SARS-CoV-2 Antibodies in Commercial Immunoglobulin Products Show Markedly Reduced Cross-reactivities Against Omicron Variants

**Background:** Patients with immunoglobulin G deficiency receive prophylactic Ig replacement therapy (IgRT) derived from pooled donor plasma to reduce infection frequency and severity. Each batch contains IgG from at least 1000 healthy individuals, reflecting donor population serostatus. SARS-CoV-2 vaccines were developed against the ancestral Wuhan strain spike protein, but new variants with spike mutations emerged, reducing vaccine efficacy against infection. While vaccines remain effective against severe disease in immunocompetent individuals, immunodeficient patients have increased mortality. The degree to which vaccine-induced antibodies in commercial Ig products cross-react with and neutralize emerging variants was unknown.

**Methods:** Seventy-four commercial Ig batches from CSL Behring (n=29), Octapharma (n=2), and Takeda (n=43) were analyzed. Fifty-two consecutive batches used from March 2021 to September 2022 were included, plus 22 older batches (earliest from September 2019) as pre-pandemic controls. All samples were adjusted to 100 g/L IgG concentration. Binding antibodies (IgG) and neutralizing antibodies (ACE2 blocking) were measured using V-PLEX SARS-CoV-2 10-plex panels (Meso Scale Diagnostics) against the original Wuhan strain and nine variants: Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2 AY.4), IHU (B.1.640.2), and Omicron BA.1, BA.1+L452R, BA.1.1, BA.2, and BA.3. Plasma samples from two XLA patients on IgRT (one also received sotrovimab) were analyzed for comparison.

**Key Results:** Ig batches produced after July 2021 (approximately 18 months after the first US COVID-19 case and 7 months after US vaccination started) consistently contained high quantities of anti-spike IgG against the Wuhan strain. Anti-nucleocapsid antibodies remained low, confirming that donor immunity was primarily vaccine-induced. Binding antibodies to all variants increased in parallel with Wuhan strain antibodies over time, and the variant/Wuhan strain ratio remained horizontal over time, indicating cross-reactivity rather than variant-specific infection exposure. When assessing relative cross-reactivity among unequivocally positive batches, reactivity decreased proportionally with the date the variant emerged, with exceptions: Delta showed stronger reactivity than the earlier Beta variant, and IHU showed stronger reactivity than Omicron BA.1 despite appearing simultaneously. Among Omicron subvariants, BA.1.1 and BA.3 had the lowest binding. Neutralizing potential against Alpha was nearly equivalent to Wuhan, but neutralizing potential against Beta and all Omicron variants was markedly lower. The IHU variant showed strong binding but not correspondingly elevated neutralization. In the two XLA patients, cross-reactivity patterns mirrored the Ig batches, except the sotrovimab-treated patient had unexpectedly high IHU binding and neutralization. Omicron variants universally showed low binding and neutralizing capacity in both patients.

**Clinical Implications:** Commercial Ig products reflect vaccine-induced immunity in the plasma donor population with a production delay of several months. While these products contain substantial antibodies against the original Wuhan strain and show some cross-reactivity to variants, neutralizing capacity against Omicron variants is markedly reduced—consistent with industry reports of approximately 20-fold lower neutralization against Omicron versus Wuhan. This suggests that standard IgRT may provide limited protection against Omicron for antibody-deficient patients. XLA patients, who lack endogenous antibodies, may potentially become long-term SARS-CoV-2 carriers, though T-cell immunity from vaccination likely provides protection against severe disease. The emergence of Omicron-specific and bivalent vaccines may improve future Ig product content if adopted by the plasma donor population. Clinicians should be aware that current IgRT products have variable and generally reduced activity against circulating variants, and additional preventive or therapeutic strategies may be needed for immunodeficient patients during periods of Omicron dominance.