Antibody-Dependent Enhancement and How it Relates to the Current COVID-19 Pandemic
One of the most disconcerting aspects of the COVID-19 pandemic is the wide range of presentations that occur across patients. Some are asymptomatic, only finding out that they had the virus through antibody testing, while others can have severe respiratory syndromes requiring a ventilator to stay alive. Outside of predisposing factors like age and comorbidities, it is seemingly random who will struggle and who won’t. While this phenomenon may still baffle us, there is a possible explanation of what is causing such severe lung damage in the most serious cases. The proposed mechanism deals with a process called an antibody-dependent enhancement, and it may have implications in both treating patients with acute infection and the development of a COVID-19 vaccine in the future.
What is Antibody-dependent Enhancement (ADE)?
Starting with the basics of acquired immunity, the body takes pieces of proteins from viruses that it can recognize, called antigens, then it makes antibodies that attach to that specific protein in order to prevent the virus from replicating in our cells, thereby making it easier for other immune cells to destroy. Due to viruses’ fast evolution, there can be multiple serotypes of the same virus, different versions of the virus with very minute differences. Our immune system is structured so that the antibodies that “stick around” long after the original infection has resolved are not the ones that can easily take out a different viral serotype (1); however, they are still specific enough to interact with that virus. Thus, some viruses have been able to use the interaction with those antibodies to enter cells, via cell receptors, in order to replicate. This process facilitates viral replication, which increases the host’s overall virility, leading to a more severe presentation (1). This effect has been seen in multiple viruses, including the SARS-Cov-1 virus, MERS, and Dengue. While ADE is proven in other viruses, there is significant debate in the scientific community about whether COVID-19 is able to use the ADE mechanism, or how many severe cases could be attributed to ADE. There is contradictory evidence coming from several case reports from China suggesting worse outcomes in cases of re-infection, as opposed to several animal studies indicating that macaques re-infected with COVID-19 showed no signs of infection (2).
Potential mechanism of severe lung disease in COVID-19
Based on studies of both the original SARS virus and feline infectious peritonitis virus (FIPV) (1), which both belong to the coronavirus family, and observational studies on COVID-19, one possible cause of severe pneumonia and acute respiratory distress syndrome (ARDS) caused by the virus comes through dysfunctional activation of the immune system. Based on the levels of a specific antibody, IgG, found in COVID-19 patients with ARDS, it is thought this dysfunction could be triggered through ADE (3). But the exact mechanism is unknown. Normally the immune cells in the lungs produce inflammatory cytokines to fight infection in the lungs while simultaneously releasing healing factors to protect lung tissue from permanent damage. Eventually, as the infection clears, the inflammatory factors are reduced, and the healing factors are increased to help the lungs recover (4). However, in some cases of coronavirus infection, possibly due to the interaction of immune cells and virions facilitated by ADE, more immune cells were secreting inflammatory factors, and those inflammatory factors were still being secreted after the virus had been cleared from the lungs, meaning lung pathology is not necessarily tied to viral load (4). This creates a kind of positive feedback loop, where massive infiltration by immune cells causes damage to the lungs and other organs (3). Apart from several studies showing this mechanism in animal models, observational studies during the original SARS outbreak in Hong Kong showed that patients with significant lung pathology developed pro-inflammatory antibodies faster than other patients and in much higher levels (4), most likely leading to a significant portion of them developing ARDS, the lung syndrome responsible for patients being placed on ventilators. This is an important discovery as it shows a possible mechanism for the most severe pathology associated with COVID-19 and where we might intervene to effectively treat these patients.
What implications does ADE have for a COVID-19 vaccine?
While it is unclear what the role of ADE is in active infection of COVID-19, it is certainly something that must be considered in the continued development of vaccines and treatment for COVID-19. There have already been concerns expressed by those in the scientific community about the risks of rushing the development of a COVID-19 vaccine without testing it properly. ADE has featured prominently in the development of vaccines for viruses in the past, including Dengue (1) and RSV (2). In a study of Dengue vaccination, it was found that protection was conferred from a vaccination as long as antibody levels remained above a certain threshold, and in subjects below that threshold, severe forms of Dengue fever, such as Dengue hemorrhagic fever and shock syndrome, were approximately eight times more likely to occur (1). Other examples include the 2008-09 flu vaccine, possibly worsening the H1N1 pandemic, and a series of RSV vaccines in the 1960s, leading to severe adverse effects, although evidence for both is not conclusive (5). Regardless, ADE poses a challenge to vaccine developers in that they have to ensure antibody response from the body is adequate to neutralize different serotypes of the virus in order to avoid the conditions that would allow it to utilize ADE. This is even more apparent when taken in the context of the pandemic, where the first vaccine recipients would most likely be vulnerable populations. Not only would these populations be extremely vulnerable if the virus were able to use ADE to enhance virility, but with a poorly developed vaccine, they will be more likely to have the conditions under which ADE would occur. While there is scant evidence that ADE is a significant part of COVID-19 infection, it is an idea worth considering before putting all the metaphorical eggs into the single basket of distributing a vaccine that was not tested as rigorously as it might have been if there wasn’t a global pandemic going on.
1. Negro F. Is antibody-dependent enhancement playing a role in COVID-19 pathogenesis? Swiss Med Wkly [Internet]. 2020 Apr 16 [cited 2020 Jun 30]; Available from:
2. Peeples L. News Feature: Avoiding pitfalls in the pursuit of a COVID-19 vaccine. Proc Natl Acad Sci. 2020 Apr 14;117(15):8218–21.
3. Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020 May;20(5):269–70.
4. Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H, et al. Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019 Feb 21;4(4):e123158.
5. Hotez PJ, Corry DB, Bottazzi ME. COVID-19 vaccine design: the Janus face of immune enhancement. Nat Rev Immunol. 2020 Jun;20(6):347–8.