In a recent study posted to the medRxiv* pre-print server, researchers from Australia and Switzerland gathered data to help track and manage ongoing and future infection waves by new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) Omicron globally.

Study: SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern. Image Credit: Fit Ztudio / ShutterstockStudy: SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern. Image Credit: Fit Ztudio / Shutterstock


The determinants of preferential spread of BA.5 over BA.2.12.1 and BA.4 Omicron sub-variants are complex, including the prevalence of infection, coronavirus disease 2019 (COVID-19 ) vaccine coverage, and the time from prior antigenic exposure. Among the vaccinated population, the changes in the mechanism of viral entry might also be determining viral tropism and subsequent disease severity. More importantly, previous studies have used animal models to highlight a shift in BA.5 tropism back to pre-Omicron lineages.

About the study

In the present study, the researchers developed a rapid and more sensitive 20-hour live virus neutralization platform (R20) to demonstrate the relative transmission threat of SARS-CoV-2 variants in previously infected and vaccinated populations. It enabled neutralization studies on primary viral isolates retrieved from patients’ nasopharyngeal swabs. Additionally, it helped determine which monoclonal antibodies (mAbs) retained potency against the isolated variants. More importantly, R20 could capture subtle changes in viral tropism towards or away from the angiotensin-converting enzyme 2 (ACE2)-transmembrane protease, serine 2 (TMPRSS2) pathway.

The researchers isolated primary nasopharyngeal swabs from a cohort of Australian donors, who were triple vaccinated but still contracted Omicron BA.1 infection sometime during the overlapping waves of Omicron BA.2 and BA.5.  To this end, they used a genetically engineered ACE2/TMPRSS2 cell line to determine BA.5 infectivity to particle ratios and establish the mode of entry of BA.5 relative to other Omicron sublineages. Notably, the study platform is novel in having used primary diagnostic samples to map the increased or decreased use of TMPRSS2, revealing in real-time when a variant starts expanding within a community based on subtle viral tropism changes.

The researchers also tested 13 batches of polyclonal immunoglobulin G (IgG) collected from over 10,000 plasma donors (both convalescents and vaccinated) in late 2021 before the beginning of the Omicron wave in the United States. They pooled concentrated IgG batches to assess BA.5 infectivity and humoral neutralization in vitro. Finally, the team tested the neutralization potential of clinical-grade therapeutic mAbs sotrovimab and Evusheld against Omicron sub-variants.

Study findings

The study platform detected that the sera from the infected and vaccinated individuals or donor IgGs potently neutralized the ancestral SARS-CoV-2 strain (clade A). However, the neutralization potential of patient sera against all Omicron sub-lineages was reduced by seven to 15-fold compared to a 4.3 and 1.5-fold decrease observed for Beta and Delta relative to clade A, respectively.

Further, all 13 polyclonal human IgG batches neutralized Omicron lineages BA.1, BA.2, and BA.5 similarly. Additionally, BA.5 infectivity was equivalent to clade A, and it significantly reduced neutralization titers across all donors from the Australian cohort, similar to BA.1. 

The more significant the drop of 50% cell death in culture (LD50) in the presence of the TMPRSS2 inhibitor Nafamostat, the more TMPRSS2 is being used by the viral isolate for host cell entry. The authors observed a seven-fold drop in infectivity of BA.5 in the presence of Nafamostat, confirming its greater sensitivity to Nafamostat and increased infectivity to particle ratio over other Omicron sublineages. Evusheld potency dropped against BA.5 compared to BA.2. On the contrary, Sotrovimab could not neutralize BA.2 but actively neutralized BA.5, albeit at lower potency than SARS-CoV-2 clade A.


The study highlighted that all Omicron sublineages, including BA.5, represent a continuing challenge for current vaccination strategies. BA.1 and BA.2 had similar tropism towards cells of the upper respiratory tract, whereas BA.5 appeared to have evolved tropism towards pre-Omicron variant entry pathways. It not only gave BA.5 greater antibody evasion potential but an increased transmission potential in the community. Unfortunately, prior Omicron infections in those triple-vaccinated helped mount potent responses to early pre-Omicron variants but not substantially against BA.5. Hence, in the future, vaccine strategies that can rapidly increase neutralization breadth to current variants would be more pragmatic.

Additionally, researchers should closely monitor tropism changes in future SARS-CoV-2 variants, especially as tropism aligns with greater disease severity. The assays used in the current study only needed primary diagnostic samples to analyze the infectivity of a variant as soon as it emerged within the community. Therefore, in such cases, they could prove quite valuable.

*Important notice

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

Journal reference:

  • SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern, Anupriya Aggarwal, Anouschka Akerman, Vanessa Milogiannakis, Mariana Ruiz Silva, Gregory J Walker, Andrea Kindinger, Thomas Angelovich, Melissa Churchill, Emily Waring, Supavadee Amatayakul-Chantler, Nathan Roth, Germano Coppola, Malinna Yeang, Tyra Jean, Charles S.P. Foster, Alexandra Carey Hoppe, Mee Ling Munier, Daniel Christ, David Ross Darley, Gail Matthews, William D Rawlinson, Anthony D Kelleher, Stuart G Turville, medRxiv pre-print 2022, DOI: https://doi.org/10.1101/2022.07.07.22277128, https://www.medrxiv.org/content/10.1101/2022.07.07.22277128v1


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