A new study published in Communications Medicine has identified distinct patterns of inflammatory and neurological proteins in the blood of individuals with long COVID, separating them from those who recovered or were never infected.
Research conducted by scientists in Australia and Norway also examined how vaccination and subsequent infections affected these protein levels, offering new insights into the biological underpinnings of the condition.
Study Design and Methodology
Researchers analyzed blood samples from participants in Victoria, Australia. Samples were collected 6 to 9 months after the participants' initial SARS-CoV-2 infection and before any COVID-19 vaccination. The study included three groups:
- Healthy individuals who had never been infected with SARS-CoV-2.
- Individuals who had recovered from COVID-19.
- Individuals diagnosed with long COVID.
Using a technique called multiplexed affinity proteomics, scientists measured 182 inflammatory and neurology-related proteins in the blood. A subset of participants also provided additional blood samples after receiving a third (booster) dose of the COVID-19 vaccine and after experiencing a breakthrough infection. Machine learning analyses and linear mixed-effects models were used to identify candidate biomarkers and analyze how protein levels changed over time. All participants provided written informed consent, and the study received ethical approval from institutional review boards.
Key Findings on Protein Differences
The study identified several proteins that differed significantly between the three groups.
Long COVID vs. Healthy and Recovered Individuals:
- Several proteins were identified as potential discriminators for long COVID.
- Interleukin-20 (IL-20) was found to be elevated in individuals with long COVID compared to the other groups.
- Other proteins that differed between long COVID and healthy individuals included C-type lectin domain containing 10A (CLEC10A), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and hydroxyacylglutathione hydrolase (HAGH).
Recovered Individuals vs. Healthy Individuals:
- People who had recovered from COVID-19 also showed protein differences compared to healthy individuals.
- Fibroblast growth factor 19 (FGF-19) and cystatin D (CST5) were associated with recovery status.
Vaccination and Reinfection Responses
The study also tracked changes in participants' immune responses after vaccination and subsequent infections.
Antibody Responses:
- After receiving a booster dose, all groups developed strong antibody responses characterized by high levels of spike-specific immunoglobulin G (IgG).
- Following a breakthrough infection, individuals with long COVID and those who had recovered showed lower levels of spike-specific antibodies compared to newly infected healthy individuals.
Inflammatory and Neurological Protein Markers:
- Some protein markers, including sirtuin 2 (SIRT2) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), decreased after reinfection compared to their levels before vaccination.
- The inflammatory patterns observed after the initial infection were not replicated following reinfection in individuals with long COVID.
- In people with long COVID, vaccination did not worsen inflammation. Inflammatory protein levels either stabilized or decreased following vaccination.
Study Context and Limitations
The authors noted that an estimated 5% to 30% of people infected with SARS-CoV-2 continue to experience symptoms months later, a condition known as long COVID. They stated that immune dysregulation is thought to be a possible cause, but conclusive biological markers have not been established.
The researchers noted that the study was small and exploratory. They stated that the findings are preliminary and require validation in larger cohorts.
Additional Study on Antibody Levels in the Omicron Era
In a separate study published in the British Journal of Biomedical Science, researchers at Okayama University investigated antibody levels in 275 patients with long COVID during the Omicron era. The study found that:
- Levels of antibodies against the SARS-CoV-2 spike protein were strongly associated with the number of vaccine doses received.
- Levels of antibodies against the nucleocapsid protein reflected infection-related factors such as disease severity and time since infection.
- Patients experiencing memory impairment had significantly lower levels of spike antibodies than those without memory problems.
- Higher spike antibody levels were associated with better self-reported quality of life.