Emerging SARS-CoV-2 variant BA.3.2 is more poorly neutralized by responses focused on other contemporary strains

Abstract BA.3.2, a saltation variant of SARS-CoV-2 has 73 mutations in the spike sequence compared to ancestral Wuhan spike. BA.3, isolated from South Africa in November 2021 at a similar time to the BA.1 and BA.2 Omicron sub-lineages, appeared to fade out, however BA.3.2 was identified in South Africa in late 2024 and subsequently detected in other countries, maintaining a low-level presence. More recently derivatives of BA.3.2, largely BA.3.2.2, have markedly increased, comprising 13% (272/2099) of sequences deposited in March 2026 and have become dominant in several countries. Here we compare the neutralization capacity of serum collected a year ago from vaccinated volunteers and find that BA.3.2.2 is not more difficult to neutralize than other contemporaneously circulating strains such as XFG. However, we find that BA.3.2.2 is not neutralized by most of a panel of mAbs which potently neutralize the JN.1 variant. We explain this by structural analyses and suggest that the large evolutionary distance between JN.1-related variants and BA.3.2.2 is skewing the immune responses, increasing susceptibility to BA.3.2.2 accounting for its current uptick. Furthermore, structure and affinity measurements reveal a significantly remodelled RBD in the down configuration and increased affinity for ACE2. Finally, we looked at escape of BA.3.2.2 from commercially produced therapeutic mAbs and find that BA.3.2.2 has regained susceptibility to two mAbs produced by AstraZeneca.