Abstract
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.
Highlights
Both seasonal and pandemic influenza pose significant public health concerns
By confronting our models with the data from the human vaccination trials we found that the key mechanism preventing effective boosting of the responses to the stem of HA is masking of the stem by pre-existing antibodies developed during previous infections and vaccinations
We discuss how this masking effect could be overcome in a “universal” influenza vaccine
Summary
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].We are currently able to generate vaccines against seasonal influenza based on knowledge of its global patterns of spread and mechanisms of evolution, such as antigenic drift, that lead to gradual annual changes in the surface proteins of the virus. 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]. We are currently able to generate vaccines against seasonal influenza based on knowledge of its global patterns of spread and mechanisms of evolution, such as antigenic drift, that lead to gradual annual changes in the surface proteins of the virus. Current vaccine technologies are not protective against pandemic influenza strains, to which people have little or no pre-existing humoral immunity. Pandemic influenza generally occurs due to larger antigenic changes (shifts), and when these novel strains enter the human population they typically cause severe disease [2, 8]
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