What is Antibody-Dependent Enhancement (ADE)?

Part I: The Fundamentals

A few times on my blog, I’ve discussed antibody-dependent enhancement (ADE) but I’m seeing it come up more and more as we approach EUA and eventually approval for COVID-19 vaccines, so I thought it would be helpful for people to have a separate post discussing it in some depth.

Part II: The Whole Story

Lu, L. L., Suscovich, T. J., Fortune, S. M., & Alter, G. (2018). Beyond binding: antibody effector functions in infectious diseases. Nature Reviews. Immunology, 18(1), 46–61. Figure 3, summarizing the different effector functions of antibodies. Antibodies do bind and neutralize viruses and toxins, but they can also do many other things. For instance, they prevent biofilm formation (IgA antibodies, which are very abundant at mucosal surfaces, are particularly good at this). They can also stimulate release of chemokines- small proteins that direct cells to the source of the chemokines. Furthermore they can activate other cells of the immune system, like neutrophils, macrophages, and NK cells. In viral infection, antibody-dependent cellular cytotoxicity (ADCC) can be very important for killing infected cells, and in particular, afucosylated antibodies (antibodies without fucose sugars on them) are very good at this. IgG antibodies are also very important activators of complement (IgM can also do this but to a lesser extent). Fc receptors on the surfaces of cells can sense antibodies and their signaling can change the behavior of cells.
Arvin, A. M., Fink, K., Schmid, M. A., Cathcart, A., Spreafico, R., Havenar-Daughton, C., … Virgin, H. W. (2020). A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature, 584(7821), 353–363. Figure 2, summarizing potential mechanisms by which ADE might occur. Note that these are also normal physiological actions of antibodies, and it is not clear what drives pathogenic responses and what drives protective responses.
  • induce respiratory burst from neutrophils (which releases reactive oxygen species, ROS, and reactive nitrogen species, RNS, that while important in host defense, do also cause damage to neighboring cells in a somewhat indiscriminate manner)
  • mediate antibody-dependent cellular cytotoxicity (wherein antibodies bind to viral proteins still budding off the surface of a cell, triggering an NK cell to kill the infected cell)
  • promote maturation of dendritic cells (mature dendritic cells go on to license immune responses and need danger signals to do this; FcγRIIb is also expressed on these cells and thus their maturation depends on the relative balance of FcγRIIb compared with activating members of the FcγR family)
  • Induce the release of cytokines and chemokines that recruit other cells of the immune system to the site of insult
  1. ADE is rare and limited to only a few infections. Even though evidence of ADE can be observed in preclinical models for many pathogens, the cases in which it has demonstrated true clinical evidence are scant.
  2. ADE in vitro does not equate to ADE in vivo.
  3. ADE in an animal model does not, unfortunately, predict ADE in humans.
  4. ADE does not necessarily mean a dead end for vaccine prospects. Dengue, the most famous offender, will soon have a vaccine which does not cause ADE.
  5. ADE does not occur at all levels of antibodies but rather within a specific window, typically as they start to wane. This is explained by a drop in the total avidity of neutralizing antibodies.
  6. Convincing evidence of ADE for COVID-19 has not been demonstrated in nearly a year of this pandemic, despite highly prevalent use of convalescent plasma, indicating it is either very rare, or it doesn’t happen. The conclusion from either outcome is that you should not be concerned about it occurring from a possible COVID-19 vaccine that has passed through clinical trials.

Part III: Non-ADE Mechanisms of Vaccine-induced Disease Enhancement

References

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Edward Nirenberg

Edward Nirenberg

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I write about vaccines here. You can find me on Twitter @enirenberg and at deplatformdisease.com (where I publish the same content without a paywall)