Antibody-dependent Enhancement (ADE) and Vaccines

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.

Is ADE caused by a disease?

Most diseases do not cause ADE, but one of the best studied examples of a pathogen that can cause ADE is dengue virus. Dengue virus is one of the most common infections in the world, infecting hundreds of millions and killing tens of thousands of people each year. Unlike viruses like measles or mumps that only have one type, dengue virus has four different forms, called “serotypes.” These serotypes are very similar, but slight differences among them set the stage for ADE. If a person is infected by one serotype of dengue virus, they typically have mild disease and generate a protective immune response, including neutralizing antibodies, against that serotype. But, if that person is infected with a second serotype of dengue virus, the neutralizing antibodies generated from the first infection may bind to the virus and actually increase the virus’s ability to enter cells, resulting in ADE and causing a severe form of the disease, called dengue hemorrhagic fever. 

Is ADE caused by vaccines?

On a few occasions ADE has resulted from vaccination:

  • Respiratory syncytial virus (RSV) — RSV is a virus that commonly causes pneumonia in children. A vaccine was made by growing RSV, purifying it, and inactivating it with the chemical formaldehyde. In clinical trials, children who were given the vaccine were more likely to develop or die from pneumonia after infection with RSV. As a result of this finding, the vaccine trials stopped, and the vaccine was never submitted for approval or released to the public.
  • Measles — An early version of measles vaccine was made by inactivating measles virus using formaldehyde. Children who were vaccinated and later became infected with measles in the community developed high fevers, unusual rash, and an atypical form of pneumonia. Upon seeing these results, the vaccine was withdrawn from use, and those who received this version of the vaccine were recommended to be vaccinated again using the live, weakened measles vaccine, which does not cause ADE and is still in use today.

Both the RSV and measles vaccines that caused ADE were tested in the 1960s. Since then, other vaccines have successfully been created by purifying and chemically inactivating the virus with formaldehyde, such as hepatitis A, rabies, and inactivated polio vaccines. These more recent vaccines do not cause ADE…[   ]

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