SARS-CoV-2 recombinant subvariant XBB.1.5 is growing rapidly


SARS-CoV-2 recombinant subvariant XBB.1.5 is growing rapidly in the United States, carrying an additional Ser486Pro substitution compared to XBB.1 and outcompeting BQ.1.1 and other XBB sublineages. The underlying mechanism for such high transmissibility remains unclear.

SARS-CoV-2 subvariants BQ.1.1 and XBB.1 have been circulating globally with superior growth advantages over most Omicron mutants (Fig. S1A). However, XBB.1.5, a subvariant of the recombinant mutant XBB, has recently shown a substantial growth advantage over BQ.1.1 and XBB.1. XBB.1.5 has rapidly become the dominant strain in the United States and is highly likely to cause the next global wave of COVID-19 with the enhanced transmissibility (Fig. S1B) 1.

XBB/XBB.1 is already demonstrated to be extremely evasive against the neutralization of plasma/serum from vaccinated or convalescent individuals and monoclonal antibodies (mAbs), even stronger than that of BQ.1.1 2-5.

Compared to XBB.1, XBB.1.5 carries a Ser486Pro mutation on the spike protein, a rare 2-nucleotide substitution compared to the ancestral strain (Fig. S1C). The mechanism behind the rapid transmission of XBB.1.5, especially the impact of Ser486Pro, requires immediate investigation.

Here, using vesicular stomatitis virus (VSV)-based pseudovirus neutralization assays, we evaluated the neutralization titers against XBB.1.5 of convalescent plasma from individuals who had received 3 doses of CoronaVac prior to BA.1, BA.5, or BF.7 breakthrough infection (BTI). A cohort of convalescents from BA.5 BTI who had received at least two doses of BNT162b2 or mRNA-1273 is also included in the analysis.

Human ACE2 (hACE2)-binding affinity of XBB.1.5 receptor-binding domain (RBD) was also examined by surface plasmon resonance (SPR) assays, in comparison to that of XBB.1, BQ.1.1, and BA.2.75. Plasma samples associated with CoronaVac were collected on average 4 weeks after hospital discharge (Table S1). Plasma samples associated with the mRNA vaccine were collected within 2-3 weeks after hospital admission (Table S1).

Plasma samples from CoronaVac-vaccinated BA.1/BA.5/BF.7 BTI showed a substantial decrease in plasma 50% neutralization titer (NT50) against XBB.1 and XBB.1.5 compared to that against B.1 (D614G) variant (Fig. 1A). Specifically, plasma from post-CoronaVac BA.5 BTI showed a 44-fold decrease in NT50 against XBB.1 compared to that against B.1, while the decrease is 39-fold for XBB.1.5.

For post-CoronaVac BF.7 BTI, the plasma NT50 against XBB.1 and XBB.1.5 was decreased 31 and 27-fold respectively compared to that against B.1. A similar trend was also observed in plasma from mRNA-vaccinated BA.5 BTI and post-CoronaVac BA.1 BTI. The above results indicate the humoral immune escape ability of XBB.1.5 is comparable to XBB.1, in fact slightly weaker.

Figure 1XBB.1.5 exhibits enhanced hACE2 binding with strong antibody evasion(A) NT50 against SARS-CoV-2 B.1 (D614G), XBB.1, and XBB.1.5 pseudovirus using plasma from BA.1 (n=50), BA.5 (n=36), or BF.7 (n=30) BTI convalescents with 3 doses of CoronaVac in prior, and BA.5 BTI convalescents with 3 or 4 doses of vaccination in prior including at least two doses of mRNA vaccines (BNT162b2 or mRNA-1273) (n=10).
(B) Pseudovirus 50% inhibition concentration (IC50) of therapeutic neutralizing antibodies. Green, white, and red backgrounds indicate IC50 < 100ng/mL, > 100ng/mL, and > 10,000ng/mL (limit of detection, marked as an asterisk), respectively.
(C) SPR sensorgrams measuring the hACE2-binding affinity of SARS-CoV-2 BQ.1.1, XBB/XBB.1, and XBB.1.5 RBD. The fitted association rate constants (ka), dissociation rate constants (kd), and dissociation equilibrium constants (KD) are shown.

Compared to XBB.1, XBB.1.5 exhibited similar evasion against therapeutic mAbs (Fig. 1B). Evusheld and Bebtelovimab could not neutralize XBB.1.5 pseudovirus. S309 is still active but weak against XBB.1.5. SA58 is escaped, while SA55 remains highly effective against XBB.1.5 2,6.

Previous deep mutational scanning studies have shown that Pro486 may enhance the affinity to human ACE2 (hACE2) compared to Ser486 7. Indeed, the hACE2-binding affinity of XBB.1.5 RBD (with a dissociation constant KD of 3.4 nM) was comparable to that of BA.2.75 (KD=1.8 nM) and much stronger than that of XBB.1 (KD=19 nM) and BQ.1.1 (KD=8.1 nM) (Fig. 1C and S2). These results suggest that the probable reason for the significant growth advantage of XBB.1.5 over XBB.1 is that it gained substantially higher ACE2 binding affinity through the Ser486Pro mutation, while retaining an extremely high immune evasion capability.

With stronger immune escape ability than BQ.1.1 but limited by weaker ACE2 binding affinity, XBB and XBB.1 have only prevailed in a few countries, such as Singapore and India, in the past few months, while BQ.1.1 has quickly become the global dominant strain. Given its enhanced hACE2-binding affinity but comparable antibody evasion, the prevalence of XBB.1.5 demonstrates that receptor-binding affinity will substantially affect the transmissibility, but the underlying mechanism still needs further investigation.

Also, whether the increased receptor-binding affinity would cause a difference in pathogenicity compared to XBB is unclear and requires immediate research 8. Moreover, the strong affinity to hACE2 may allow XBB.1.5 to acquire additional immune-escape mutations, similar to the evolution trend of BA.2.75, when met with substantial immune pressure 9. Therefore, the circulation of XBB.1.5 needs to be closely monitored, and the development of effective neutralizing antibodies and vaccines against XBB.1.5 is urgently needed.

Y.C. is a co-founder of Singlomics Biopharmaceuticals and inventor of provisional patents associated with SARS-CoV-2 neutralizing antibodies, including SA55 and SA58. All other authors declare no competing interests.

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