Symptoms of coronavirus disease 2019 (COVID-19) can persist beyond the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, typically around 28 days after initial diagnosis. Post-acute consequences of coronavirus disease 2019 (PASC), often referred to as “long-COVID,” is often used to describe the presence of these long-term symptoms after initial recovery from COVID-19. PASC can cause significant morbidity despite apparent clearance of SARS-CoV-2 from the body.
Several mechanisms for long COVID evolution have been proposed, such as B. the persistence of SARS-CoV-2 or a dysregulation of the immune system with altered humoral reactions. However, more research is needed to determine the exact mechanisms responsible for this condition.
To learn: Impact of cross-coronavirus immunity on post-acute consequences of COVID-19. Photo credit: joshimerbin / Shutterstock.com
In a recently published study on the medRxiv* Preprint servers allow researchers to run comprehensive antibody (Ab) profiles against SARS-CoV-2, several endemic pathogens and vaccine antigens in patients with rheumatic diseases with or without PASC. This information was used to determine whether SARS-CoV-2 or other pathogen-directed humoral responses develop in a unique manner in long-COVID.
About the study
In the present study, researchers examined changes in humoral immune responses to SARS-CoV-2, common CoVs, herpesviruses, and multiple vaccine antigens to investigate whether pathogen-directed Abs could provide information relevant to Long COVID pathogenesis. Furthermore, they focused on a single long COVID endotype, applying systems serology to patients with rheumatic diseases who developed mild to moderate SARS-CoV-2 infection, 50% of whom developed long COVID.
From March 1st, 2020 all sautoimmune rheumatic disease (SARD) participants with polymerase chain reaction (PCR) or antigen-confirmed COVID-19 were identified by the Massachusetts General Brigham (MGB) Health System. In addition, the patient information was supplemented by rheumatological referrals from SARS-CoV-2 infected patients.
The study included people who did not require hospitalization for COVID-19 and excluded people with a history of fibromyalgia, mechanical back pain, osteoarthritis, gout, or pseudogout without SARD.
Antigen-specific isotype titers and Fc receptor (FcR) binding were measured by multiplex Luminex assays. Mean fluorescence intensity (MFI) values and avidity index values were also calculated.
Ab-dependent neutrophilic phagocytosis (ADNP) and seropositive assays were also performed. To investigate accumulation of a specific inflammation-related COVID long endotype, humoral responses of COVID-19-recovering patients with SARD were assessed.
The isotype, subclass, and Fc-R binding profiles against SARS-CoV-2 nucleocapsid (N), spike (S), S-subunit 2 (S2), and S-receptor binding domain (RBD) were evaluated between the two groups of rheumatism patients. The team investigated whether changes in humoral responses to commonly administered vaccines and endemic pathogens could provide insight into humoral differences between SARD patients with and without long-COVID.
The team assessed Ab isotypes and Fc gamma receptor (FcγR) binding titers across multiple antigens, including antigens routinely incorporated into vaccines such as rubella, tetanus, mumps and measles, herpesviruses including cytomegalovirus (CMV), herpes simplex virus 1 (HSV1), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV), as well as other CoVs expressing the S, S1, and S2 proteins of OC43, HKU1, and SARS-CoV-1 use.
Humoral responses against other endemic pathogens such as respiratory syncytial virus (RSV), Staphylococcus aureus, influenza virus and pathogenic control organisms such as Ebola were evaluated. Partial least squares discriminant analysis (PLS-DA) and elastic net regularization were performed to visualize the humoral differences between the two groups.
The analysis profiled 17 long-term COVID and SARD patients and 26 short-term COVID patients, 95% of whom were vaccinated against COVID-19. In addition, 79% of the study participants were women.
Rheumatoid arthritis was the most commonly reported rheumatic disease, while tumor necrosis factor (TNF) inhibitors were the most commonly used therapeutics.
Reduced anti-SARS-CoV-2 S and S2 immunoglobulin M (IgM) and IgG2 titers and higher OC43- and CMV-directed inflammatory Ab titers have been observed in long COVID patients. Conversely, not long-COVID individuals showed more significant isotype/subclass titers but no FcγR binding titers. Anti-CMV responses were primarily driven by CMV seroprevalence imbalances.
SARS-CoV-2 spike-directed responses are lower in people who have been affected. (A, B, C, D) Violin plots show IgG1, IgG2, IgA1, and IgM titers against SARS-CoV-2 nucleocapsid (N) and spike in subjects who have experienced PASC (yellow) and in Individuals without PASC (red). ). A two-tailed Mann-Whitney U test determined significance. (E,F,G,H) Radar plots show the mean percentile rank of antibody titers and Fc receptor (FcR) binding against nucleocapsid, spike (Full spike, RBD and S2 domain) and for individuals in whom PASC (Yellow ) and those who didn’t (red). Significance was determined by a two-tailed Mann-Whitney U test. *p=0.05, p<**0.05
Anti-OC43 responses were primarily driven by high avidity anti-OC43 IgM titers. Class-switched FcγR-binding OC43 responses were inversely correlated with the quality and quantity of anti-SARS-CoV-2 humoral responses.
Notably, OC43 S FcγR-binding Abs were significantly increased in long COVID patients, while IgG3 and IgM titers were not increased. This suggests an expansion of highly inflammatory IgG1 responses rather than novel OC43-Ab evolution in long COVID patients. Taken together, these results suggest a possible role of the former common CoV backbooster as a driver of incomplete SARS-CoV-2 Ab production in SARD patients who have developed a long COVID.
Anti-S2 responses trended toward stronger IgG1, IgG2, IgA, and IgM responses, as well as specific opsonophagocytic FcRs, including FcγR2a and FcγR 2b, in non-long-COVID patients. In addition, increased levels of anti-RSV IgM/IgG3, anti-influenza hemagglutinin (HA) FcγR2a and FcγR2b binding titers, anti-SARS-CoV-S1 IgA and anti-tetanus IgG-Ab/IgM-Ab selectively in non-long-fortified COVID individuals.
In contrast, anti-OC43 S FcγR3a and FcγR3b and anti-CMV gB FcγR2a/3b/IgM binding titers were enriched in long COVID patients. Therefore, long COVID appears to be associated with significantly altered polyclonal-type humoral responses to vaccines and common pathogens.
Overall, the study results underscore the potential role of previous CoV shared imprinting or “antigenic original sin” in the incomplete maturation of SARS-CoV-2-specific humoral immunity as a marker and potential mechanism in the persistence of long COVID symptoms.
medRxiv publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health behavior or treated as established information.