Serum Level of Anti-Nucleocapsid, but Not Anti-Spike Antibody, Is Associated with Improvement of Long COVID Symptoms

Abstract

Background: Long COVID is a condition characterized by long-term sequelae persisting after the typical convalescence period of COVID-19. Previous reports have suggested the role of an unsatisfactory immune response and impaired viral clearance in the pathogenesis of long COVID syndrome. We focused on potential associations between post-vaccination changes of antibody titers and the severity of long COVID symptoms and factors influencing the state of remission observed in patients with long COVID after vaccination.

Methods: The severity of long COVID symptoms and serum anti-SARS-CoV-2 spike (S-Ig) and nucleocapsid (NC-Ig) levels were assessed in 107 post-COVID subjects at two time points: at baseline, and 17-24 weeks later. Besides, vaccination status was also assessed. Symptoms were evaluated based on the Chalder fatigue scale (CFQ-11) and visual analogue scale (VAS).

Results: Serum level of S-Ig and NC-Ig at baseline were significantly higher in the patients with non-severe fatigue than those with severe fatigue, and this difference remained significant at follow-up in the case of NC-Ig. NC-Ig level above median was as an independent predictor for complete remission at follow-up. The difference in NC-Ig levels in subgroup analyses (severe fatigue vs. non-severe fatigue; complete remission vs. incomplete remission or progression) was found to be significant only in patients who received vaccination.

Conclusions: The immune response against the SARS-CoV-2 nucleocapsid may play a more important role than the spike in the course of long-term COVID syndrome.

Keywords: fatigue; long COVID; nucleocapsid; spike; vaccination.

Figure 1

Association between the severity of post-COVID fatigue and serum level of anti-SARS-CoV-nucleocapsid immuneglobulins at baseline and follow-up visits. We used the Chalder-fatigue scale (CFQ-11) to establish a case definition for severe fatigue by utilizing a bimodal scoring system ranging between 0–11. A case of severe fatigue was defined as a score of 4 or more. Group A, (N = 30): patients experienced severe fatigue neither at baseline nor at follow-up (bimodal score < 4 at both visit). Group B, (N = 6): patients only had severe fatigue at follow-up (bimodal score ≥ 4), and baseline bimodal score was <4. Group C, (N = 20): patients had severe fatigue (bimodal score ≥ 4) at the baseline visit but not at follow-up. Group D, (N = 51): at both visits, patients experienced severe fatigue (bimodal score ≥ 4). Time of baseline visit was at least 30 days after COVID-19 symptom onset. Next, follow-up visit was 17–24 post-baseline weeks. Nucleocapsid IgA + IgM + IgG level (NC-Ig). Statistical analysis was performed using Mann–Whitney-U test in each group, respectively.

Figure 2

Patients with severe fatigue show decreased level of serum antiSARS-CoV-2 nucleocapsid-Ig (A + M + G) antibody levels both in unvaccinated (non-severe fatigue, N = 9 vs. severe fatigue, and N = 14) and vaccinated (non-severe fatigue, N = 41 vs. severe fatigue, and N = 43) individuals but significance is observed only in the vaccinated group. The case definition of severe fatigue was established using a combination of a bimodal scoring system and the CFQ-11 scale, resulting in a final score ranging between 0–11. A score of 4 or more was defined as severe fatigue. Statistical analysis was performed using Mann–Whitney-U test.