Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants

Abstract

SARS-CoV-2 adaptation to its human host is evidenced by the emergence of new viral lineages with distinct genotypic and phenotypic characteristics, termed variants of concern (VOCs). Particular VOCs have become sequentially dominant globally (Alpha, Delta, Omicron) with each evolving independently from the ancestral Wuhan strain. Omicron is notable for its large number of Spike mutations found to promote immune escape and re-infection. Most recently, Omicron BA.4 and BA.5 subvariants have emerged with increasing levels of adaptive immune escape threatening vaccine effectiveness and increasing hospitalisations. Here, we demonstrate that the most recent Omicron variants have enhanced capacity to antagonise or evade human innate immune defenses. We find Omicron BA.4 and BA.5 replication is associated with reduced activation of epithelial innate immune responses versus earlier BA.1 and BA.2 subvariants. We also find enhanced expression of innate immune antagonist proteins Orf6 and N, similar to Alpha, suggesting common pathways of human adaptation and linking VOC dominance to improved innate immune evasion. We conclude that Omicron BA.4 and BA.5 have combined evolution of antibody escape with enhanced antagonism of human innate immunity to improve transmission and possibly reduce immune protection from severe disease.

mRNA vaccines and hybrid immunity use different B cell germlines to neutralize Omicron BA.4 and BA.5

“…Our nAb panel, built during the last three years of the COVID-19 pandemic, were identified from people receiving two or three mRNA vaccine doses, and from SARS-CoV-2 infected people that had been subsequently vaccinated with the BNT162b2 mRNA vaccine 16,17 . In agreement with previous studies performed mainly with whole sera [6][7][8] , we observed that two mRNA vaccine doses were not sufficient to mount a protective antibody response against omicron variants.…”

“…Different scenarios could explain the fast spreading of these new sublineages and the ability to outcompete previous omicron variants. Examples are the lack of the G496S mutation in the Spike (S) protein, which results in increased human angiotensin-converting enzyme 2 (hACE2) binding affinities compared to other omicron variants 5 , the evolution of novel mutations on the S protein, which conferred enhanced resistance to neutralizing antibodies 6 , and the ability to better suppress and antagonize the innate immune defenses 7 . The SARS-CoV-2 neutralizing antibodies target the receptor binding domain (RBD) and N terminal domain (NTD) of the S protein, which is a trimeric glycoprotein exposed on the surface of the virus 8,9 .…”

Self-assembling short immunostimulatory duplex RNAs with broad-spectrum antiviral activity

“…51 Importantly, the emerging SARS-CoV-2 Omicron subvariants BA.4 and BA.5 are notable for their ability to enhance innate immune suppression. 52 Thus, in addition to demonstrating potent antiviral effects in the COVID-19 mouse model, our results demonstrate that these duplex RNAs can overcome viral antagonism of human innate immunity, at least in human lung epithelial and endothelial cells maintained in organ chips that have been previously shown to recapitulate human lung pathophysiology with high fidelity. 53,54…”

Global landscape of the host response to SARS-CoV-2 variants reveals viral evolutionary trajectories

“…Based on these data and our previous observations (52), we next hypothesized that Omicron subvariants evolved enhanced innate immune suppression by modulating the expression of specific viral proteins known to inhibit interferon responses. Interrogation of global viral RNA and protein expression during infection revealed differences in the production of structural and accessory proteins, but not non-structural proteins, across the Omicron subvariants (Fig.…”