Original antigenic sin

Original antigenic sin, also known as antigenic imprinting or the Hoskins effect, refers to the propensity of the body's immune system to preferentially utilize immunological memory based on a previous infection when a second slightly different version of that foreign pathogen (e.g. a virus or bacterium) is encountered. This leaves the immune system "trapped" by the first response it has made to each antigen, and unable to mount potentially more effective responses during subsequent infections. Antibodies or T-cells induced during infections with the first variant of the pathogen are subject to a form of original antigenic sin, termed repertoire freeze.
The phenomenon of original antigenic sin has been described in relation to influenza virus, dengue fever, human immunodeficiency virus (HIV) and to several other viruses.
This phenomenon was first described in 1960 by Thomas Francis Jr. in the article "On the Doctrine of Original Antigenic Sin". It is named by analogy to the theological concept of original sin. According to Thomas Francis, who originally described the idea, and cited by Richard Krause:
"The antibody of childhood is largely a response to dominant antigen of the virus causing the first type A influenza infection of the lifetime. [...] The imprint established by the original virus infection governs the antibody response thereafter. This we have called the Doctrine of the Original Antigenic Sin."
In B cells.
During a primary infection, long-lived memory B cells are generated, which remain in the body, and provide protection from subsequent infections. These memory B cells respond to specific epitopes on the surface of viral proteins in order to produce antigen-specific antibodies, and are able to respond to infection much faster than B cells are able to respond to novel antigens. This effect shortens the amount of time required to clear subsequent infections.
Between primary and secondary infections, or following vaccination, a virus may undergo antigenic drift, in which the viral surface proteins (the epitopes) are altered through natural mutation, allowing the virus to escape the immune system. When this happens, the altered virus preferentially reactivates previously activated high-affinity memory B cells and spur antibody production. However, the antibodies produced by these B cells generally ineffectively bind to the altered epitopes. In addition, these antibodies inhibit the activation of higher-affinity naive B cells that "would" be able to make more effective antibodies to the second virus. This leads to a less effective immune response and recurrent infections may take longer to clear.
Original antigenic sin is of particular importance in the application of vaccines. In dengue fever, the effect of original antigenic sin has important implications for vaccine development. Once a response against a dengue virus serotype has been established, it is unlikely that vaccination against a second will be effective, implying that balanced responses against all four virus serotypes have to be established with the first vaccine dose. However, in 2015, a new class of highly potent, neutralizing antibodies that is effective against all four virus serotypes has been isolated, bringing hope for the development of a universal dengue vaccine.
The specificity and the quality of the immune response against novel strains of influenza is often diminished in individuals who are repeatedly immunized (by vaccination or recurrent infections). However, the impact of antigenic sin on protection has not been well established, and appears to differ with each infectious agent vaccine, geographic location, and age. Researchers found reduced antibody responses to the 2009 pandemic H1N1 influenza vaccine in individuals who had been vaccinated against the seasonal A/Brisbane/59/2007 (H1N1) within the previous three months.
In cytotoxic T cells.
A similar phenomenon has been described in cytotoxic T cells (CTL). It has been demonstrated that during a second infection by a different strain of dengue virus, the CTLs prefer to release cytokines instead of causing cell lysis. As a result, the production of these cytokines is thought to increase vascular permeability and exacerbate damage to endothelial cells.
Several groups have attempted to design vaccines for HIV and hepatitis C based on induction of CTL response. The finding that the CTL response may be biased by original antigenic sin may help to explain the limited effectiveness of these vaccines. Viruses like HIV are highly variable and undergo mutation frequently; due to original antigenic sin, HIV infection induced by viruses that express slightly different epitopes (than those in a viral vaccine) would fail to be controlled by the vaccine. In fact, the vaccine might make the infection even worse, by "trapping" the immune response into the first, ineffective, response it made against the virus.