Viral Immunity in Immunoglobulin Products: Global Immunity Debt and Autoimmunity in the Postpandemic Era

Immunoglobulin (Ig) replacement therapy is commonly used to prevent infections in individuals with low IgG levels. These therapies are derived from pooled plasma donations from thousands of healthy individuals worldwide. This study examined 85 unique Ig batches produced between May 2017 and June 2023 to assess changes in antibody composition, particularly in response to the SARS-CoV-2 pandemic. Using high-throughput assays, IgG reactivity was measured against over 283,000 viral peptides from 527 virus species and nearly 12,000 human proteins. Antibodies against more than 200 virus species were detected, with 27-mainly respiratory and herpesviruses-present in over half the batches. SARS-CoV-2 antibodies emerged in products from July 2021 onward. During the pandemic, antibody levels against influenza, HSV-1, and enterovirus C declined, while those against RSV and Epstein-Barr virus increased. Autoantibodies targeting 55 human proteins were found in multiple batches, with TRIM21/Ro52 antibodies rising in parallel with SARS-CoV-2 antibodies. Principal component analysis showed that neither manufacturer nor geographic origin significantly explained overall antibody profiles, though some manufacturer-specific effects were noted in autoantibody content. These findings highlight pandemic-driven shifts in global antiviral immunity and autoantibody prevalence, with potential implications for immune health and autoimmune disease risk.