Based on report published in NIH’s The National Library of Medicine, which indicated that autoimmunity can impact how COVID is treated, Dr Bharesh Dedhia, consultant, Critical Care, PD Hinduja Hospital and Medical Research Centre, Khar, Mumbai reflects on need for measuring immunogenicity and testing to assess pathogenic priming
Pathogenic priming, known as Antibody Mediated Enhanced Disease or Antibody Dependent Enhancement (ADE) is a real phenomenon, but this has not occurred with the COVID-19 vaccine. Under certain very rare circumstances, a body can produce antibody that when it later encounters the real germ, actually enhances disease.
ADE occurs when the antibodies generated during an immune response recognise and bind to a pathogen, but they are unable to prevent infection. Instead, these antibodies act as ‘Trojan horse,’ allowing the pathogen to get into cells and exacerbate the immune response
ADE can result from a vaccine, as was the case with one vaccine from the 1960s.The classic example of that was a vaccine developed against the Respiratory Syncytial Virus in the 1960s. When children who got it, got sick after they got exposed to RSV. That stopped once the vaccine was withdrawn.
We would have seen the phenomenon with COVID-19 vaccines in the laboratory, during animal testing and during early trials. The vaccines were authorised for use since ADE did not occur.
Neither COVID-19 disease nor the new COVID-19 vaccines have shown evidence of causing ADE. People infected with SARS-CoV-2, the virus that causes COVID-19, have not been likely to develop ADE upon repeat exposure.
Autoimmunity and impact of COVID-19 treatment
So, how does autoimmunity due to the risk of pathogenic priming affect the treatment of COVID-19? Who are the kind of people likely to be impacted by pathogenic priming and how does it affect them?
If autoimmunity due to the risk of pathogenic priming affects the treatment of COVID-19, is actually happening and proved, then it would explain why some patients are sicker and that would make the treatment of COVID-19 more challenging and difficult.
The autoimmune phenomenon would make the body’s own immune cells attack and kill other cells and tissues and organs. Thus patients would likely be a lot sicker with higher complications and death rates. More immunosuppressants would be required, leading to more secondary bacterial and fungal infections. Indeed, this clinical scenario is routinely seen in extremely sick and critical COVID patients.
ADE has been documented to occur through two distinct mechanisms in viral infections (not in COVID-19 at present): by enhanced antibody-mediated virus uptake into Fc gamma receptor IIa (FcγRIIa)-expressing phagocytic cells leading to increased viral infection and replication, or by excessive antibody Fc-mediated effector functions or immune complex formation causing enhanced inflammation and immunopathology.
Both ADE pathways can occur when non-neutralising antibodies or antibodies at sub-neutralising levels bind to viral antigens without blocking or clearing infection. Susceptible individuals are likely to be elderly, those with dysregulated immune systems, with a history of autoimmune disorders and with comorbidities like diabetes etc.
Though there is currently no evidence that pathogenic priming is happening with COVID-19 vaccines, if that were to happen, then it would definitely reduce the efficacy of the COVID-19 vaccines.
Immunogenicity however, is a more complex measure of how well a vaccine works, and measures the type of immune responses that the vaccine generates and their magnitude over time. The immune response is measured with the level of antibodies especially the neutralising antibodies, and the T-cell response to the infection.
The overall level of antibodies a person has produced can be measured through techniques such as ELISA (enzyme-linked immunosorbent serum assay), and specific neutralising antibodies can be screened for via virus neutralising assays. T-cells have many roles in the immune response, including activating other immune cells, producing cytokines – secreted factors which can activate or inhibit other immune activity – and even directly killing infected or abnormal cells. Measurement of T-cell responses can be more complex than the measurement of antibody levels, but through assays such as enzyme-linked immunospot assays it is possible to define which types of T-cells are present and at what level.
Testing is required to assess pathogenic priming
Complex laboratory testing is required to document pathogenic priming. ADE can be measured in several ways, including in vitro assays (which are most common for the first mechanism involving FcγRIIa-mediated enhancement of infection in phagocytes), immunopathology or lung pathology. Higher infection rates of target cells occur in an antibody-dependent manner mediated by Fc–FcR interactions. ADE via enhanced infection is commonly measured using in vitro assays detecting the antibody-dependent infection of cells expressing FcγRIIa, such as monocytes and macrophages. Also enhanced disease and immunopathology are caused by excessive Fc-mediated effector functions and immune complex formation in an antibody-dependent manner. The antibodies associated with enhanced disease are often non-neutralising. ADE of this type is usually examined in vivo by detecting exacerbated disease symptoms, including immunopathology and inflammatory markers.
ADE (of the second type described above) are often identified by clinical data, including symptom prevalence and disease severity, rather than by the specific molecular mechanisms that drive severe disease. The presence of complex feedback loops between different arms of the immune system makes it very difficult (although not impossible) to conclusively determine molecular mechanisms of ADE in human and animal studies, even if the clinical data supporting ADE are quite clear.