Research Article: Antibodies with ‘Original Antigenic Sin’ Properties Are Valuable Components of Secondary Immune Responses to Influenza Viruses

Date Published: August 18, 2016

Publisher: Public Library of Science

Author(s): Susanne L. Linderman, Scott E. Hensley, Andrea J. Sant.


Human antibodies (Abs) 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 Abs. Here, we characterized the specificity and functionality of Abs elicited in mice that were sequentially exposed to two antigenically distinct H1N1 influenza virus strains. Many Abs 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. We found that OAS and non-OAS Abs target the same general region of the influenza hemagglutinin protein and that B cells expressing these two types of Abs can be clonally-related. Surprisingly, although OAS Abs bound with very low affinities, some were able to effectively protect against an antigenically drifted viral strain following passive transfer in vivo. Taken together, our data indicate that OAS Abs share some level of cross-reactivity between priming and recall viral strains and that B cells producing these Abs can be protective when recalled into secondary immune responses.

Partial Text

Influenza viruses continuously acquire mutations in antigenically important regions of the hemagglutinin (HA) and neuraminidase (NA) proteins through a process termed ‘antigenic drift’. Single HA mutations can dramatically reduce antibody (Ab) recognition of influenza viruses [1]. Although influenza infections lead to strain-specific lifelong immunity [2], humans are routinely re-infected with antigenically drifted influenza strains throughout life. Most humans are infected with seasonal influenza viruses by 3 years of age [3] and then re-infected with antigenically drifted strains every 5–10 years [4].

Most vaccines elicit protective Abs and memory B cells that are poised to respond quickly to a secondary exposure [11]. Formulating effective vaccines against rapidly changing pathogens, such as influenza viruses, is challenging [12–14]. Influenza vaccines are less effective when viruses acquire mutations in Ab binding sites on the HA, as was the case during the 2014–2015 influenza season [15]. B cells primed against older influenza strains are recruited upon exposure with new influenza strains, even when major HA antigenic changes have occurred. For example, prior seasonal H1N1 exposure heavily influenced the types of Abs that were elicited in humans against the 2009 pandemic H1N1 strain [16–19]. mAbs isolated from humans exposed to the 2009 pandemic H1N1 strain recognize epitopes that are conserved on older seasonal H1N1 strains, and these mAbs have a high level of somatic mutation indicating that they were likely derived from a memory B cell pool [19]. Immune skewing towards epitopes present in older viral strains is likely a result of memory B cells clones outcompeting naïve B cell clones that are specific for epitopes present in new viral strains [20–22]. In the case of the 2009 pandemic H1N1 strain, many of these cross-reactive mAbs were protective and so the recall of B cell clones originally primed by seasonal H1N1 viruses was likely advantageous to the host.




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