The Breadth of the Neutralizing Antibody Response to Original SARS-CoV-2 Infection is Linked to the Presence of Long COVID Symptoms

Background: The associations between longitudinal dynamics and the breadth of SARS-CoV-2 neutralizing antibody response with various Long COVID (LC) phenotypes prior to vaccination are not known. The capacity of antibodies to cross-neutralize a variety of viral variants may be associated with ongoing pathology and persistent symptoms. Methods: We measured longitudinal neutralizing and cross-neutralizing antibody responses to pre- and post-SARS-CoV-2 Omicron variants in participants infected during the early waves of the COVID-19 pandemic, prior to widespread rollout of vaccines. Cross-sectional regression models adjusted for clinical covariates and longitudinal mixed-effects models were used to determine the impact of the breadth and rate of decay of neutralizing responses on the development of LC symptoms in general, as well as LC phenotypes. Results: Neutralizing responses to the original infecting strain were not associated with LC in cross-sectional analyses. However, cross-neutralization ID50 levels to Omicron BA.5 approximately 4 months following acute infection were independently and significantly associated with greater odds of LC and with persistent gastrointestinal and neurological symptoms. Longitudinal modeling demonstrated significant associations between overall levels and rates of decay of neutralization capacity and LC phenotypes. A higher proportion of participants had antibodies capable of neutralizing Omicron BA.5 compared with BA.1 or XBB.1.5 variants. Conclusions: Relationships between immune responses and LC are likely complex but may involve the breadth of antibody neutralization responses.

Amanda M Buck, Amelia N Deitchman, Saki Takahashi, Scott Lu, Sarah A Goldberg, Rebecca Hoh, Meghann C Williams, Marian Kerbleski, Tyler-Marie Deveau, Sadie E Munter, James Lombardo, Terri Wrin, Christos J Petropoulos, Matthew S Durstenfeld, Priscilla Y Hsue, J Daniel Kelly, Bryan Greenhouse, Jeffrey N Martin, Steven G Deeks, Michael J Peluso, Timothy J Henrich