The FLARE Four
- Antibody-dependent enhancement (ADE) is a phenomenon in which antibodies elicited by infection with one viral serotype paradoxically promote both viral replication and an overly exuberant immune response upon exposure to a new infecting serotype
- Anti-coronavirus antibodies are probably present in many people and ADE may occur during SARS-CoV-2 infection and lead to severe symptoms
- While the ADE hypothesis is intriguing, it is unlikely to be the sole determinant of severe COVID-19. Specifically, the ADE hypothesis does not explain why children are generally spared from severe disease
- Studies are needed to define the immune mechanisms promoting severe COVID-19
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Severe COVID-19 is associated with a failure to clear SARS-CoV-2 despite high levels of inflammatory cytokines. Recently, researchers have proposed in Microbes and Infection that this phenomenon can be explained by antibody-dependent enhancement (ADE), a dysfunctional immune response best described in dengue virus infection.
Background on ADE
Viruses can acquire mutations that change surface proteins, leading to distinct viral serotypes. After infection with one viral serotype, the host will produce antibodies recognizing the viral surface proteins, which protect against re-infection. The development of antibodies to one serotype may not protect from a second serotype, even if antibody-binding to the second serotype occurs.
In ADE, antibodies to one viral serotype not only fail to protect against a second viral serotype, but actually do harm. Specifically, antibodies to one viral serotype drive uptake of a newly infecting serotype into immune cells, promoting viral replication and an overly exuberant immune response.
ADE and Dengue Virus
Ideas about ADE originated in studies of dengue virus infection. Most infected individuals are asymptomatic or minimally symptomatic, but a small proportion, including children, develop dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Individuals experiencing a second dengue virus infection with a distinct serotype are at increased risk for DHF/DSS and studies have suggested that this occurs, in part, due to ADE.
ADE and Coronaviruses
Coronaviruses commonly infect humans, so anti-coronavirus antibodies are likely present in many people. Several groups have suggested that prior infection with non-SARS coronaviruses promoted severe SARS in 2002–2004.
Now, ADE is speculated to be responsible for severe COVID-19. Prior infection with a non-SARS coronavirus might result in a sub-neutralizing level of coronavirus antibodies that both enhance SARS-CoV-2 replication and promote inflammation.
While the ADE hypothesis is intriguing, it is unlikely to be the sole determinant of severe COVID-19. Specifically, the ADE hypothesis does not explain why children, who are frequently infected with coronaviruses and exhibit ADE in other contexts such as Dengue virus infection, are generally spared from severe COVID-19.
ADE may occur in certain individuals infected with SARS-CoV-2, but it seems less likely to be the dominant immune-mediated mechanism driving severe COVID-19. Studies are needed to define the immune mechanisms promoting severe COVID-19.
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