The study, based on a population cohort in England, measured levels of antibodies to the SARS-CoV-2 virus
Vaccination and repeated exposure to the virus have reduced the severity of new infections with SARS-CoV-2. However, a considerable portion of people are left with chronic, disabling post-infectious symptoms known as long COVID or Post-COVID condition (PCC).
“The mechanisms leading to PCC are not well understood, but could involve aberrant immune responses to the virus,” explains Sarah Beale, END-VOC researcher at University College London (UCL) and study coordinator. Together with colleagues at UCL and the Barcelona Institute for Global Health (ISGlobal), they explored how the immune system behaves in people who develop PCC, compared to those who fully recover.
The research team followed over 2,000 participants from the Virus Watch community cohort, regularly collecting blood samples through finger-prick tests. Their goal was to understand differences in antibody responses after SARS-CoV-2 infection and vaccination. Everyone in the study had mild-to-moderate infections and did not require hospital care.
Higher levels of anti-N antibodies
They found that people who developed long COVID showed a stronger and more prolonged immune response to the virus itself—specifically, they had higher levels of anti-nucleocapsid (anti-N) antibodies, which are produced in response to infection. In fact, people with PCC were nearly twice as likely to show a measurable antibody response compared to those who had an acute infection but recovered fully.
This stronger immune response was most noticeable in people who were unvaccinated and infected before the Omicron variant became dominant. Interestingly, vaccination responses—measured through anti-spike (anti-S) antibodies—did not differ significantly between the two groups. This suggests that differences in antibody response were specific to infection.
The findings suggest that long COVID may be linked to prolonged or heightened immune activation after the initial infection. “Our study extends previous evidence suggesting altered adaptive immune responses in long COVID, and highlight the importance of longitudinal studies,” says Sarah Beale. This could help researchers better understand what causes long COVID and eventually improve diagnosis and treatment.
Reference
Beale, S., Yavlinsky, A., Moncunill, G. et al. Anti-nucleocapsid and anti-spike antibody trajectories in people with post-covid condition versus acute-only infections: a nested longitudinal case-control study within the Virus Watch prospective cohort. Nat Commun. 2025. https://doi.org/10.1038/s41467-025-58766-7
