Sensitivity of SARS-CoV-2 Omicron BA.2.75 to neutralization by monoclonal antibodies and sera

By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Sep 5 2022

In a recent study published in The Lancet Infectious Diseases, researchers assessed the sensitivity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant BA.2.75 spike (S) protein to neutralization by monoclonal antibodies (mAbs) and sera obtained from Swedish individuals.

Background

Several COVID-19 (coronavirus disease 2019) vaccines have been developed globally to curtail SARS-CoV-2 transmission and prevent COVID-19 severity outcomes; however, vaccine efficacy has been affected by the highly mutant and immune-evasive SARS-CoV-2 Omicron variant. Recently, Omicron subvariants such as Omicron BA.2.12.1, Omicron BA.4, and Omicron BA.5 have emerged with greater immune-evasiveness than prior Omicron subvariants and have caused COVID-19 waves globally.

An emerging Omicron subvariant, BA.2.75, has been in >15 nations as of 19 July 2022 and contains nine more SARS-CoV-2 S mutations than BA.2. Evaluating the neutralization sensitivity of novel SARS-CoV-2 variants such as BA.2.75 is essential for informing public health policy-making. As COVID-19 histories increase in complexity and a sizeable proportion of SARS-CoV-2 infections go unidentified, assessments of population-level immunity are increasingly essential to understand and contextualize the immune-evasiveness of novel SARS-CoV-2 variants.

About the study

In the present study, researchers assessed Omicron BA.2.75 neutralization by mAbs and sera obtained from Swedish individuals.

Blood samples were obtained from 20 Sweden residents between November 8 and 14, 2021, and from 20 Sweden residents between April 11 and 17, 2022, to evaluate BA.2.75 S neutralization by mAbs and serum. The two time periods correlated with time points pre- and post-BA.1 and BA.2 dominance periods (between December 2021 and February 2022) and an expansion of booster vaccine doses.

The geometric mean half maximal inhibitory concentration (ID₅₀) titers among sera were obtained pre- and post-BA.1 and BA.2 and comparatively assessed. The neutralization potency of mAbs such as cilgavimab, tixagevimab, bebtelovimab, imdevimab, casivirimab, etesevimab, and bamlanivimab against BA.2.75 was assessed and compared to that against the ancestral D614G strain.

The contribution of Omicron BA.1 and BA.2 infections, and booster vaccinations, with coverage in Stockholm expanding among adults between November 8 and 14, 2021, and between April 11 and 17, 2022, was evaluated. The concordance of the relative sensitivity of BA.2.75 to sera obtained from the study cohort with those observed among individuals who were administered CoronaVac vaccinations with and without breakthrough infections by Omicron BA.1 or BA.2 subvariants was assessed.

Results

The neutralization potency of cilgavimab against Omicron BA.2.75 was 11-fold lower than that against the D614G ancestral strain and similar to that against Omicron BA.5. Tixagevimab showed extremely weak BA.2 neutralization but partially restored neutralization potency against Omicron BA.2.75 which may be due to the amino acid (aa) reversion at SARS-CoV-2 S position 493.

Bebtelovimab potently neutralized BA.2.75, although the neutralization potency for Omicron BA.2.75 was lower by seven-fold, possibly due to the presence of the G446S mutation. Other mAbs such as imdevimab, casivirimab, etesevimab, and bamlanivimab, did not show BA.2.75 neutralization.

BA.2.75 neutralization was observed with the least geometric mean ID₅₀ titers for all the SARS-CoV-2 variants assessed by sera obtained pre-Omicron BA.1 and Omicron BA.2 waves with BA.2.75 neutralization titers lower by eight-fold compared with those for the ancestral D614G strain. For sera obtained pre-BA.1 and BA.2 waves, the BA.2.75 neutralization titers were significantly lesser than those observed for BA.2 neutralization and comparable to those for BA.5. neutralization.

Sera obtained post-Omicron BA.1 and Omicron BA.2 waves showed considerably greater D614G neutralization and enhanced cross-neutralization of Omicron subvariants. The geometric mean titers of sera obtained post-BA.1 and BA.2 waves for BA.2.75 neutralization were more than seven-fold greater than those of sera obtained pre-Omicron BA.1 and Omicron BA.2 waves. The findings indicated a combined contribution of Omicron BA.1 and BA.2 infections, and booster vaccinations, with coverage in Stockholm expanding among adults from five percent between November 8 and 14, 2021, to 59% between April 11 and 17, 2022.

Between April 11 and 17, 2022, titers for BA.2.75 neutralization were marginally but significantly lesser than those observed for BA.2 neutralization and comparable to titers observed for BA.5 neutralization. The relative sensitivity of BA.2.75 to sera obtained from the study cohort was largely concordant with those observed among individuals who had received CoronaVac vaccinations with and without breakthrough infections by Omicron BA.1 or BA.2 subvariants.

Conclusion

Overall, the study findings showed that the immune-evasiveness of the emerging Omicron subvariant, BA.2.75, was not greater than the currently dominating Omicron BA.5 subvariant among Swedish donor samples. BA.2.75 largely maintained neutralization sensitivity to bebtelovimab despite a marginal reduction in potency and exhibited moderate susceptibility to cilgavimab and tixagevimab.