The role of immune activation and antigen persistence in acute and long COVID

Abstract

In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the global coronavirus disease 2019 (COVID-19) pandemic. Although most infections cause a self-limited syndrome comparable to other upper respiratory viral pathogens, a portion of individuals develop severe illness leading to substantial morbidity and mortality. Furthermore, an estimated 10%–20% of SARS-CoV-2 infections are followed by post-acute sequelae of COVID-19 (PASC), or long COVID. Long COVID is associated with a wide variety of clinical manifestations including cardiopulmonary complications, persistent fatigue, and neurocognitive dysfunction. Severe acute COVID-19 is associated with hyperactivation and increased inflammation, which may be an underlying cause of long COVID in a subset of individuals. However, the immunologic mechanisms driving long COVID development are still under investigation. Early in the pandemic, our group and others observed immune dysregulation persisted into convalescence after acute COVID-19. We subsequently observed persistent immune dysregulation in a cohort of individuals experiencing long COVID. We demonstrated increased SARS-CoV-2-specific CD4+ and CD8+ T-cell responses and antibody affinity in patients experiencing long COVID symptoms. These data suggest a portion of long COVID symptoms may be due to chronic immune activation and the presence of persistent SARS-CoV-2 antigen. This review summarizes the COVID-19 literature to date detailing acute COVID-19 and convalescence and how these observations relate to the development of long COVID. In addition, we discuss recent findings in support of persistent antigen and the evidence that this phenomenon contributes to local and systemic inflammation and the heterogeneous nature of clinical manifestations seen in long COVID.

Serological markers and long COVID—A rapid systematic review

“…68,69 Several factors preceding (e.g. age, sex and comorbidities) 3,4,15,[18][19][20] and during (hyperinflammation, immunodepression and varying immunomodulatory strategies) 21,[23][24][25][26][27][28][29][30] SARS-CoV-2 infection may influence long COVID manifestations and post-infection serological trends. Controlling for potential confounders is a critical prerequisite to establishing the magnitude and direction of relationships between serological markers and long COVID.…”

“…Given the utility of serological testing to identify past infection, these efforts may illuminate potential differences in antibody detection that are associated with the presence of persisting symptoms, or specific long COVID phenotypes. 5,12,17,[21][22][23][24][25][26][27][28][29][30] Some studies have found that people with long COVID are more likely to elicit a robust humoral response, as compared to people with past COVID-19 infection and no long COVID, which could result from viral antigen persistence or over-activation of the immune system. [24][25][26][27] On the contrary, findings that people with long COVID are more prone to nonresponse, weak response or early waning of antibodies may indicate impaired functional antiviral response.…”

“…5,12,17,[21][22][23][24][25][26][27][28][29][30] Some studies have found that people with long COVID are more likely to elicit a robust humoral response, as compared to people with past COVID-19 infection and no long COVID, which could result from viral antigen persistence or over-activation of the immune system. [24][25][26][27] On the contrary, findings that people with long COVID are more prone to nonresponse, weak response or early waning of antibodies may indicate impaired functional antiviral response. 21,23,[28][29][30] However, investigation of associations between long COVID and serological markers are complicated by differences in inclusion criteria, study procedures, serological assays, choice of antibody and target antigen, timing of follow-up for long COVID assessment and serological sampling, methods of statistical analysis, and completeness of reporting.…”

“…Most of the evidence to date is on adult populations. Given the utility of serological testing to identify past infection, these efforts may illuminate potential differences in antibody detection that are associated with the presence of persisting symptoms, or specific long COVID phenotypes 5,12,17,21–30 . Some studies have found that people with long COVID are more likely to elicit a robust humoral response, as compared to people with past COVID‐19 infection and no long COVID, which could result from viral antigen persistence or over‐activation of the immune system 24–27 .…”

Serological markers and Post COVID-19 Condition (PCC) – A rapid review of the evidence

“…Given the utility of serological testing to identify past infection, these efforts may illuminate potential differences in antibody detection that are associated with the presence of persisting symptoms, or specific PCC phenotypes [5,12,17,[21][22][23][24][25][26][27][28][29][30]. Some studies have found that people with PCC are more likely to elicit a robust humoral response, as compared to people with past COVID-19 infection and no PCC, which could result from viral antigen persistence or over-activation of the immune system [24][25][26][27]. On the other hand, findings that people with PCC are more prone to non-response, weak response, or early waning of antibodies may indicate impaired functional antiviral response [21,23,[28][29][30].…”