Original antigenic sin
Original antigenic sin (first described in 1960 by Thomas Francis, Jr. in the article On the Doctrine of Original Antigenic Sin, also known as 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 entity (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. 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.
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 lower-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. The specificity and the quality of the immune response 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.
In cytotoxic T cells
A similar phenomenon has been described in cytotoxic T cells (CTL). Several groups have attempted to design vaccines for HIV and hepatitis C based on induction of cytotoxic (CTL) responses. The recent finding that CTL 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, and thus, 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.
- by Thomas Francis, Jr. in Proceedings of the American Philosophical Society, Vol. 104, No. 6 (Dec. 15, 1960), pp. 572-578) according to The Swine Flu Episode and the Fog of Epidemics by Richard Krause in CDC's Emerging Infectious Diseases Journal Vol. 12, No. 1 January 2006 published December 20, 2005
- FDA Center for Biologics Evaluaion and Research Vaccines and Related Biological Products: Advisory Committee JULY 26, 2001 changed to html by google.
- Deem, Michael W.The Adaptive Immune Response Rice University
- Lambert, Paul-Henri, Margaret Liu and Claire-Anne Siegrist (2005) Can successful vaccines teach us how to induce efficient protective immune responses? (full text-html) Nature Medicine:11, S54 - S62
- McMichael, Andrew J. (1998). "Immunology: The original sin of killer T cells" (HTML). Nature 394. pp. 421–422. Retrieved 2006-05-25.