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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.

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:

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.

“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.

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.

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.

A more recent example of ADE following vaccination comes from dengue virus:

Dengue virus — In 2016, a dengue virus vaccine was designed to protect against all four serotypes of the virus. The hope was that by inducing immune responses to all four serotypes at once, the vaccine could circumvent the issues related to ADE following disease with dengue virus. The vaccine was given to 800,000 children in the Philippines. Fourteen vaccinated children died after encountering dengue virus in the community. It is hypothesized that the children developed antibody responses that were not capable of neutralizing the natural virus circulating in the community. As such, the vaccine was recommended only for children greater than 9 years of age who had already been exposed to the virus.

Other viral vaccines that target multiple types of a virus have been safely used, including vaccines against polio (3 types), rotavirus (5 types), and human papillomavirus (9 types).

Should I be concerned that my child will develop ADE after receiving a vaccination?

Today’s routinely recommended vaccines do not cause ADE. If they did, like those described above, they would be removed from use. Phase III clinical trials are designed to uncover frequent or severe side effects before a vaccine is approved for use. Find out more about how vaccines are developed and approved for use.

Can the new COVID-19 vaccines cause ADE?

Neither COVID-19 disease nor the new COVID-19 vaccines have shown evidence of causing ADE. People infected with SARS-CoV-2, the virus that causes COVID-19, have not been likely to develop ADE upon repeat exposure. This is true of other coronaviruses as well. Likewise, studies of vaccines in the laboratory with animals or in the clinical trials in people have not found evidence of ADE.

Following the experience with dengue vaccine, early during the COVID-19 pandemic, concerns about ADE were top of mind. During this time, a few scientists tried to predict whether ADE would occur by evaluating genes for similarities and differences. While this was a useful approach at a time when we did not have much information about what might happen in people, we have since accumulated several lines of clinical evidence that confirm ADE is not an issue for COVID-19 or the vaccines:

People who are infected with SARS-CoV-2, or its variants, do not become more susceptible to ADE.

Many vaccinated people have been exposed to the virus, and its variants, and most of them have developed no disease or mild symptoms. A very small number have experienced more severe disease (“breakthrough infection”), and these individuals have not shown evidence of ADE.

Unfortunately, some people continue to spread misinformation suggesting that ADE is an ongoing concern for COVID-19 vaccines; however, scientists and clinicians are continuing to monitor COVID-19 infections and, to date, no evidence to validate this concern has emerged.

Source : The Children’s Hospital of Philadelphia

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