Challenges in Determining the SARS-CoV-2 Omicron Variant's Intrinsic Severity

A novel, quickly circulating SARS-CoV-2 variant, now known as omicron, was recently identified thanks to active genomic surveillance and open communication by South African scientists and public health practitioners. 1 Scientists and the general public have been attentively following the clinical impacts of the omicron-variant wave that has swept across the community, in order to quantify the variant's relative transmissibility, immune evasion capabilities, and severity in comparison to earlier variations. The growth advantage of Omicron over the delta version has now been shown in several places.

Omicron's quick expansion across South Africa has resulted in fewer hospitalizations and fatalities per reported case than earlier Covid-19 waves, a fact that some members of the public are naturally ready to attribute to the variant's inherent predisposition to cause less severe sickness. When inferring about omicron's inherent features, particularly its severity, on the basis of population-level evidence, care is advised even more than with earlier variations.

The level of immunity in afflicted populations is a key aspect to consider when interpreting omicron's population-level severity. After three prior waves dominated by the D614G, beta, and subsequently delta genotypes, South Africa recorded its lowest daily case count since the pandemic's beginnings in mid-November 2021. Although the cause of this brief time of control is unknown, earlier waves' immunity (notably the delta-variant wave) and a vaccination campaign that began ramping up in mid-2021 and targeted the elderly are considered to have had a role.

As a result, Omicron infected a South African population with far higher immunity than any prior SARS-CoV-2 variant, particularly among those who were most at risk for catastrophic results. Although boosters minimize infection risk and vaccines' efficacy against hospitalization is mostly intact, Omicron has been proven to be considerably better than earlier variations at infecting persons who have some degree of preexisting immunity due to vaccination or a previous infection.

As a result, a greater proportion of persons infected with omicron will have prior immunity than those infected with earlier versions, both because more people now have immunity and because omicron is better fitted to infect people with preexisting immunity.

The case fatality rate (CFR) is a useful indicator of the severity of an illness, but not all infections are documented, and the proportion of cases found may alter over time. It's crucial to understand the difference between the CFR and the infection fatality rate (IFR), especially because more serious illnesses are more likely to be reported. Because those with prior immunity are likely to have less severe consequences from recurrent infection, comparisons between omicron's population-level severity, whether assessed by CFR or IFR, and that of preceding variations (see figure) become more difficult.

Furthermore, both viral and host qualities are likely to influence the chance of a person with preexisting immunity having a productive infection and the clinical aspects of that illness. When such infections are caused by variants that have a lower intrinsic immune-evasion capability, such as delta, the population with preexisting immunity that becomes infected is expected to include a disproportionate share of people with less effective immune responses, whether due to immunologic defects, a less robust response to vaccination or previous infection, or the waning of a previously protective immune response.

Because of immunosenescence in elderly populations, certain persons with less robust infection defense may be at a higher-than-average risk of poor outcomes from these diseases. If, on the other hand, a variant's immune-evasion capacity is mostly determined by its own features, such as a divergent spike protein, more people with strong immune responses may be infected — and their illnesses may be milder. Even if omicron had the same intrinsic potential to produce severe disease as earlier variations, each of these variables would tend to drive down the CFR, perhaps including the CFR for breakthrough infections, to a rate lower than past versions.