471. In-Depth Characterization of SARS-CoV-2 Variants Causing Breakthrough COVID-19 Among Hospitalized Immunocompromised (IC) Patients with or without Prior Exposure to Tixagevimab-Cilgavimab (T/C) Pre-Exposure Prophylaxis (PrEP)

Abstract Background PrEP with T/C can prevent COVID-19 hospitalization and death in IC patients (pts) up to 6 months after injection. However, in the USA, authorization of T/C PrEP was paused in Jan 2023 due to loss of in vitro activity of T/C against dominant circulating SARS-CoV-2 variants, although loss of clinical efficacy is unclear. We investigated in vivo mechanisms of viral breakthrough in hospitalized IC pts with vs without prior T/C exposure. Methods We analyzed remnant clinical SARS-CoV-2 PCR-positive swabs and sera from IC pts hospitalized at UPMC. SARS-CoV-2 variants and mutants were determined by whole genome sequencing and anti-RBD IgG levels by an enzyme immunoassay. Results From Mar 28, 2022, to Mar 3, 2023, 72% (174/243) of swabs were successfully sequenced from 170 pts (Table 1). Median age was 67 yrs; 49% were male. IC conditions included organ transplant (23%) and hematologic cancer (32%) (Table 2). In IC patients with sequenced swabs, 21% received T/C (Table 3). Variant frequency mirrored national trends (Table 3). BA.5, XBB.1, and BF.7 were less common in T/C vs non-T/C pts (28.57% vs 47.54%; 25.00% vs 32.43%; 2.86% vs 6.56%). BA.2 and BQ.1 were more common in T/C vs non-T/C pts (26.32% vs 16.36%; 50.00% vs 41.25%). The R346T and K444T/R/N mutations were more common in T/C vs non-T/C pts: 54% vs 41% and 37% vs 22% (Table 3). Anti-RBD IgG titers from 56% pts at the time of infection were higher in T/C vs non-T/C pts (median [U/mL, IQR] 1,524,000 [463,666–2,841,800] vs 433,380 [0–2,189,800], respectively). COVID-19 mortality was numerically lower in T/C vs non-T/C pts (11% [4/35] vs 21% [28/135], respectively, P=0.21). Mortality differences were consistent across variant epochs (Table 1). Conclusion Breakthrough COVID-19 caused by SARS-CoV-2 variants with R346T or K444T/R/N mutations is more common in IC pts who received T/C PrEP vs those who did not. Though authorization of T/C was paused due to increased prevalence of non-neutralized variants, such variants were not consistently more common in hospitalized IC pts with breakthrough COVID-19 who had received T/C. Anti-RBD IgG titers were higher and mortality was lower for T/C vs non-T/C pts. Longer follow-up is needed to further delineate the mechanisms of breakthrough infection by T/C status. Disclosures Ghady Haidar, MD, Allovir: Grant/Research Support|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|NIH: Gr