Antibody-dependent Enhancement (ADE) and Vaccines

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Immune responses to pathogens involve many cells and proteins of the immune
system. Early during an infection, these responses are non-specific, meaning that
although they are directed at the pathogen, they are not specific to it. This is
called innate immunity. Within a few days, adaptive immunity takes over; this
immunity is specific to the invading pathogen. Adaptive immune responses
include antibodies. A major goal of antibodies is to bind to the pathogen and
prevent it from infecting, or entering, a cell. Antibodies that prevent entry into
cells are called neutralizing antibodies. Many vaccines work by inducing
neutralizing antibodies. However, not all antibody responses are created equal.
Sometimes antibodies do not prevent cell entry and, on rare occasions, they may
actually increase the ability of a virus to enter cells and cause a worsening of
disease through a mechanism called antibody-dependent enhancement (ADE).
What is ADE?
ADE occurs when the antibodies generated during an immune response
recognize and bind to a pathogen, but they are unable to prevent infection.
Instead, these antibodies act as a “Trojan horse,” allowing the pathogen to get
into cells and exacerbate the immune response.
Importantly, when a vaccinated person subsequently gets infected, this is not
automatically evidence of ADE. Specifically, if a vaccinated person gets infected
with the pathogen against which the vaccine protects, three different scenarios
can occur:
1. Mild illness – In this scenario, the person may experience some symptoms,
but they are more of an inconvenience and last only a few days (typically
about 1-3 days). For many respiratory and gastrointestinal infections (e.g.,
influenza, COVID-19, and rotavirus), this is common. These mild
symptoms are evidence that the vaccine worked.
2. “Breakthrough illness” – Traditionally, this term has been reserved for
vaccinated people who get more severely ill, requiring hospitalization or
experiencing untoward outcomes, such as disease complications (e.g.,
pneumonia) or death. In this case, the vaccine may not have worked at all
or it did not induce high enough levels of immunity to effectively stop an
infection.
3. ADE – In this scenario, the antibodies that the vaccine generated actually
help the virus infect greater numbers of cells than it would have on its own.
In this situation, the antibodies bind to the virus and help it more easily get
into cells than it would on its own. The result is often more severe illness
than if the person had been unvaccinated. ADE can occur after disease and
has on occasion been identified following vaccination, as described below.
Any vaccine that has been found to cause ADE has stopped being used or,
more recently as described below for dengue vaccine, been recommended
only for those who will not be affected by ADE. Evidence of ADE has not
emerged for COVID-19 vaccines even though concerns have been raised.