SARS-CoV-2 subvariants Omicron BQ and XBB exhibit exceptional immune evasion properties

In a recent study published in Cellresearchers have demonstrated the exceptional immune evasion properties of Omicron severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subvariants BQ and XBB.

Background

To date, XBB and XBB.1 and BQ.1 and BQ.1.1 represent the most resistant SARS-CoV-2 variants. The BQ subvariants evolved from Omicron BA.5, while the XBB subvariants are recombinants of the sublines derived from Omicron BA.2, BA.2.75 and BJ.1.

Interestingly, these variants have accumulated multiple spike (S) mutations and continue to diversify and evolve. For example, XBB has 14 more S mutations than the parental strain BA.2, including five and nine in the N-terminal domain (NTD) and receptor binding domain (RBD), respectively, while XBB.1 has an additional G252V mutation.

About the study

In the present study, the researchers evaluated the neutralization of XBB, XBB.1, BQ.1 and BQ.1.1 by sera from five cohorts. The first two cohorts included individuals who received three doses plus a fourth booster dose of messenger ribonucleic acid (mRNA) COVID-19 vaccines. They labeled these two cohorts as 3-hit WT/4-hit WT. The next cohort had received three doses of one of the COVID-19 mRNA vaccines, who also received a fourth boost of recently licensed bivalent mRNA vaccines (3 WT + bivalent injections). The remaining two cohorts had individuals with BA.2 and BA.4/5 infectious breakthroughs.

The researchers used the serum neutralization test results to construct an antigenic map that presented the antigenic distances between D614G, the wild-type SARS-CoV-2 variant, and the Omicron subvariants.

The team constructed pseudoviruses for each subvariant and each mutation found within the subvariants. Then they evaluated these against a panel of 23 monoclonal antibodies (mAbs) targeting SARS-CoV-2 S epitopes. This panel mainly had mAbs with substantial neutralizing activity against Omicron, for example, bebtelovimab. It also contained the therapeutic mAb cocktail Evusheld, a combination of mAb, COV2-2196 and COV2-2130.

Study results

Compared to the ancestral D614G strain, serum neutralization titers against XBB, XBB.1 and BQ.1, BQ.1.1 decreased from >37-fold to >71-fold in the “3 WT injections” cohort. Additionally, most samples did not neutralize these new subvariants at a serum dilution of 1:100. Conversely, the geometric mean titers (GMTs) of sera from the two breakthrough cohorts were significantly higher. The antigenic map showed that the BA.5 BQ.1.1 derivative derived from its parent strain as much as the latter derived from D614G; eventually, it became almost six times more resistant to neutralization than BA.5.

Interestingly, each unit of antigenic shift made a two-fold difference in serum neutralization susceptibility of a SARS-CoV-2 variant. As a result, XBB.1 was ~63 times more resistant to neutralization than its parent strain. It is also by far the most antigenically distinct Omicron subvariant.

Bebtelovimab and Evusheld failed to neutralize BQ.1 or BQ.1.1. Similarly, the BQ subvariants showed complete resistance to class 1 and 3 RBD mAbs, under the effects of the N460K mutation and the R346T and K444T mutations, respectively. Since BQ.1.1 had an additional R346T mutation, it eluded class 3 RBD mAbs more strongly than BQ.1. The S mutations shared between BQ.1.1, XBB and XBB.1 suggested convergent evolution to evade antibodies attacking these S regions. Finally, the S proteins of the BQ and XBB subvariants have comparable binding affinities to the enzyme converting human angiotensin 2 (hACE2) like their predecessor, suggesting that they have mutated for better fitness. Yet other factors were also at play.

conclusion

Overall, vaccination with or without previous SARS-CoV-2 infection and even booster injections of novel bivalent mRNA vaccines (WA1-BA.5) conferred no protection against any of the four sub- variants of Omicron XB and BQ. Moreover, the researchers found the extent of their antigenic drift quite alarming. Current and previous findings on serum neutralization of some sarbecoviruses have indicated that XBB and XBB.1 are much more distant than sarbecoviruses.

Together, these results highlighted that the recently emerged Omicron BQ and XB subvariants may further compromise the effectiveness of current COVID-19 vaccines, which, in turn, could increase cases of infection and reinfection. Unfortunately, since the BQ and XBB sublines are resistant to bebtelovimab, the only mAb active against circulating SARS-CoV-2 strains, clinicians have no therapeutic mAbs cleared for treatment. This raises enormous concern, especially for millions of immunocompromised patients. Since they do not respond adequately to COVID-19 vaccines, there is an urgent need to develop active mAbs for clinical use.

More importantly, the current study highlighted how difficult it would be to anticipate the antigenic trajectory of SARS-CoV-2. Nonetheless, the development of next-generation COVID-19 vaccines and mAb therapies will need to take this into account to design products that offer broader protection against the ever-evolving SARS-CoV-2.