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 1 Anti-spike titer by manufacturing date in 158 IVIG and SCIG lots Anti-Wuhan-Hu-1 spike titers in 158 lots of 6 different IVIG and SCIG products, manufactured between December 2019 to December 2021. LOD: limit of detection. Dotted line represents the median anti-spike titer in 20 healthy donors, 14 days post completion of 2 dose series of Pfizer-BioNTech mRNA vaccination. Bars indicate interquartile range. Ig products initial concentration was 10 mg/ml. Figure 2 IG product neutralizing activity against of WA1/2020 by manufacturing date Neutralization activity against WA1/2020 in 158 lots of 6 different IVIG and SCIG commercial products manufactured between December 2019 to December 2021. LOD: limit of detection. Dashed lower line represents the presumptive protective titer: >1/50, as described by Khoury et al. (Nature Medicine, 2021). Top dotted line represents the median anti-WA1/2020 neutralization activity in 20 healthy donors, 14 days post completion of 2 dose series of Pfizer-BioNTech mRNA vaccination. Ig products initial concentration was 10 mg/ml. Figure 3 Anti-spike titer in IVIG products, by first month of infusion Anti-Wuhan-Hu-1 spike titers in 68 lots of 3 IVIG commercial products by first month of infusion – August 2021 to April 2022, compared to 20 healthy donors (blue dots) anti-spike titers, pre-vaccination, 14 days post completion of 2 dose vaccination with Pfizer-BioNTech mRNA vaccination and 90 days post completion of vaccination. LOD: limit of detection. Dotted line represents healthy donors’ post vaccination median anti-spike titer. Ig products initial concentration was 10 mg/ml. Bars indicate median with interquartile range. Kruskal-Wallis with Dunn’s post-test. Only significant differences are shown: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. 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.
【저자키워드】 COVID-19, SARS-CoV-2, spike, neutralization, IVIG, CVID, Antibody deficiency disorder, Immunoglobuline replacement therapy,