How do clinical outcomes in patients infected with different Omicron subvariants differ?

In a recent study posted to the medRxiv* preprint server, researchers compare the clinical outcomes, upper respiratory viral loads, and viral recovery of different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants on cell cultures.

Study: Omicron Subvariants: Clinical, Laboratory, and Cell Culture Characterization. Image Credit: Mayboon/Shutterstock


Since the SARS-CoV-2 Omicron variant emerged in November 2021, various Omicron subvariants have evolved, carrying new mutations that grant them improved immune evasion abilities. While the BA.1 subvariant caused the largest number of infections worldwide between December 2021 and January 2022, each new subvariant displaced the previous one and exhibited increased neutralization escape.

Studies have found that the number of cases, the severity of infection, and subsequent hospitalization or mortality varied from one region to another for each of the subvariants. The geographical variation of the outcomes could be related to the number of prior infections and vaccination coverage in the country. This study examines the differences in clinical outcomes, viral load, and viral recovery of the various Omicron subvariants in the United States (U.S.).

About the study

The present study used the remnant lateral mid-turbinate nasal or nasopharyngeal swabs from testing symptomatic and asymptomatic patients at the Johns Hopkins Health System (JHHS) between December 2021 and July 2022. The SARS-CoV-2-positive clinical specimens were used for whole genome sequencing.

The clinical and vaccination data of the SARS-CoV-2-positive patients were used to understand the clinical outcomes of each subvariant infection corresponding to the vaccination status. The viral loads were calculated based on cycle threshold values (Ct) of the polymerase chain reaction (PCR) tests.

VeroE6TMPRSS2 (VT) and VeroE6-ACE2-TMPRSS2 (VAT) cell cultures were infected with aliquots of swab specimens to study the recovery of the virus. The cultures were incubated for seven days or until the cytopathic effect (CPE) confirmed infection. The presence of SARS-CoV-2 in the VT and VAT cells was confirmed using reverse transcriptase PCR.

A 50% tissue culture infectious dose (TCID50) assay was used to measure the infectious virus titers in VT and VAT cells. Various statistical analyses such as Chi-square analysis, Fisher Exact test, Mann-Whitney U test, and one-way analysis of variance (ANOVA) were used to examine the correlations between variables.


The results reported that the highest SARS-CoV-2-positivity rates and coronavirus disease 2019 (COVID-19)-related hospitalizations were between December 2021 to January 2022 during the dominance of the BA.1 subvariant. The predominance of BA.1.1 and BA.2 between February and April 2022 correlated with decreased cases and hospital admissions.

The emergence of the BA.2.12.1 and BA.5 subvariants resulted in a plateaued increase in cases between May and July 2022. The subvariants that emerged after BA.1 resulted in a slight increase in hospitalizations but reduced mortality.

The authors believe that the variation in hospitalization rates for each subvariant could be due to factors such as increased home testing with only severe cases seeking hospital admissions, as well as seasonality with more COVID-19 cases during the colder and drier months. The waning of vaccination-induced immunity could also be responsible for the increase in hospitalizations for the most recent subvariants.

The cell cultures showed reduced recovery of the BA.2 viruses and a corresponding reduction in the number of cases during the predominance of BA.2. This pattern was different from what was observed in other countries such as China, Japan, and Denmark, indicating the dependence of subvariant emergence, spread, and severity on the immune response factors within a community based on prior infections and vaccination coverage.

The study also reported that BA.1 had the highest viral load in the upper respiratory tracts compared to all other Omicron subvariants. Furthermore, BA.5 exhibited higher transmission and predominance than BA.4 despite having identical spike protein residues and neutralization escape abilities. The two subvariants also showed increased re-infection capability in patients with prior BA.1 and BA.1.1 infections. The BA.5 subvariant was also associated with higher infectious virus recovery in cell cultures.

According to the authors, the difference in the recovery of infectious BA.2 and BA.5 subvariant viruses is correlated to the increased immune escape exhibited by BA.5, which contributed to the increased infectivity and rise in the number of cases during BA.5 dominance.


In summary, the study compared the number of cases, hospitalization rates, viral load, and viral recovery in cell cultures for the SARS-CoV-2 Omicron subvariants that emerged in November 2021 in the U.S.

The findings indicated that BA.1 was associated with the highest number of infections but had a lower viral load than subsequent Omicron subvariants. Although BA.4 and BA.5 have identical spike protein structures and immune escape abilities, BA.5 exhibited increased transmission and predominance as well as increased viral recovery from swabs. The study highlights the differential infectability of the Omicron subvariants associated with vaccination- and prior infection-induced immunity in various countries.

*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.

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