What is the severity of SARS-CoV-2 Omicron BA.4 and BA.5 variant infections in relation to BA.2 infections?

Clinical Trials & Research

In a recent study posted to the medRxiv* preprint server, researchers compared clinical outcomes of coronavirus disease 2019 (COVID-19) cases due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 and Omicron BA.4/BA.5 variants based on the Kaiser Permanente Southern California (KPSC) health records between April 29 and July 2, 2022.

Study: Association of SARS-CoV-2 BA.4/BA.5 Omicron lineages with immune escape and clinical outcome. Image Credit: Sutthituch/Shutterstock


The incidence of BA.4/BA.5 variants infections among individuals with pre-existing immunity against SARS-CoV-2 from previous infections or vaccinations has raised health concerns relating to the Omicron BA.4/BA.5 immune-evasiveness. The clinical implications of BA.4 and BA.5 emergence have been unclear, with varying counts of BA.4/BA.5 infections associated with hospitalizations and deaths.

About the study

In the present longitudinal study, researchers assessed the differential severity of Omicron BA.4/BA.5 infections in relation to Omicron BA.2 infections.

The number of COVID-19 vaccinations administered was identified via linkage to the California immunization registry data. Nearly 19% (4.7 million members as of 2022) of the South Californian population receives care from KPSC via prepaid, federally sponsored or employer-provided insurance plans. Outpatient COVID-19 cases were recruited with a home-based monitoring program based on standard criteria for inpatient admissions and ED referrals.

In-network delivery data comprising diagnosis, clinical notes, vaccinations, prescriptions and laboratory reports, is captured by the KPSC in real-time via patient electronic health records (EHRs), and out-of-network care is captured via reimbursements for insurance claims. The team excluded individuals identified as SARS-CoV-2-positive in hospital-based settings or those identified as SARS-CoV-2-positive ≤90 days prior to the commencement of the study. In addition, individuals were excluded if they disenrolled before the end date of the study or after 60 days of their date of testing.

The study outcomes/endpoints were: (i) emergency department (ED) presentation; (ii) ED presentation with symptoms occurring ≤2 weeks days after symptom onset; (iii) inpatient admissions; (iv) inpatient admissions with symptoms occurring ≤2 weeks after symptom onset; (v) intensive care unit (ICU) admissions; (vi) mechanical ventilation needs; and (vii) deaths.

For outcomes such as ED presentations, symptomatic ED presentations, hospitalizations, and symptomatic hospitalizations, follow-up assessments were performed ≤30 days after testing SARS-CoV-2 positive in outpatient settings. For outcomes such as ICU admissions, mechanical ventilation needs and deaths, the participants were followed up for ≤30 days of their SARS-CoV-2-positive outpatient test reports. In addition, sensitivity analyses were performed by repeating the survival analyses of ED presentations and symptomatic ED presentations for cases with prior COVID-19 history.

Molecular tests for SARS-CoV-2 detection included real-time polymerase chain reaction (rt-PCR) analysis and probes targeted at the SARS-CoV-2 nucleocapsid (N), open reading frames 1 a/b (ORF1a/b) and spike (S) genes. S-gene target failure (SGTF) analysis was used to distinguish between BA.2 and BA.4/BA.5 variants. Logistic regression models and Cox proportional models (survival analysis) adjusted for included covariates were used for the analysis. The adjusted odds ratios (OR), adjusted hazard ratios (aHR) and the crude 30-day incidence rates per 1,000 cases were calculated.


A total of 65,694 outpatient COVID-19 cases (out of 81,880 total cases) were analyzed, of which, 26% (n=16,753) were BA.4/BA.5 infections and 75 % (n=-48,941) were Omicron BA.2 infections, respectively. From cases randomly selected by KPSC for genomic sequencing in 2022, 99.6% (n=243) and 99% (n=406) of Omicron BA.4 and Omicron BA.5 cases showed SGTF and contrastingly, SGTF was not observed in 98% (n=2,000) of Omicron BA.2 cases.

Among Omicron BA.4/BA.5 case individuals, 17%, 2.5%, 24%, 49%, and 7.5% of individuals received zero, one, two, three and four COVID-19 vaccine doses, respectively, prior to their diagnoses. The corresponding vaccination rates among Omicron BA.2 case individuals were 18%, 2.5%, 25%, 49%, and 5.9%, respectively. The aORs of receiving three and four doses of COVID-19 vaccines were 1.1-fold and 1.3-fold higher for Omicron BA.4/BA.5 infections compared to Omicron BA.2 infections.

Prior COVID-19 history ≥90 days prior to SARS-CoV-2-positive test results was documented for 4.5% and 2.9% of Omicron BA.4/BA.5 cases and Omicron BA.2 cases, respectively. The aORs of prior COVID-19 documentations were 1.6-fold higher for Omicron BA.4/BA.5 cases than Omicron BA.2 cases. For 4,349 cases of BA.4/BA.5 infections, crude 30-day incidence rates for symptomatic ED presentations, all ED presentations, symptomatic inpatient admissions, all inpatient admissions, and ICU admissions were 25, 26, 2.3, 3.0, and 0.2, respectively, with no mechanical ventilation needs and deaths.

For 32,592 Omicron BA.2 infection cases, the corresponding rates for symptomatic ED presentations, all ED presentations, symptomatic inpatient admissions, all inpatient admissions, mechanical ventilation needs, ICU admissions, and deaths were 24, 26, 2.6, 3.0, 0.1, 0.3, and 0.2, respectively. The aHRs for Omicron BA.4/BA.5 infection cases compared to Omicron BA.2 infection cases were 1.1, 1.1, 1.0, 1.1, and 0.9 for symptomatic ED presentations, all ED presentations, symptomatic hospitalizations, all inpatient admissions, and ICU admissions, respectively.

No Omicron BA.4/BA.5 infection cases needed mechanical ventilation or died and thus, aHRs could not be calculated for the two outcomes. Omicron BA.4/BA.5 cases diagnosed in outpatient settings had 55% greater odds of prior COVID-19 history prior compared to contemporaneous outpatient-diagnosed Omicron BA.2 cases, and modestly greater odds of receiving ≥3 doses of COVID-19 vaccines.

Overall, the study findings showed that despite elevated risks of Omicron BA.4 and BA.5 breakthrough infections among previously infected or vaccinated individuals, the lowered severity of Omicron BA.2 infections was persistent with Omicron BA.4/BA.5 infections.

*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:

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