Antibody-Dependent Enhancement: 
How it can make vaccine dangerous. 8

It is perhaps more of a technical question, but it’s an important one from a clinical perspective. Designing drugs and vaccines against viruses is very complicated. And one potential problem is called Antibody-Dependent Enhancement (ADE). And ADE can make things worse, not better for the patient. What is antibody-dependent enhancement? And how is it relevant for the treatment and vaccine design for the COVID-19 coronavirus. So antibody-dependent enhancement is a worry with other viruses. It is a big worry with flaviviruses, like dengue fever virus, for example. And what happens is the antibodies that you make against the vaccine, say, or maybe from an infection can actually be used by the virus to get into cells that bind that antibody. So what happens is the antibody doesn’t block the infection. But it forms a bridge between the virus and a new class of target cells. And so this can make a not very serious disease very serious. And the classic case is again the dengue hemorrhagic fever. You get, after you raise antibodies, just a slightly different form of dengue. And indeed, the dengue fever vaccine has been hampered by its ability to increase infections and hospitalizations in individuals who have never had dengue fever disease. So there is a literature in the case of coronavirus, in the case of SARS-1, mostly associated with animals, that antibodies can indeed make things worse, either through conventional antibody-dependent enhancement of the kind that I just described. Or through other mechanisms involving complex relationships with specific classes of T cells. And this is, I would say, at best, a circumstantial case at the moment. But it does really reflect a sort of a back of the mind worry for all vaccine developers. In our mind, the best way to avoid this possibility is to focus on antibodies that are very effective at blocking the virus and avoiding antibodies that do not block the virus. Because we know that antibodies that block the virus mediate less effective antibody-dependent enhancement, less robust enhancement, than antibodies that do not block the virus. In the case of engineered antibodies, we can avoid this completely by modifying a piece of the antibody so that it cannot enhance viral infection. And that’s quite good for the passive use of antibodies. And we can also monitor convalescent sera, sera from individuals [who recovered from COVID-19 coronavirus infection]. We have to make sure that the dominant property of the COVID-19 convalescent sera is to neutralize or block the infection rather than to enhance the infection. So we can monitor and control the possibility of that, in most cases. Where it’s less easy to control [antibody-dependent enhancement] is in the context of a vaccine. And that’s because humans are very different. And they have a range of responses [to vaccines]. You can’t always predict what the response is. You can’t predict the intensity of a response [to vaccine]. And you can’t predict the nature of the response. So that’s why we believe that it’s very important to focus on those regions of the [corona]virus that are less likely to mediate antibody-dependent enhancement. As long as there are questions that antibody-dependent enhancement exists in the case of coronavirus. However, it should be reiterated that there’s no definitive evidence that antibody-dependent enhancement is playing a role in current COVID-19 pathology. And there’s no evidence that a coronavirus vaccine in humans would make things worse.