Why Are Omicron Variants Less Lethal?

Omicron-derived SARS-CoV2 variants (exemplified most recently by XBB1.5(1)) are highly adept at evading immunity against vaccines and infection with previous variants and many parts of the world are currently experiencing high infection rates, yet deaths and hospitalizations have not proportionally increased. Why is this? Could previous waves have already killed those most vulnerable? Has increased herd immunity, perhaps due to T cell immunity, resulted in protection from the more serious sequelae? Or could it be that omicron is intrinsically less pathogenic than previous variants, even though it’s more infectious?

As to whether decreased lethality might be due to SARS-CoV2 already having killed off the most susceptible people, it is not a question easily answered, as susceptibility is multi-factored. Perhaps there has been a reduction of those most genetically vulnerable to the virus. The genes most responsible for susceptibility are not well understood, although immune response genes such as those involved in interferon pathways seem likely to play a role(2). Age plays a major role in susceptibility, however, so natural aging of the population will continually replenish some of the susceptible subpopulations.

Given that a large majority of the population has been vaccinated, infected, or both, it would seem likely that existing immunity would make current variants less lethal. However, mutations in the spike protein (especially the large number in the omicron spinoffs) enable variants to evade neutralizing antibodies against previous variants(3). And even bivalent vaccines and exposure to current variants are not completely effective against current variants because the antibody response tends to be polarized by the initial encounter by a phenomenon called “original antigenic sin” or more accurately immune imprinting(4). Durable and effective immunity due to T cell immunity seems more possible and T cell epitopes to multiple SARS-CoV2 proteins are abundant(5). Killer T cells can clear infections although they don’t prevent it; this could explain why although new variants are more infectious, they are less lethal. For a further elaboration on this point, please see(6). Evasion from T cell immunity seems rarer than that from neutralizing antibodies, in that T cell epitopes tend to be far more conserved in new variants(7, 8). This may help explain how wider herd immunity has led to a reduction of more serious outcomes of infection and give the appearance of an apparent reduction in intrinsic pathogenicity.

Could, however, the omicron spinoffs actually be intrinsically less pathogenic? A recent study using chimeric recombinant viruses in a susceptible mouse model showed that this indeed may be the case(9). Substituting the omicron BA.1 spike protein gene into the original Wuhan genome yielded a virus with a somewhat reduced lethality from the pure Wuhan virus, but one that was still more lethal than the pure BA.1, indicating that the BA.1 S protein was pathogenically attenuated, but not to a degree that could explain the difference between BA.1 and Wuhan. However, introducing omicron mutations (of which there are only two, a point mutation and a three amino acid deletion) into the nsp6 gene of the Wuhan genome also containing the S protein of BA.1 completely recapitulated the reduced lethality of the pure BA.1, indicating that nsp6 is the major contributor to the less pathogenic phenotype of the omicron variants. The function of nsp6 involves sequestration of the intracellular viral RNA replication complex in combination with several other viral proteins, protecting the complex from damage from, for example, RNAses.

This study generated a great deal of public concern regarding “gain of function” studies. Given that the work was performed under appropriate biosafety conditions and given that the created recombinants were

all less lethal than the Wuhan strain itself, which already exists in nature), it is somewhat difficult to understand the degree of concern. The work also seems potentially quite useful from a medical standpoint; it provides insight into pathogenic determinants of SARS-CoV2, may identify druggable targets, and may help understand similar properties of other similar viruses.

So why are the omicron spinoffs seemingly less pathogenic, even though more infectious? From the discussion above, there seems likely a combination of reasons. Although perhaps unknowable, there could have been a depletion of some of the most susceptible populations. Stable T cell epitopes, widely targeted by vaccines, infections, or both, likely contribute to protection against severe outcomes even if not against infections. The studies implicating nsp6 and to a lesser degree the spike protein clearly show an intrinsic component leading to reduced lethality. What is less clear is what future path SARS-CoV-2 evolution will take.

We should mention that a new omicron variant has been reported that is so far limited to the United Kingdom, and its pathogenicity seems similar to the other omicron variants.


1. Uriu, K., et al., Enhanced transmissibility, infectivity and immune resistance of the SARS-CoV-2 Omicron XBB.1.5 variant. bioRxiv, 2023: p. 2023.01.16.524178.

2. van der Made, C.I., et al., Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA, 2020. 324(7): p. 663-673.

3. Qu, P., et al., Extraordinary Evasion of Neutralizing Antibody Response by Omicron XBB.1.5, CH.1.1 and CA.3.1 Variants. bioRxiv, 2023: p. 2023.01.16.524244.

4. Brazil, R., How your first brush with COVID warps your immunity. Nature, 2023. 613(7944): p. 428-430.

5. Tarke, A., et al., Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases. Cell Rep Med, 2021. 2(2): p. 100204.

6. Carabelli, A.M., et al., SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat Rev Microbiol, 2023: p. 1-16.

7. Choi, S.J., et al., T cell epitopes in SARS-CoV-2 proteins are substantially conserved in the Omicron variant. Cell Mol Immunol, 2022. 19(3): p. 447-448.

8. Riou, C., et al., Escape from recognition of SARS-CoV-2 variant spike epitopes but overall preservation of T cell immunity. Sci Transl Med, 2022. 14(631): p. eabj6824.

9. Chen, D.Y., et al., Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.1 attenuation. Nature, 2023.

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