Breakthrough SARS-CoV-2 outcomes in immune-disordered people during the Omicron era: a prospective cohort study.

Introduction: Immune-deficient/disordered people (IDP) elicit a less robust immune response to COVID-19 vaccination than the general US population. Despite millions of IDP at presumed elevated risk, few population-level studies of IDP have been conducted in the Omicron era to evaluate breakthrough infection-related outcomes. Methods: We followed a prospective cohort of 219 IDP and 63 healthy volunteers (HV) in the USA from April 2021 (Alpha variant peak) to July 2023 (Omicron XBB variant peak). IDP had a primary or secondary immune disorder. All participants were≥3 years old and received COVID-19 vaccines external to this study. We quantified anti-spike IgG titre levels by ELISA, measured breakthroughs via participant reports and laboratory tests on saliva samples, compared breakthrough incidence among HV and IDP, assessed infection complications (persistent infections, reinfections and post-acute sequelae of COVID-19 (PASC)) and used surveys to capture COVID-19 symptoms and preventive attitudes/behaviours. Results: Among IDP, the incidence of initial breakthrough infection was 8.8 (95% CI 4.5 to 62.5) times higher during than before the Omicron era. There were 88 initial breakthrough infections among IDP (incidence rate 23.7/100 person-years) and 28 among HV (27.3/100) throughout the study period. While COVID-19 symptoms were generally mild, five participants, all IDP, were hospitalised. In traditional analyses and an emulated trial, the quantity of anti-spike IgG 1 month after participants' most recent pre-infection vaccination was not associated with breakthrough. HV and IDP frequently practiced infection-limiting behaviours, but IDP were more likely to continue such behaviours after vaccination. IDP experienced persistent infections, PASC and reinfections more commonly than HV. Conclusions: Breakthrough rates in IDP were largely equivalent to HV. However, IDP experienced a slightly higher frequency of symptoms, hospitalisations, infection persistence, PASC and reinfections than HV. Further study is needed to elucidate the immunological mechanisms that increase the risks of such complications in IDP.