Virus World

Highlights

Summary

The Omicron subvariant BA.2 accounts for a large majority of the SARS-CoV-2 infection worldwide today. However, its recent descendants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively. That these novel Omicron subvariants carry additional mutations in their spike proteins raises concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of our COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. On the other hand, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called Class 2 and Class 3 regions of the receptor-binding domain (RBD). The F486V mutation found in BA.4/5 facilitates escape from certain Class 1 and Class 2 antibodies to the RBD but compromises the spike affinity for the cellular receptor ACE2. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab (LY-COV1404) retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

Preprint in bioRxiv (May 26, 2022):

https://doi.org/10.1101/2022.05.26.493517 

Omicron is the evolutionarily most distinct SARS-CoV-2 variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2 and previous SARS-CoV-2 VOCs, but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding BMEM cells against epitopes shared broadly amongst variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. While selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.

Published in Science (June 2, 2022):

https://doi.org/10.1126/sciimmunol.abq2427 

As cases rise in the U.S. and other parts of the world, Omicron subvariants are a continued culprit. Experts are watching closely to see if further mutations of the virus may become even more contagious, or may gain the ability to evade immunity from prior infections and vaccinations.

BA.4 and BA.5 in South Africa

When South African scientists sounded the alarm about Omicron in November, they identified three versions of the variant, called BA.1, BA.2, and BA.3. BA.1 first spread rapidly through South Africa and the rest of the world in December and January; BA.2 then outcompeted BA.1 to become the dominant strain globally. Now, South African scientists are sounding the alarm again: this time about new Omicron lineages, dubbed BA.4 and BA.5. These two lineages have driven another new surge in the country, with both cases and hospital admissions rising sharply in recent weeks. The surge might be starting to slow, as of late this week, but it’s unclear if this trend will continue.  South Africa saw a huge BA.1 surge in November and December, then didn’t see much of a BA.2 bump—likely because so many people infected with BA.1 had immunity to this variant. But BA.4 and BA.5 may be a different story, according to a preprint from Alex Sigal and colleagues at the Africa Health Research Institute. Sigal and his collaborators tested neutralizing antibodies—a commonly-studied aspect of immune system protection—from BA.1 against BA.4 and BA.5. They found that a BA.1 infection offered relatively limited protection against BA.4 and BA.5, especially if the person who had BA.1 was unvaccinated. “BA.4 and BA.5 have potential to result in a new infection wave,” the authors wrote. This study is a preprint, not yet peer-reviewed. But it’s still a major warning sign for the U.S. and other countries: watch out for BA.4 and BA.5.

BA.2 subvariants in the U.S.

Meanwhile, here in the U.S., BA.2 continues to mutate and spread rapidly. The BA.2.12.1 subvariant, first identified by the New York State health department in mid-April as a sublineage that spreads even faster than BA.2, is now causing more than one-third of new COVID-19 cases in the country, according to CDC estimates. In New York and New Jersey, BA.2.12.1 is causing over 60% of new cases; it’s no coincidence that these states are also reporting some of the highest case and hospitalization rates in the country right now. New England, mid-Atlantic, South, and Midwest states are also seeing high proportions of BA.2.12.1. The CDC’s variant proportions estimates don’t yet include BA.4 and BA.5, but other reports suggest that these subvariants are already in the U.S. and starting to compete with our homegrown BA.2 lineages. Marc Johnson, a leading wastewater expert in Missouri, posted on Twitter yesterday that he’s seeing “a circus of Omicron sublineages” in his state, including BA.4 and BA.5. Also worth noting: a new U.S. study (shared as a preprint last week) found that, actually, Omicron is not inherently less severe than other variants. In comparing hospitalization and mortality risks after accounting for vaccination and medical risk factors, the researchers behind this study found little difference between the Omicron wave and prior periods. While this study also has yet to be peer-reviewed, it doesn’t bode well for future Omicron-driven surges.