Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continuously mutates, posing a threat to human immunity. By late 2025, the BA.3.2.2 sublineage of the BA.3.2 variant emerged globally, becoming a new variant of concern. Researchers and public health authorities have questioned whether the recently introduced JN.1-based mRNA vaccine would be effective against this new variant. The impact of vaccine-induced immunity on variant viruses is a key indicator for determining future immunization policies and vaccine update strategies.

Previous studies have mainly focused on minor mutations within the JN.1 lineage. As a result, the antigenic analysis between the BA.3.2.2 variant, which has followed an independent evolutionary path, and vaccine-induced immunity may have been insufficient. In particular, the impact of prior infection history on the immune response after vaccination has not been clearly elucidated. This knowledge gap has been a major obstacle to responding quickly to new outbreaks.

Key Findings

The researchers conducted a detailed analysis of the neutralizing antibody response against eight variants in serum from 25 individuals vaccinated with the JN.1 mRNA vaccine. The experimental subjects were divided into a negative group with no prior infection and a positive group with prior infection, based on the presence of antibodies against the nucleocapsid (N) protein of the coronavirus. The results showed that after vaccination, the neutralizing antibody titers against all variants increased significantly in both groups.

Notably, the BA.3.2.2 variant exhibited a cross-neutralizing ability against the new variant in both the N antibody-negative and -positive groups. Although the neutralizing titers were slightly lower compared to the JN.1 variant, which is the basis of the vaccine, it showed that a sufficient level of antibodies to inhibit the virus was formed.

When the researchers conducted antigenic cartography, interesting results were obtained. Compared to other derived variants of the existing JN.1 lineage, the BA.3.2.2 variant occupied an antigenically isolated position in terms of biological domain. This indicates that the two groups of viruses are employing different immune evasion strategies.

This antigenic difference leads to markedly different results in the evaluation of the efficacy of monoclonal antibody therapeutic agents used in clinical practice. Currently, sipavibart (AZD3152), developed by AstraZeneca for therapeutic use, effectively neutralized the BA.3.2.2 variant. However, it completely lost neutralizing activity against other JN.1-descendant variants with the F456L mutation. In contrast, pemivibart (VYD222) and SA55 antibodies maintained broad neutralizing activity against both lineages.

This difference in neutralizing response is due to the structural characteristics of the viral spike protein. In the case of the BA.3.2.2 variant, the wild-type phenylalanine (F) amino acid at position 456 of the spike protein is preserved. This allows the class 1 and class 2 antibody epitopes, which are major targets of the human immune system, to be maintained without modification. This structural preservation provides a strong mechanistic basis for the cross-neutralization of BA.3.2.2 by JN.1 vaccine recipients. Furthermore, it explains the key reason why the sipavibart antibody was able to maintain its binding affinity to this variant.

Significance and Prospects

This study provides an important milestone in the development of vaccine strategies. If the BA.3.2.2 variant becomes the dominant strain globally, sipavibart may be a useful clinical option. In particular, it is expected to be of great help to vulnerable populations, such as immunocompromised individuals, who cannot form sufficient antibodies with vaccination alone.

However, this study is based on in vitro neutralization assays at the laboratory level, and it is difficult to fully represent the defensive efficacy in the actual human body. Additional clinical trials are needed to verify the clinical spread of the virus and the therapeutic effect in actual patient populations. In the future, it is urgent to monitor the genetic trajectory of emerging variant viruses in real time and to establish preventive and therapeutic measures tailored to them.