Comparison of the Clinical Features, Viral Shedding and Immune Response in Vaccine Breakthrough Infection by the Omicron and Delta Variants

Abstract

Background: On 26 November 2021, the World Health Organization designated the B.1.1.529 lineage of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) as the fifth variant of concern, Omicron. Infections have quickly spread worldwide but understanding of the viral dynamics and the cytokine and cellular immunological response during infection remain limited. 

Methods: Detailed patient-level data from 174 age-matched patients with sequence confirmed Omicron or Delta infection (87 from each group) admitted to the National Centre for Infectious Diseases, Singapore were analysed in an observational cohort study. All patients had received a primary vaccination series against SARS-CoV-2. Peripheral blood samples for measurement of SARS-CoV-2 immunological parameters were obtained from a subset. Respiratory samples were collected for viral cultures and correlated to corresponding PCR cycle threshold (Ct) values. 

Results: Omicron and Delta variant infections in this hospitalized cohort were mild with only 3 (3/87; 3%) and 14 (14/87; 16%) developing pneumonia respectively. Omicron infections were more likely to present with sore throat (46·0 vs 23·0%, p=0·005). Neutrophil counts and C-reactive protein (CRP) were significantly lower among the Omicron cohort (Median neutrophil 2·95 [IQR 2·16 – 3·96] vs 4·60 [IQR 3·76 – 6·10] x 109/L, p<0·001; Median CRP 5·7 [IQR 2·0 – 10·0] vs 12·0 [IQR 6·1 – 22·0] mg/L, p<0·001).  Mean peak viral loads were significantly lower with Omicron infection (Ct 17·6 [IQR 16·3 – 19·3]) compared with Delta infection (Ct 14·9 [IQR 13·9 – 19·0]) (p=0·001). The pattern and rate of change in viral load based on Ct values was similar between Omicron and Delta. At the time of infection, vaccine breakthrough infections with the Omicron variant had a low concentration of proinflammatory cytokines, chemokines, and growth factors at the acute phase of infection, but a more robust IFN-γ response. Less dysregulated immune cell profiles were also observed, including a lower immature neutrophil cell count in Omicron breakthrough cases 

Conclusions: Omicron infections resulted in mild vaccine breakthrough illness in the majority of patients. Compared with Delta, Omicron infections were more frequently associated with upper respiratory tract infections, had lower viral loads, lower levels of pro-inflammatory cytokines and less dysregulated immune cell profiles.

Funding: This work was supported by the Biomedical Research Council (BMRC), A*CRUSE (Vaccine monitoring project), the A*ccelerate GAP-funded project (ACCL/19-GAP064-R20H-H) from Agency of Science, Technology and Research (A*STAR), Singapore National Medical Research Council COVID-19 Research Fund (COVID19RF-001; COVID19RF-007; COVID19RF-0008; COVID19RF-060; OF-LCG19May-0034), Singapore National Medical Research Council Centre Grant Program – Diabetes, Tuberculosis and Neuroscience CGAug16M009 and A*STAR COVID-19 Research funding (H/20/04/g1/006).

Declaration of Interest: None to declare.

Ethical Approval: Waiver of informed consent for collection of clinical data from individuals infected with the Omicron variant was granted by the Ministry of Health (MOH), Singapore, under the Infectious Diseases Act as part of the COVID-19 outbreak investigation. Retrospective data collection from individuals with Delta infection was approved by the institutional ethics committee (REF: 2020/01122). Written informed consent was obtained from study participants for collection of biological samples after review (REF DSRB: 2012/00917).

Keywords: COVID-19, SARS-CoV-2, Delta, Omicron, variants of concern, vaccine breakthrough