Original Antigenic Sin

The concept of 'Original Antigenic Sin' for influenza--which proposes that immune memory of previously encountered older flu strains weakens the response against threats from current strains--has been around since the 1960s. The idea is that, because some parts of a current flu virus are familiar to the immune system, antibodies specific to older flu strains are 'recalled' and produced at the expense of the creation of new antibodies specific to the current strain, and that these 'original antigenic sin' antibodies are detrimental to the host since they react poorly with the current strain against which defense is needed.

To study 'original antigenic sin' antibodies, researchers studied antibody responses in mice that were sequentially exposed to different influenza strains[1]. Most antibodies against influenza viruses recognize one of two highly variable proteins on the virus surface. The researchers focused their analysis on the antibody repertoire against one of them, hemagglutinin, or HA.

Human antibodies elicited by influenza viruses often bind with a high affinity to past influenza virus strains, but paradoxically, do not bind to the viral strain actually eliciting the response. This phenomena is called 'original antigenic sin' (OAS) since this can occur at the expense of generating new de novo antibodies. The researchers characterized the specificity and functionality of antibodies elicited in mice that were sequentially exposed to two antigenically distinct H1N1 influenza virus strains. Many antibodies elicited under these conditions had an OAS phenotype, in that they bound strongly to the viral strain used for the first exposure and very weakly to the viral strain used for the second exposure. It appeared that OAS and non-OAS antibodies target the same general region of the influenza hemagglutinin protein and that B cells expressing these two types of antibodies can be clonally-related. Surprisingly, although OAS antibodies bound with very low affinities, some were able to effectively protect against an antigenically drifted viral strain following passive transfer in vivo. Taken together, the data indicates that OAS antibodies share some level of cross-reactivity between priming and recall viral strains and that B cells producing these antibodies can be protective when recalled into secondary immune responses.

[1] Linderman et al: Antibodies with 'Original Antigenic Sin' Properties Are Valuable Components of Secondary Immune Responses to Influenza Viruses in PLoS Pathogens – 2016