Randomised controlled trials for mpox in endemic countries

The study investigates why the SARS-CoV-2 Omicron subvariant XBB.1.5 spread rapidly in late 2022, particularly in the USA, and assesses whether its growth advantage over contemporaneous lineages (XBB.1 and BQ.1.1) arises from enhanced transmissibility, infectivity, and/or immune escape. Understanding these virological features is important for anticipating global spread and informing public health responses.

The authors contextualize XBB.1.5 within Omicron evolution: BQ.1 lineages derive from BA.5, while XBB is a recombinant of two BA.2 lineages. Prior work by the group characterized emerging Omicron subvariants (e.g., BA.4/BA.5 and BA.2.75). A contemporaneous preprint by Yue et al. reported that both strong ACE2 binding and antibody evasion contribute to XBB.1.5 transmissibility. WHO issued a rapid risk assessment on XBB.1.5 in 2022. The authors previously showed S:Y144del increases immune escape, providing a basis to examine its reversion (ins144Y) in XBB.1.5.

• Epidemic dynamics analysis estimating the relative effective reproduction number (Re) from sequence/epidemiological data to compare XBB.1.5 with parental XBB.1 and with BQ.1.1 in the USA.
• Yeast surface display assay to quantify the dissociation constant (Kd) of the XBB.1.5 spike receptor-binding domain (RBD) for human ACE2 versus XBB.1.
• Lentivirus-based pseudovirus assays to measure relative infectivity of XBB.1.5 compared with XBB.1.
• Neutralization assays using sera from individuals with BA.2 and BA.5 breakthrough infections to assess antibody resistance of XBB.1.5 relative to B.1.1, BA.2, and BA.5.
• Comparative analyses of variants carrying reversion at spike position 144 (ins144Y) to evaluate effects on fitness (Re), infectivity, and neutralization sensitivity.

• Growth advantage: XBB.1.5 has a relative Re approximately 1.2 times greater than XBB.1 and is outcompeting BQ.1.1 in the USA as of December 2022, suggesting likely rapid global spread.
• ACE2 binding: Yeast display showed a 4.3-fold lower Kd for XBB.1.5 RBD versus XBB.1, indicating markedly stronger ACE2 affinity, attributed to the S:S486P substitution.
• Infectivity: Pseudovirus assays showed ~3-fold higher infectivity of XBB.1.5 compared with XBB.1.
• Antibody resistance: Neutralization assays showed robust resistance of XBB.1.5 to sera from BA.2 breakthrough infections (41-fold reduction vs B.1.1; 20-fold vs BA.2) and BA.5 breakthrough infections (32-fold vs B.1.1; 9.5-fold vs BA.5).
• S:Y144del reversion (ins144Y): A subset of XBB.1.5 genomes lack the S:Y144del; however, XBB.1.5+ins144Y exhibits a lower Re than original XBB.1.5. The 144Y insertion increases infectivity of XBB.1 but not of XBB.1.5, and increases sensitivity to BA.2/BA.5 breakthrough sera. Thus, reversion does not improve XBB.1.5 fitness.

The combined data indicate that XBB.1.5’s rapid expansion is driven by improved transmissibility stemming from both enhanced ACE2 binding (via S486P) and maintained strong antibody evasion. The superior ACE2 affinity translates into higher pseudovirus infectivity without sacrificing immune resistance, explaining its growth advantage over XBB.1 and BQ.1.1. The observation that reversion of S:Y144del reduces fitness and increases serum sensitivity in XBB.1.5 suggests the original S:Y144del configuration remains optimal for immune escape within this lineage.

XBB.1.5 is, as of January 2023, the most successful XBB lineage, having acquired S486P that substantially strengthens ACE2 binding while retaining pronounced immune resistance, resulting in higher transmissibility and outcompetition of other circulating Omicron subvariants. Future work should monitor ongoing spike evolution, assess clinical outcomes and vaccine effectiveness against XBB.1.5 and descendants, and evaluate therapeutic antibody and antiviral performance.