriers of autoantibodies neutralizing low concentrations of either IFN-α2 or IFN-ω (100 pg/mL), RRD jumped from 5.8 in ≥70-year-olds to 17.0 in comparators younger than 70 years. Having autoantibodies against both IFN-α2 and IFN-ω had the strongest impact on RRD, with estimates of 7.2 in individuals ≥70 years and 188.3 in younger counterparts.

A similar effect was reported for carriers of autoantibodies neutralizing high levels of type 1 IFNs (10 ng/mL). RRDs were 6.8 and 62.4 in older and younger individuals, respectively, who showed activity against IFN-α2 or IFN-ω. The presence of autoantibodies against both type 1 IFNs was likewise associated with the highest RRDs, yielding corresponding estimates of 12.9 and 156.6 in older and younger individuals.

“For all types of autoantibodies, RRDs were three to 26 times higher in subjects under 70 years old than in older individuals,” the researchers said. “[This] may be partly explained epidemiologically, by the larger contribution of other mortality risk factors, such as comorbid conditions, which become more frequent with increasing age.”

“Despite their increasing prevalence with age, autoantibodies against type I IFNs make a decreasing contribution to the risk of COVID-19 death with age, due to the progressive development of additional age-dependent risk factors,” they added.

In contrast, the presence of such autoantibodies aggravated COVID-19 IFR, but its effect strengthened with age. Activity against both IFN-α2 and IFN-ω, for example, was associated with IFR estimates ranging from 0.84 percent in individuals <40 years of age to 40.5 percent in comparators ≥80 years old.

“Overall, autoantibodies against type I IFNs are associated with very high RRD and IFR values, and the magnitude of this effect appears to be much larger than that of other known common risk factors apart from age, such as maleness, comorbidities, or the most significant common genetic variant on chromosome 3, all of which have been associated with life-threatening COVID-19,” the researchers said.

“Further investigations are required to determine the contribution of these autoantibodies to other severe viral diseases and to elucidate the mechanisms underlying their development, which may be age dependent,” they added.