SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility over BA.2¹. The new variants’ receptor binding and immune evasion capability require immediate investigation. Here, coupled with Spike structural comparisons, we show that BA.2.12.1 and BA.4/BA.5 exhibit comparable ACE2-binding affinities to BA.2. Importantly, BA.2.12.1 and BA.4/BA.5 display stronger neutralization evasion than BA.2 against the plasma from 3-dose vaccination and, most strikingly, from post-vaccination BA.1 infections. To delineate the underlying antibody evasion mechanism, we determined the escaping mutation profiles², epitope distribution³ and Omicron neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory. The resulting elicited antibodies could neutralize both wildtype and BA.1 and are enriched on non-ACE2-competing epitopes. However, most of these cross-reactive NAbs are heavily escaped by L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1; nevertheless, these NAbs are largely escaped by BA.2/BA.4/BA.5 due to D405N and F486V, and react weakly to pre-Omicron variants, exhibiting poor neutralization breadths. As for therapeutic NAbs, Bebtelovimab⁴ and Cilgavimab⁵ can effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

SARS-CoV-2 Omicron 亚系 BA.2.12.1、BA.4 和 BA.5 表现出比 BA.2 更高的传播性¹ 。新变体的受体结合和免疫逃避能力需要立即研究。在这里，结合 Spike 结构比较，我们表明 BA.2.12.1 和 BA.4/BA.5 表现出与 BA.2 相当的 ACE2 结合亲和力。重要的是，BA.2.12.1和BA.4/BA.5对来自3剂疫苗接种的血浆以及最引人注目的是来自疫苗接种后BA.1感染的血浆表现出比BA.2更强的中和逃避能力。为了描述潜在的抗体逃避机制，我们确定了 1640 种 RBD 定向中和抗体 (NAb)（包括从 BA.1 康复者中分离出的 614 种）的逃逸突变谱² 、表位分布³和 Omicron 中和功效。有趣的是，疫苗接种后 BA.1 感染主要回忆野生型诱导的体液记忆。由此产生的抗体可以中和野生型和 BA.1，并且在非 ACE2 竞争性表位上富集。然而，大多数这些交叉反应性 NAb 都被 L452Q、L452R 和 F486V 严重逃脱。 BA.1 感染还可以诱导 BA.1 特异性抗体的新克隆，从而有效中和 BA.1；然而，由于 D405N 和 F486V，这些 NAb 在很大程度上被 BA.2/BA.4/BA.5 逃脱，并且对 Omicron 之前的变体反应较弱，表现出较差的中和广度。至于治疗性NAb，Bebtelovimab ⁴和Cilgavimab ⁵可以有效中和BA.2.12.1和BA.4/BA.5，而S371F、D405N和R408S突变会破坏大多数广泛的sarbecovirus NAb。总之，我们的结果表明 Omicron 可能会进化出突变来逃避 BA.1 感染引起的体液免疫，这表明 BA.1 感染可能会导致 Omicron 突变。1 衍生的疫苗加强剂可能无法针对新的 Omicron 变种实现广谱保护。