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The human immune response to dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity.
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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.
ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they are unable to prevent infection. 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:. 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. 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.
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. 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.
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. 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. 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 or the vaccines:. Unfortunately, some people continue to spread misinformation suggesting that ADE is an ongoing concern for COVID vaccines; however, scientists and clinicians are continuing to monitor COVID infections and, to date, no evidence to validate this concern has emerged.
The risk of developing severe disease from dengue is higher for individuals with a secondary infection than for those with a primary infection. Previous studies indicated that it is possible that CYD-TDV vaccination could mimic a primary infection in patients who had never been exposed to the virus seronegative , causing their first true exposure to natural infection to result in a severe secondary infection.
In efficacy and safety trials of CYD-TDV, excess hospitalizations for dengue were observed among vaccine recipients 2 to 5 years of age, but baseline serostatus was not obtained for all children. Researchers in this study determined the baseline serostatus of the children, aged 2 to 16 years, enrolled in these trials to assess safety and efficacy results based on serostatus.
In seronegative children, the likelihood of hospitalization or severe virologically confirmed dengue was much greater in vaccine recipients than those who received placebo. Seropositive vaccine recipients had a lower likelihood of hospitalization or severe disease compared with placebo recipients.
Investigators assessed the long-term safety and efficacy of a tetravalent dengue vaccine CYD-TDV in three clinical trials of more than 30, children between the ages of 2 and 16 years of age in Asia and Latin America.
Regarding safety, children vaccinated between 2 to 5 years of age in Asia were shown to have an increased risk of hospitalization secondary to dengue three years after the first vaccine dose compared with children who received placebo.
However, the risk of hospitalization in the fourth and fifth years after vaccination was the same as that in children who received placebo.
Due to this safety signal in younger patients, CYD-TDV was first submitted for approval for use in children over the age of 9 years. However, after completion of this study, an increased risk of hospitalization and severe disease in children who were seronegative prior to vaccine was found.
This caused the manufacturer to change the label to restrict vaccination to subjects who are seropositive at the time of vaccination. Identification of viral epitopes associated with ADE or neutralization is important for this purpose.
In addition, clear understanding of the cellular events after virus entry through ADE has become crucial for developing efficient intervention.
However, the mechanisms of ADE still remain to be better understood. More rigorous, reasonable and safe immune procedures are also important issues to be solved in future vaccine development. National Center for Biotechnology Information , U. Adv Immunol. Published online Sep Author information Copyright and License information Disclaimer. All rights reserved. Elsevier hereby grants permission to make all its COVIDrelated research that is available on the COVID resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source.
Abstract In some cases, antibodies can enhance virus entry and replication in cells. Keywords: Coronavirus, Antibody-dependent infection enhancement, Vaccine. ADE of representative virus 2. The molecular mechanism that produces ADE 3. Molecular signaling events in ADE In addition to promoting the entry of viruses, ADE also affects the immune response of cells, inhibiting the antiviral activity of cells and thus promoting infection.
Open in a separate window. Cellular compartmentalization Cellular compartmentalization is used as a defense against human pathogens in both specialized and nonspecialized phagocytes.
Mask or remove the antigen part that produces ADE Screaton developed a stable ZIKV E protein dimer vaccine that has no precursor membrane proteins and does not expose the immunodominant fusion loop epitope.
Block or interfere with the binding of the antigen-antibody complex to the receptor Because of its own advantages that monoclonal antibody has become an important direction in the development of new vaccines. Effect of adjuvant and inactivation selection on ADE The choice of adjuvant will also affect the immune effect. Table 1 Key characteristics of antibody-dependent enhancement ADE infected by different viruses. FcR mediated virus-antibody immune complexes infect monocytes, macrophages, and dendritic cells 2.
Increased susceptibility to other serotypes 2. ADE and plasma viral load is positive correlation. ADE accelerates immunosuppression and disease progression 2. References Anderson L.
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Immunological enhancement of dengue virus replication.
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