Neutralizing activity of therapeutic antibodies against clinical strains of the BA.1 and BA.2 sublines of the Omicron variant

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In a recent study published on Research Square* preprint server, the researchers conducted a in vitro analysis to assess the efficacy of monoclonal antibodies against Omicron BA.2 and BA.1 variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: In vitro activity of therapeutic antibodies against SARS-CoV-2 Omicron BA.1 and BA.2. Image Credit: Fit Zstudio/Shutterstock

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The BA.2 variant of the SARS-CoV-2 Omicron strain has largely replaced the BA.1 strain in the current coronavirus disease 2019 (COVID-19) scenario. The mutations of its spike (S) protein differ from those of the BA.1 strain. These various mutations have altered the therapeutic efficacy of monoclonal antibodies.

In previous studies, monoclonal antibodies such as sotrovimab have been given as a 500 mg intravenous (iv) injection for the initial management of infections. In addition, a 300 mg intramuscular (im) dose (150 mg Tixagevimab and 150 mg Cilgavimab) of the AZD7442 antibody cocktail was used for infection prophylaxis. However, the efficacy of a double dose regimen (Tixagevimab 300 mg and Cilgavimab 300 mg iv) has not been established.

About the study

In the present study, researchers evaluated and compared the neutralizing capacity of several monoclonal antibodies against clinical strains BA.2 and BA.1 of the Omicron variant. For reference, they used two viral strains from the same lineage-Delta B.1 strain (B.1.617.2) and the European ancestral strain D614G/BavPat1.

The monoclonal antibodies used in this study have proven their effectiveness against the Omicron BA.1 variant. These antibodies targeted the receptor binding domain (RBD) of the viral S protein and the nucleus. The antibodies tested were Sotrovimab or Vir-7831 and two other monoclonal antibodies – Tixagevimab (AZD8895) and Cilgavimab (AZD1061), independently and as part of the AZD7442/Evusheld antibody cocktail.

The neutralizing potency of these monoclonal antibodies was based on their ability to reduce the amount of viral ribonucleic acid (RNA) in VeroE6 TMPRSS2 cell lines. Viral RNA levels were measured by polymerase chain reaction-quantitative reverse transcription (qRT-PCR) two days after infection. The 50% effective concentration (EC50) values ​​were determined based on the amounts of viral RNA. Using the EC50 values, the team calculated the neutralization efficacy of all treatments and recorded them as MNU50. UNM50 allowed a realistic comparative evaluation of treatments against viral strains.

Results and discussion

The results showed that sotrovimab was less effective against BA.2 than the BA.1 variant. This was consistent with the previous in vitro studies that reported the conserved BA.1 neutralizing capacity of sotorivumab with EC50 values ​​of 55 and 441 ng/mL for the B.1 and BA.2 variants, respectively. However, the neutralizing efficacy decreased by 8 and 1.5 times compared to the ancestral strain and BA.1, respectively.

Tixagevimab demonstrated weak neutralizing capacity against BA.2 and BA.1 strains (EC50 values ​​greater than 5000 nanograms per litre). In contrast, cilgavimab neutralized the BA.2 strain with a slight increase in EC50 values ​​from approximately 33 ng/mL for the B.1 strain to 50 ng/mL for the BA.2 strain. This indicates that cilgavimab showed negligible loss of neutralization efficacy (B.1 to BA.2 variant ratio value of 1.5). Overall, cilgavimab demonstrated a 32-fold greater capacity to neutralize BA.2 than against the BA.1 strain in this study. This can be attributed to the absence of G446S genetic mutation in BA.2.

The EC50 values ​​of the Evusheld cocktail demonstrated a change from 27 ng/mL for the B.1 strain to 73 ng/mL for the BA.2 strain. This indicates that the neutralizing activity of the cocktail was 2.7 times lower for BA.2 compared to B.1, whereas BA.2 was neutralized by ten times higher potency than the BA.1 strain. Thus, Cilgavimab showed increased efficacy against BA.2 as part of the Evusheld cocktail. It was in agreement with the MNU50 values ​​(27.3 MNU50 for BA.2 and 2.8 MNU50 2.8 for BA.1).

However, the efficacy of Tixagevimab was low when used alone or in the Evusheld cocktail. Moreover, when 300 mg of the cocktail was compared to 500 mg of sotrovimab, the latter was more effective against strain BA.1 (MNU50 for Sotrovimab was 11.3 and MNU50 for AZD7442 was 2.8).

Conclusion

In summary, 500 mg of sotrovimab retained modest BA.2 neutralizing activity compared to BA.1, while 300 mg of AZD7442 was limited in activity. Although the efficacy of Cilgavimab increased when used as part of the Evusheld cocktail, the neutralizing activity of Tixagevimab remained persistently low. Therefore, further research needs to be conducted to determine whether Tixagevimab should be administered alone or as part of the AZD7442 cocktail by live analyzes.

*Important Notice

Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

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