Improvement of immune dysregulation and health-related quality of life in individuals with long COVID at 24-months following SARS-CoV-2 infection

This study investigated the humoral and cellular immune responses in individuals with long COVID (LC) compared to age and gender matched recovered COVID-19 controls (MC) over 24-months. LC participants showed elevated spike and nucleocapsid IgG levels, higher neutralizing capacity, and increased spike- and nucleocapsid-specific CD4+ T cells, PD-1, and TIM-3 expression on CD4+ and CD8+ T cells at 3- and 8-months, but these differences did not persist at 24-months. Some LC participants had detectable IFN-γ and IFN-β, that was attributed to reinfection and antigen re-exposure. Single-cell RNA sequencing at 24-month timepoint revealed similar immune cell proportions and reconstitution of naïve T and B cell subsets in LC. No significant differences in exhaustion scores or antigen-specific T cell clones were observed. These findings suggest resolution of immune activation in LC and return to comparable immune responses between LC and MC over time. Improvement in self-reported health-related quality of life at 24-months was also evident in the majority of LC (62%). PTX3, CRP levels and platelet count were associated with improvements in health-related quality of life. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We appreciate grant support from the St Vincents Clinic Foundation - the Curran Foundation, the Rapid Response Research Fund (UNSW) - Medical Research Future Fund award GNT 1175865 - - Austin Medical Research Foundation Grant - the Victorian Government - MRFF Award (2005544) - NHMRC program grant (1149990) - NHMRC Fellowships 1136322 and 1123673 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ADAPT study was approved by the St Vincents Hospital Research Ethics Committee (2020/ETH00964) and is a registered trial (ACTRN12620000554965) - ADAPT-C sub study was approved by the same committee (2020/ETH01429) - All data were stored using REDCap electronic data capture tools - Unexposed healthy donors were recruited through St Vincents Hospital and was approved by St Vincents Hospital Research Ethics Committee (HREC/13/SVH/145) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes To protect patient privacy, underlying electronic health records may be accessed via a remote server pending a material transfer agreement and approval from study steering committee. As data within this manuscript are from an ongoing clinical trial, further data will be provided by the corresponding author upon request and will require approval from study steering committee.