Currently, the CDC Data Tracker reports Omicron's subvariant BA.5 on a slight decline, while BA.4.6 and BA.2.75 (and its subtypes) are on the rise.

A quick look at this data may have most assuming that BA.5 will continue to circulate and hold its dominance. However, the last three years have shown us that a more transmissible variant or sub-variant can displace and outcompete others as a means of survival.

BA.2.75 and its subtypes are projected to be the most immune evasive subvariant to date, leading to a winter surge.

BA.2.75 contains an additional nine spike (S) gene mutations in addition to its BA.2 mutations, and several have not been previously identified in a variant of concern (VOC) or variant of interest (VOI). Its three gene amplification (N, S, and ORF1ab) follows the pattern we've observed—with variants alternating between S-gene target failure (SGTF) and three gene amplification.

Due to their optimized interaction network and epistasis effects, these newly accumulated mutations in the receptor-binding domain (RBD) could restore and gain even greater binding affinities than past variants. These changes make the virus highly transmissible.

As BA.2.75 and its subtypes and BA.5 and BA.4 all try to outcompete one another, a recombinant strain may emerge due to multiple variants infecting the same person simultaneously. This allows the variants to interact during replication by mixing their genetic materials in the human body as a way to survive and multiply.

To further complicate the situation, studies suggest that the virus's spike and non-spike mutations are now working together. The spike mutations make the virus steadily more transmissible. At the same time, the non-spike mutations appear to prolong infection, which gives the virus more time to mutate internally.

Researchers are quickly identifying the unique mutations of BA.2.75 and its eager daughter, BA.2.75.2, to assess their neutralizing antibody response. In recent serum samples from blood donors in Stockholm, Sweden, BA.2.75.2 was neutralized, on average, five-fold less potently than BA.5, representing the most neutralization resistant variant evaluated yet.

This data sounds the alarm that BA.2.75.2 may find its dominance and effectively evade humoral immunity, including areas with hybrid immunity.

We are living in an unprecedented time in history. The rapid and simultaneous emergence of variants with both evolutionary advantages and recombination patterns point toward the potential of more highly transmissible variants of concern. It's just a matter of time (likely six weeks) before we may find ourselves navigating another surge.

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