Robust antibody and T cell responses tracked longitudinally in patients with long COVID, 2025, Metaxaki et al.

[SNT Gatchaman]

Robust antibody and T cell responses tracked longitudinally in patients with long COVID

Spoiler: Authors (Addenbrooke's / Cambridge)

Marina Metaxaki; Ranjana Ram; Marianne Perera; Mark Wills; Benjamin A Krishna; Nyarie Sithole

After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, a minority of patients experience persistent or emerging symptoms, termed ‘long coronavirus disease (COVID) or post-acute sequelae of COVID-19. The molecular causes of long COVID remain unclear, but disrupted immune functions, such as inflammation and immune deficit, have been posited as factors.

In this retrospective cohort study, we measured markers of immune function in a group of patients with long COVID up to 40 months post infection. As proxies for immune function, we measured serum antibody levels, antibody neutralizing capability and production of IFN gamma (IFN-γ) and IL-2 against SARS-CoV-2 and other viral peptides. As expected, serum antibody levels increased over time with vaccinations and reinfections with later variants of SARS-CoV-2.

Patients also showed corresponding increasing SARS-CoV-2-specific IL-2 responses and stable IFN-γ responses. We observed no significant differences in immune responses among patients with ongoing long COVID, those who had recovered from it or individuals who recovered from acute COVID-19.

Overall, we found no indication of a reduction in these aspects of immune function after SARS-CoV-2 infection. This study provides a valuable foundation for further research aimed at understanding the causes of long COVID.

Web | DOI | Journal of General Virology | Open Access

 

[SNT Gatchaman]

The recruitment for this study commenced in April 2020. Across 40 months, 129 patients were recruited from the long COVID clinic at Addenbrooke’s Hospital who experienced ongoing symptoms for at least 3 months consistent with the definition of long COVID by NICE.

We found that almost half of the patients who returned for third and fourth visits recovered fully from their long COVID symptoms. However, of note is that certain symptoms, such as fatigue, persisted for much longer than others such as coughing

In the long COVID cohort, this analysis revealed a statistically significant, gradual increase in S-, Nc- and M-specific T cell IL-2 responses over time. The effect was strongest for spike-stimulated IL-2 responses, which increased 50-fold from 10 to 517 SFU per million PBMCs and weakest for membrane responses, rising from 8.5 to 80 SFU per million PBMCs. The responses to the CEF control remained stable over time, indicating that the increases in IL-2 production are specific for SARS-CoV-2.

We therefore decided to test whether the patients whose symptoms had resolved showed different immunological profiles to those who had not recovered, as this might correlate long COVID symptoms with immunodeficiency. We therefore compared anti-S and anti-Nc antibody titres as well as T cell responses to each peptide pool in nine patients who reported persistent long COVID symptoms and eight patients who reported complete symptom resolution. Across ten different variables, we found no statistically significant changes.

In summary, we have tracked anti-SARS-CoV-2 antibodies, antiviral IL-2 and IFN-γ T cell responses in long COVID over time. We conclude that long COVID patients do not show deterioration of these immune functions months or years after initial SARS-CoV-2 infection, and resolution of long COVID symptoms does not correlate with changes in these immune functions.

It should be noted that serum antibody levels and IL-2 and IFN-γ responses to SARS-CoV-2 peptide stimulation are only one aspect of the immune response which we use here as a proxy for general immunity. Additionally, although we recruited a large number of long COVID patients at the start of the study, only 15 participated for the entire 40-month duration of the study. Indeed, it is possible that the patients who chose to return for the entire duration were in better health than those who dropped out, leading to a skewing in our data.

To address these limitations, it is important that future studies have larger cohorts and evaluate immune responses in more depth, such as analysing Natural Killer (NK) cell, γδT cell and other cell functions in the future.

Our findings demonstrate that long COVID patients maintain a robust functional immune status with no evidence of immune deficiency based on clinical symptomatology and immune molecular assessment.