Immunoglobulin replacement products in current clinical use in the United States have poor neutralizing activity against SARS-CoV-2 Omicron strains

BACKGROUND: Intravenous (IV) and subcutaneous (SC) Immunoglobulin G (IG) replacement products are in wide use in patients with primary antibody deficiency syndrome (PAD). There is limited data on the levels of anti-SARS-CoV-2 spike antibodies in IG products or their ability to neutralize emerging SARS-CoV-2 variants. There is lack of data on the impact of IG therapy on serum anti-SARS-CoV-2 spike or neutralizing antibody titers in PAD patients. METHODS: We measured anti-SARS-CoV-2 anti-spike antibody levels and neutralizing titers against historical (WA1/2020) and variant (B.1.617.2 [Delta] and BA.1 [Omicron]) strains in 158 lots of 6 different IG products, collected between August 2021 to April 2022 and manufactured between December 2019 to December 2021. IG products were compared to serum from 20 healthy donors vaccinated with 2 doses of Pfizer-BioNTech mRNA vaccine. Serum anti-spike antibody level and SARS-CoV-2 neutralization activity were measured in 27 PAD patients treated with the tested IG products. RESULTS: Anti-spike antibody titers started to increase in products manufactured in March 2021 and reached peak level, comparable to vaccinated healthy donors, in products manufactured in August 2021 (Fig. 1). The neutralization activity against WA1/2020 and Delta strains showed a similar pattern (Fig. 2). However, 95% of the tested products had no neutralization activity against Omicron. Until November 2021, IVIG products infused to patients in the study had anti-spike titers comparable to unvaccinated healthy donors (Fig. 3). Beginning in February 2022, IVIG products had anti-spike titers comparable to vaccinated healthy controls. Concurrent with a rise in anti-spike antibodies in IG products, PAD patients showed an increase in serum levels of anti-spike antibody and neutralizing activity against WA1/202 and Delta but not against Omicron variants. Testing of immunoglobulin replacement products neutralization activity against emerging variants BQ.1 and BQ.1.1 is underway. [Figure: see text] [Figure: see text] [Figure: see text] CONCLUSION: The anti-SARS spike antibody and neutralization activity of IVIG products lags after the emergence of COVID-19 variants and currently have poor activity against Omicron strain. Because of the protracted manufacturing process, this is expected to be an ongoing challenge. As variants emerge, clinicians should consider additional means of protection for PAD patients such as vaccination, or prophylaxis with monoclonal antibodies.