Research Article: Multi-epitope Models Explain How Pre-existing Antibodies Affect the Generation of Broadly Protective Responses to Influenza

Date Published: June 23, 2016

Publisher: Public Library of Science

Author(s): Veronika I. Zarnitsyna, Jennie Lavine, Ali Ellebedy, Rafi Ahmed, Rustom Antia, Adam S. Lauring.


The development of next-generation influenza vaccines that elicit strain-transcendent immunity against both seasonal and pandemic viruses is a key public health goal. Targeting the evolutionarily conserved epitopes on the stem of influenza’s major surface molecule, hemagglutinin, is an appealing prospect, and novel vaccine formulations show promising results in animal model systems. However, studies in humans indicate that natural infection and vaccination result in limited boosting of antibodies to the stem of HA, and the level of stem-specific antibody elicited is insufficient to provide broad strain-transcendent immunity. Here, we use mathematical models of the humoral immune response to explore how pre-existing immunity affects the ability of vaccines to boost antibodies to the head and stem of HA in humans, and, in particular, how it leads to the apparent lack of boosting of broadly cross-reactive antibodies to the stem epitopes. We consider hypotheses where binding of antibody to an epitope: (i) results in more rapid clearance of the antigen; (ii) leads to the formation of antigen-antibody complexes which inhibit B cell activation through Fcγ receptor-mediated mechanism; and (iii) masks the epitope and prevents the stimulation and proliferation of specific B cells. We find that only epitope masking but not the former two mechanisms to be key in recapitulating patterns in data. We discuss the ramifications of our findings for the development of vaccines against both seasonal and pandemic influenza.

Partial Text

Both seasonal and pandemic influenza pose significant public health concerns. Seasonal influenza in the U.S. is estimated to lead to an economic burden of $87.1 billion [1], and pandemic influenza poses a grave threat to public health, as witnessed during the 1918–1919 Spanish influenza outbreak [2].

This paper uses simple mathematical models to explore how pre-existing antibody affects the generation of recall responses following immunization. We apply these models to the context of antibody responses to HA which is the main target of humoral immunity to influenza. The first step in this paper was to show that multiple models of immunodynamics, the ACM, FIM and EMM are consistent with previous observations describing how prior antibody limits the boosting of antibodies to HA upon re-exposure. In particular, we extend our previous study that described the epitope masking hypothesis [26] by showing that the clearance of antigen by antibodies (i.e., the ACM) and Fc-mediated inhibition of B cell activation (i.e., the FIM) could also explain these observations. This is because, in all three models, the presence of pre-existing antibody leads to lowering the expansion of specific B cells and less boosting.

In the following sections we describe the models we consider in the paper.




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