SARS-CoV-2 BA.3.2: epidemiological trends and implications for prophylactic antibodies

We read with great interest the correspondence by Zhang et al. [1], which provides a detailed epidemiological and virological update on the emerging SARS-CoV-2 BA.3.2 lineage and its subvariants. This work offers timely and important insights, particularly as BA.3.2 was designated a Variant Under Monitoring (VUM) by the WHO on December 5, 2025, reflecting its potential public health relevance. The authors’ comprehensive analysis of viral entry, antibody evasion, and global spread substantially advances current understanding of this lineage.

According to the most recent epidemiological data (December 2025), the BA.3.2.2 sublineage—defined by the spike substitutions S:K356T and S:A575S relative to ancestral BA.3.2—has shown increasing relative frequencies in several countries [2]. Two principal evolutionary trajectories are currently apparent: RE.1, predominating in Australia, and RE.2, reported at higher proportions in the Netherlands, Germany, and the UK. Modelling data from UK genomic surveillance further suggests that BA.3.2.2 has a growth advantage over the previously dominant XFG variant, supporting the notion that this lineage could expand further despite its reduced ACE2 binding and lung cell entry, as described by Zhang et al. [3]. At this stage, estimates of BA.3.2.2 prevalence and growth advantage remain uncertain due to limited sequencing coverage and should therefore be interpreted with caution.

While the continued emergence and spread of BA.3.2-derived variants raises legitimate concerns regarding immune escape—clearly demonstrated by their marked resistance to vaccine-elicited antibodies—this evolutionary shift may simultaneously reopen a therapeutic window. In contrast to JN.1-derived lineages that have dominated circulation for nearly two years (including KP.2, KP.3, LP.8.1, XEC, NB.1.8.1, and XFG), which uniformly display resistance to all currently authorized monoclonal antibodies in Asia, Europe and the United States [4,5], BA.3.2 lineages (based on currently available sequences) do not harbour the F456L substitution, a key determinant of sipavibart resistance [3]. Importantly, prior phenotypic analyses of early BA.3.2 viruses performed by the same group in March 2025 [3] demonstrated preserved susceptibility to Omi-42 (the precursor of sipavibart) as well as to tixagevimab, one of the components of the association tixagevimab/cilgavimab. Notably, sensitivity to these monoclonal antibodies was maintained even in the presence of the S:K356T and S:A575S substitutions that now characterise BA.3.2.2. Susceptibility of BA.3.2 lineages to pemivibart has not yet been evaluated and therefore remains to be confirmed experimentally. By contrast, in vitro neutralisation analyses have shown that earlier therapeutic monoclonal antibodies, including sotrovimab and bebtelovimab, are inactive against BA.3.2 [3]. Overall, although further antigenic drift could erode antibody activity over time, the absence to date of F456L selection argues that sipavibart may retain clinically meaningful activity, a hypothesis that urgently requires confirmation with updated phenotypic data.

While these epidemiological trends primarily raise concerns regarding immune escape, they therefore provide an opportunity to reassess potential therapeutic vulnerabilities. From a clinical standpoint, identifying such potential therapeutic opportunities is critical. If confirmed phenotypically, the possible re-emergence of effective monoclonal antibody–based prophylaxis, including tixagevimab-cilgavimab and/or sipavibart, would represent a substantial advance for vulnerable populations, particularly immunocompromised individuals who currently face very limited options for preventing severe COVID-19. The clinical relevance of sipavibart is supported by recent data in immunocompromised individuals showing reduced severe COVID-19 outcomes when circulating variants remained susceptible, suggesting that preserved activity against BA.3.2-derived lineages could be clinically meaningful [6]. As BA.3.2-derived lineages exhibit escape from vaccine-elicited neutralising antibodies, and vaccine effectiveness is further compromised in immunocompromised individuals, this dual limitation reinforces the potential clinical value of monoclonal antibody–based prophylaxis.

Overall, the situation underscores the need to tightly integrate genomic surveillance with systematic phenotypic characterization. Such an approach is essential not only to anticipate immune escape and viral fitness, but also to rapidly identify and exploit transient therapeutic vulnerabilities as new SARS-CoV-2 lineages continue to arise.

Disclosure statement

SF has served as a speaker for AstraZeneca, Cepheid, GSK, Moderna, MSD, and Pfizer. PL has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from AstraZeneca, GSK, Janssen, Merck Sharp & Dohme, Moderna, Pfizer, Sanofi Pasteur, and Seqirus.

CRediT authorship contribution statement

Slim Fourati: Writing – review & editing, Writing – original draft, Conceptualization. Paul Loubet: Writing – review & editing, Writing – original draft, Conceptualization.

Funding

None.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.