Association of SARS-CoV-2 BA.4/BA.5 Omicron lineages with immune escape and clinical outcome

Abstract

Expansion of the SARS-CoV-2 BA.4 and BA.5 Omicron subvariants in populations with prevalent immunity from prior infection and vaccination, and associated burden of severe COVID-19, has raised concerns about epidemiologic characteristics of these lineages including their association with immune escape or severe clinical outcomes. Here we show that BA.4/BA.5 cases in a large US healthcare system had at least 55% (95% confidence interval: 43-69%) higher adjusted odds of prior documented infection than time-matched BA.2 cases, as well as 15% (9-21%) and 38% (27-49%) higher adjusted odds of having received 3 and ≥4 COVID-19 vaccine doses, respectively. However, after adjusting for differences in epidemiologic characteristics among cases with each lineage, BA.4/BA.5 infection was not associated with differential risk of emergency department presentation, hospital admission, or intensive care unit admission following an initial outpatient diagnosis. This finding held in sensitivity analyses correcting for potential exposure misclassification resulting from unascertained prior infections. Our results demonstrate that the reduced severity associated with prior (BA.1 and BA.2) Omicron lineages, relative to the Delta variant, has persisted with BA.4/BA.5, despite the association of BA.4/BA.5 with increased risk of breakthrough infection among previously vaccinated or infected individuals.

Fig. 1. Attributes and clinical outcomes among cases diagnosed in outpatient settings.

We first illustrate total outpatient-diagnosed cases, distinguishing those not tested using the TaqPath ThermoFisher COVID-19 Combo Kit (TF) assay and those determined to exhibit or not exhibit S gene target failure (SGTF; A). All subsequent plots are restricted to the eligible sample of outpatient cases tested using the TF assay, including the proportion of cases exhibiting SGTF (B); the proportion of cases with a history of prior documented infection (C); the proportion of cases who previously received 0, 1, 2, or ≥3 COVID-19 vaccine doses (D); the proportion of cases hospitalized within 30 days following their positive test (E), and the proportion of cases experiencing severe outcomes of intensive care unit (ICU) admission, mechanical ventilation, or death within 60 days after their positive test (F). The gray shaded area in F delineates weeks with <3000 cases, precluding reliable estimation of rare endpoints. Data encompass 148,105 cases tested during the study period, among whom 106,532 were tested using the TF assay and included in primary analyses.

Fig. 2. Clinical outcomes among cases with BA.2 and BA.4/BA.5 lineage SARS-CoV-2 infection, tested 29 April, 2022 to 29 July, 2022.

Plots illustrate cumulative 30-day risk of severe clinical outcomes among cases first ascertained in outpatient settings, stratified by SGTF status for infecting subvariant (BA.4/BA.5 [SGTF]: orange; BA.2 [No SGTF]: blue), for endpoints of any emergency department (ED) presentation (A); any inpatient admission (B); inpatient admission associated with an acute respiratory infection (ARI) diagnosis (C); intensive care unit (ICU) admission (D); mechanical ventilation (E), and death (F). Shaded areas denote 95% confidence intervals around median estimates (center lines). Plotted estimates indicate absolute risk of each outcome and do not include adjustment for confounding differences between cases with BA.2 and BA.4/BA.5 infection. Adjusted hazards ratios presented in Table 3 should thus be interpreted as measures of the independent association of infecting lineage with risk of each outcome. Data encompass outcomes among 106,532 SARS-CoV-2 cases (49,976 with BA.2 infections and 59,556 with BA.4/BA.5 infections).