Cross-neutralization of Omicron BA.1 against BA.2 and BA.3 SARS-CoV-2

The Omicron variant of SARS-CoV-2, initially driven by sublineage BA.1, has been supplanted globally by BA.2, with BA.3 appearing at lower frequencies. This rapid shift underscores the urgent need to understand the cross-neutralization capabilities of immune responses generated against one Omicron sublineage against others. This study focuses on the cross-neutralization capacity of sera from individuals infected with BA.1 against BA.2, BA.3, and a pre-Omicron strain (USA/WA1/2020). Understanding this cross-reactivity is crucial for informing vaccine strategies and predicting the effectiveness of immunity acquired through natural infection with one Omicron sublineage against subsequent exposure to other variants. The ongoing evolution of SARS-CoV-2 necessitates continued research into the immunogenicity of different variants and the durability of immune responses, especially in the context of vaccine development and booster strategies. The high mutation rate of the virus, observed particularly within the spike protein, can drastically impact the neutralization capacity of antibodies elicited by prior infection or vaccination. Hence, a clear understanding of cross-neutralization is pivotal for public health preparedness and informing effective vaccination programs.

Existing literature highlights the differing clinical severities and transmission rates between Omicron subvariants BA.1 and BA.2 (Wolter et al., 2022; Lyngse et al., 2022). While some studies show differences in transmission, the impact on cross-immunity remains less clear, necessitating the current investigation.

The study utilized sera from 20 unvaccinated individuals infected with Omicron BA.1. These sera were tested for their ability to neutralize recombinant SARS-CoV-2 viruses containing the spike proteins of BA.1, BA.2, BA.3, and the pre-Omicron strain USA-WA1/2020. The neutralization assay employed a fluorescent focus reduction neutralization (FRNT) technique, measuring the 50% fluorescent reduction neutralization titers (FRNT50). Vero E6 cells were used for the assay. The recombinant viruses were generated using infectious cDNA clones, and their sequences were verified to ensure no undesired mutations. Data analysis was performed using the Wilcoxon matched-pairs signed rank test. Ethical approval was obtained (IRB number 20-0070), and the study adhered to strict biosafety protocols (BSL-3).

The BA.1-infected sera showed neutralization activity against all tested viruses. The geometric mean titers (GMTs) against BA.1, BA.2, BA.3, and USA/WA1-2020 were 445, 107, 102, and 16, respectively. This indicates that the neutralizing capacity of the BA.1-induced sera was significantly lower against the heterologous Omicron sublineages (BA.2 and BA.3) and the pre-Omicron strain compared to the homologous BA.1. Specifically, the GMT against BA.2 and BA.3 was approximately 4-fold lower than against BA.1, while the GMT against the pre-Omicron strain was 28.4-fold lower. While most sera showed higher neutralization of BA.1 compared to BA.2 and BA.3, a few exceptions existed, demonstrating some variability in individual immune responses.

The findings demonstrate partial cross-neutralization of Omicron BA.1-induced immunity against BA.2 and BA.3. While some protection is likely afforded, the reduced neutralization titers suggest that BA.2 and BA.3 infections could still occur in individuals previously infected with BA.1. The significant difference in neutralization against the pre-Omicron strain highlights the antigenic shift associated with the emergence of Omicron. These results have implications for vaccine strategies, suggesting that current vaccines may require modification or boosting to provide comprehensive protection against emerging Omicron sublineages. The authors discuss the potential roles of T cell immunity and non-neutralizing antibodies in providing broader protection against severe disease. The relatively small sample size and the heterogeneous time points of serum collection are limitations of the study.

This study demonstrates that while infection with Omicron BA.1 provides some level of cross-neutralization against BA.2 and BA.3, the reduced efficacy warrants a reassessment of current COVID-19 vaccine strategies. Further research should focus on developing vaccines that induce broader and more durable immunity against a wider range of SARS-CoV-2 variants. Larger studies with more consistent sampling are needed to confirm these findings.

The study's limitations include the relatively small sample size (n=20) of serum specimens and the heterogeneous time points of serum collection (days 8 to 62 post-infection). These factors could potentially influence the interpretation of the cross-neutralization results. The lack of data on T-cell responses also limits a full understanding of the overall immune response to the Omicron variants.