What is the relationship of Antibody-Dependent Enhancement (ADE) to heightened COVID symptoms?


Q: Is this a worry with the vaccine? What about with reinfection?”

A: Antibody-dependent enhancement or ADE is not a concern with the Pfizer and Moderna vaccines and will not likely be a concern with the other vaccines that will be approved.

Vaccine developers and the FDA are all looking carefully for any evidence of ADE, and will continue to do so. The data from the clinical trials are very convincing that the vaccine prevents disease–and does NOT make infection worse, which is what ADE is. More data is needed to understand whether ADE is an issue with SARS-CoV2 reinfections, although it is unlikely based on current available data.

First of all, what is antibody-dependent enhancement?! Let’s start with Immunology 101. Antibodies are small proteins that are made when your body has an immune response. Antibodies basically look like a Y. The side shaped like a V is unique to each antibody and will recognize different parts of the virus. The opposite side, shaped like an I, is called the Fc and is the same on all antibodies. Other cells can recognize this constant portion of antibodies.

When an antibody binds a virus there are 2 different kinds of antibodies-neutralizing and opsonizing (aka non-neutralizing).

Neutralizing antibodies are the best kind of antibodies. They bind to the virus and prevent the virus from entering your cells. These antibodies can stop infections before they occur. The goal of vaccines to develop as many neutralizing antibodies as possible.

Opsonizing antibodies bind to the virus on the unique end and then bind to other immune cells–like a macrophage–on the constant portion. Macrophages provide immune protection in part by eating and digesting what they see. Macrophages will gobble up the virus and eliminate them.

Some viruses can infect and replicate within the macrophages before the macrophages digest the virus. If this occurred, it would make viral infection worse. This is one mechanism of antibody-dependent enhancement. The good news is that SARS-CoV-2 does not likely infect macrophages. Another mechanism of ADE is the formation of complexes, clumps of antibodies, that activate the immune system and can be dangerous when it occurs in your lungs. This form of over-active immune response likely DOES occur doing severe COVID-19 infections, and is part of what makes the disease dangerous. But we will focus on the question on whether ADE is specifically triggered by vaccines or re-infection.

After the first SARS-CoV virus started circulating back in 2003, scientists began developing a vaccine against it. Even though the SARS-CoV pandemic ended before a vaccine, scientists continued forward with vaccine development to learn how to do so for this type of virus. The original vaccine design included using a whole inactivated virus. When they tried this vaccine in animal models they found that it resulted in enhanced viral infection of SARS-CoV. Using the whole inactivated virus as a vaccine resulted in antibody dependent enhancement. This understanding coupled with the knowledge that the spike protein of the virus is how the virus enters the cells led scientists to design a better vaccine for SARS-CoV-2.

Rather than using the whole virus, all the vaccines under development focus on the spike protein of SARS-CoV-2. Because the spike protein is how the virus gets into the cell, scientists predicted more neutralizing antibodies can be made by focusing on arming the immune system against the spike protein. Having a high concentration of neutralizing antibodies prevents ADE. Thus far, this scientific hypothesis has been shown to be successful with many of the vaccines in development.

There is no antibody dependent enhancement with the current vaccine SARS-CoV-2 vaccines that are approved for emergency use. The Pfizer and Moderna vaccines dramatically decrease severe and symptomatic infections with SARS-CoV-2. There is no evidence for enhancement of viral infection in people who have been vaccinated, even people who were accidentally vaccinated while they were actively infected. Other vaccines that follow in approval would also need to decrease severe and symptomatic infection with SARS-CoV-2.

The data for SARS-CoV-2 reinfection is much more limited. SARS-CoV-2 produces a variable immune response in each person. Some people have more antibodies than others, and it changes over time–so it is hard to predict what will happen during re-infection. Current data with re-infection is limited to a handful of case studies. Most of the cases have less severe infections upon re-infection, but there has been at least one case of more severe disease upon re-infection. We do not know why the case was more severe upon re-infection.

Convalescent plasma, a blood product from someone that was previously infected with SARS-CoV-2, is currently being used as treatment for SARS-CoV-2. The “active ingredients” in convalescent plasma are the neutralizing antibodies that were produced in the body after infection. There is no evidence that convalescent plasma enhances COVID-19, which we would expect to see if ADE was at play. Convalescent plasma has been shown to have varying concentrations of neutralizing antibodies. All of these data together–from convalescent plasma to case studies imply that there is unlikely to be ADE upon re-infection in the vast majority of people. This is an ongoing area of research and more data are needed.

Because the first SARS-CoV vaccine attempts did produce ADE in animal models, scientists and the FDA have been carefully monitoring for ADE with SARS-CoV-2 vaccines. We have seen no evidence of ADE with the Pfizer and Moderna vaccines. For the other vaccines to be approved for use, there must also be no evidence for ADE. Scientists have been able to design vaccines that lead to more productive immune responses with neutralizing antibodies by focusing on the spike protein. Less data is available upon re-infection because of variability in the immune responses and limited number of re-infections thus far.

Scientific article on ADE for SARS-CoV2

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