SARS-CoV-2

In early 2020 as the world was grappling with the spread of a novel coronavirus, scientists believed that viral evolution was not going to be a strong player in the long-term outcomes of the pandemic. SARS-CoV-2 is a coronavirus, and coronaviruses tend to evolve slower than most other RNA viruses (like HIV), because they come equipped with the ability to proofread. That is, as the virus replicates, it can double check to make sure that the RNA being replicated is correct.

This scientific assumption, coupled with significant under-sampling due to lack of testing capacity and a virus-naive global population that didn't require significant immune escape, led to an apparent phase of evolutionary stagnation. It took 8 months before the virus finally had a significantly divergent variant.

After 8 months of relative evolutionary stasis, SARS-CoV-2 threw humanity the first (of what would be many) evolutionary curve balls. Alpha seemed to appear out of nowhere, with mutations that shifted the virus and the trajectory of the pandemic into a new direction. At the same time two other highly divergent variants (later referred to as Beta and Gamma) evolved independently.

Within the first 12 months of the pandemic, everything scientists thought they knew about coronaviruses (and therefore SARS-CoV-2) was being thrown out the window. Not only were these new and highly divergent variants evolving independently of one another in completely different parts of the world, they were also significantly more transmissible. Suddenly, a virus that seemed content with the status quo, and seemingly coming under control, showed the world its true form.

Even as vaccines were slowly being administered in early 2021, they showed they were no match for the ingenuity of this virus. The second year of the pandemic became the year of the variants, including Alpha, Beta, Gamma, and finally Delta in summer 2021. Each variant seemingly more divergent than the last, with marked increases in transmission and virulence.

The discovery of Omicron in November 2021 gave rise the next evolutionary stage of SARS-CoV-2. Previous variants of concern came about in waves, which each new variant gradually building up over time, establishing dominance and extinguishing all other circulating variants. When Omicron appeared in South Africa in late 2021, it had more mutations, just in it's spike protein, that all the other variants had in their entire genomes.

BA.1, the first [of many] Omicron variant swept through the globe in January 2022 infecting millions every day. In a single 24 hours, on Monday, January 31, 2022 the United States recorded a record 1.35 million COVID cases. But unlike previous variants which after an initial surge calm back down, almost immediately after BA.1 set infection, hospitalization, and death rates around the globe, it was replaced by another sister variant, BA.2, which continued to diversify into sub-lineages such as BA.2.75. By summer another Omicron lineage (BA.5), completely distinct from BA.1 and BA.2, appeared setting the stage for yet another phase of the pandemic's evolution.

BA.5 failed to do what every prior variant had succeeded in, it was unable to establish global dominance. However, to its credit it had a new trick up its sleeve, the ability to evolve convergently. The era of SARS-CoV-2 divergent evolution had come to a close.

Up until and including Omicron, SARS-CoV-2 evolution seemed to be occurring in individuals. Intra-host evolution is where a single, often immunocompromised individual, is infected for a prolonged amount of time, and in that time the virus is able to mutate. This leads to new divergent variants.

However, since BA.5, most new variants appear to be resulting from inter-host evolution. This type of evolution occurs when multiple variants are all circulating within a population at the same time and none are able to dominant and replace the others, but rather there are multiple variants all co-circulating at the same time, overlapping and simultaneously and independently mutating for similar environmental fitness. So instead of a dominant variant, instead there's a swam of variants, or "variant soup" as it became dubbed.

What is essentially happening is that all of these variants are simultaneously evolving and overlapping, but never replacing each other. Since most of the population has varying levels of immunity (either from vaccination, previous infection, or both), the goal of these new variants is to do two things: 1) increase transmission, and 2) evade immunity.

By mid-2022, the situation with variant evolution had become considerably more complex, with hundreds of (sub)variants identified, all of them falling within “Omicron”. This meant that discussions of the most important variants have only two formal naming options: WHO Greek letters (which is all currently “Omicron”) or an increasingly complex collection of PANGO lineages (in many cases now several layers of “aliases” deep)

SARS-CoV-2 variant trackers began to identify the most concerning subvariants with informal "nicknames". In September 2021, the subvariant BA.4.6 became the first Omicron variant with a nickname, "Aeterna". Since then almost two-dozen Omicron subvariants have been given informal nicknames based on Greek mythological creatures.

Recombination is the exchange of genetic material between two distinct organisms which produce an "offspring" that has a combination of traits that are not found in either parent. Numerous RNA viruses (including coronaviruses) are capable of genetic recombination when at least two viral genomes are present in the same host cell.

Recombinant viral variants can occur when a single person is infected with multiple distinct variants at the same time, allowing the two different variants to interact during replication. When their genetic materials mix they create a new hybrid, or a recombinant variant.

In the naming of SARS-CoV-2 variants, recombinant strains use a different naming system that begins with an X followed by sequential letters (XA, XB, XC....then XAA, XAB, etc.), and no numbers unless there is an unamibiguous descendant (ex. XB, XB.1).

In fall 2022 a new recombinant strain appeared in Singapore, called XBB. Unlike previous recombinant strains that were usually a combination of two distinct variants (often Delta and Omicron), this new recombinant strain was a recombination of two convergent BA.2 strains; BJ.1 (a sublineage of  BA.2.10) and BM.1.1 (a sublineage of BA.2.75).

XBB was considered to be the most immune-evasive COVID variant ever. The ability of XBB to evade immunity is “extreme,” approaching the level of immune evasion shown by SARS (SARS-CoV-1), a coronavirus that infected thousands and caused nearly 800 deaths in the early 2000s. Some scientists even started referring to it as SARS-3, since it was as genetically distinct from the wild-type SARS-CoV-2 virus as SARS-CoV-2 was from SARS-CoV-1.

XBB was dubbed "Gryphon" by evolutionary biologist Ryan Gregory in early October 2022, and since its emergence it quickly began to dominant the SARS-CoV-2 viral landscape. Today the vast majority of circulating variants across the globe are descendants of XBB (aka the "Gryphon Family").

• Gryphon = XBB* (recombinant of BJ.1 ["Argus"] & BM.1.1.1["Mimas"])
• Hippogryph = XBB.1 (child of Gryphon)
• Kraken = XBB.1.5 (child of Hippogryph)
• Hyperion = XBB.1.9.1 (descendant of Hippogryph, but not Kraken)
• Arcturus = XBB.1.16 (descendant of Hippogryph, but not Kraken)
• Acrux = XBB.2.3 (descendant of XBB Gryphon)
• Bellatrix = FY.4 [alias of XBB.1.22.1] (descendant of Hippogryph)

Since SARS-CoV-2 was first identified in Wuhan, China in late 2019, thousands of variants have emerged, many of those variants went on to become variants of interest or variants of concern due to their increased infectiousness, immune evasiveness, and global dominance: most notably Alpha, Beta, Delta, and Omicron.

However, over time and with each new more infectious variant, their pathogenicity and case fatality rates progressively decreased. By the time Omicron appeared in late 2021, it infected millions each day, but compared to the sheer number of infections, the number of people who became severely ill or died as a result decreased significantly.

In early 2022 it seemed as though the pandemic was really over and we were reaching what appeared to be a stable level of endemic disease; that is, there was a stable baseline number of infections, hospitalizations, and deaths, but after January 2022 healthcare systems were able to manage the caseload and it was no longer causing emergency situations.

But that is not what ended up happening...

No More Waves, It's Variant Soup!

After the first Omicron wave hit in late 2021/early 2022, there was no drop back down to low levels of cases as was the case with every previous major variant. Instead, sub-variants emerged, including BA.2 and BA.4 (in mid-2022), BA.5 (late 2022), and finally the current dominance of the BA.2 recombinant family XBB* (in early 2023). Each new sub-variant is evolving simultaneously and co-circulating with the other Omicron sub-variants, but no longer replacing previous variants.

Based on how previous variants had progressively decreasing virulence, public health experts, clinicians, and researchers all believed that these Omicron sub-variants would behave in similar manner to their SARS-CoV-2 variant predecessors. However, recent research is questioning that projection.

A report published in the journal Cureus on June 8, 2023 found "an exponential increase in the pathogenicity of these later Omicron subvariants."

In DeGrasse's report, they obtained confirmed COVID-19 case rates per 100,000 and COVID-19 deaths per 100,000  in the U.S. from the CDC's dataset for all SARS-CoV-2 variants. They identified the peak cases and corresponding deaths and from there case fatality rates (CFR) were calcuated for the original Wuhan strain, Alpha, Beta, Delta, Omicron (BA.1), as well as for each major Omicron sub-variant (BA.2/BA.4, BA.5 and XBB.1.5).

Table 1: Primary Data and Calculated Case Fatality Rates (CFR) of SARS-CoV-2 and Variants in the United States of America.

What they found was the original Omicron variant (BA.1) had the lowest case fatality rate (0.0032), but from that point forward each successive sub-variant exhibited an upward trend in CFR. The CFR of XBB.1.5 (0.0086) is close to that of the Delta strain (0.0124). However, even more striking is that the increase between each Omicron sub-variant is not linear but, instead, fit an exponential growth model almost perfectly (R²= 0.9992).

The authors conclude that, "because the goodness-of-fit was excellent, we extrapolated the curve to the putative next major Omicron variant and found a predicted CFR of 0.0413. This value is 2.5 times greater than that of the Alpha variant and is nearly 60% of the original Wuhan strain CFR."

The CFR of the XBB.1.5 subvariant has risen to pathogenicity near that of the Delta strain; world data also show a significant “death spike” due to Omicron XBB.1.5 during the week of January 15, 2023 (102% of Delta).

Present results show that SARS-CoV-2 Omicron subvariants have increased in pathogenicity to XBB.1.5 which has a CFR near that of the Delta strain. Recent increases in CFR are exponential, and we fit these data to a positive exponential function with high confidence (R² = 0.9992). Extrapolation to the next putative Omicron subvariant suggested that the CFR should be in the vicinity of 0.04, which would make it more dangerous than the Alpha variant and 60% as lethal as the original Wuhan strain. Though we hope that this does not come to pass, caution is yet warranted at this time. Small-molecule therapeutics like chlorpheniramine maleate may offer adequate protection against increasingly pathogenic subvariants of the SARS-CoV-2 coronavirus.