PT  - JOURNAL ARTICLE
AU  - Christopher S. Anderson
AU  - Mark Y. Sangster
AU  - Hongmei Yang
AU  - Sidhartha Chaudhury
AU  - David J. Topham
TI  - Computer Simulations of the Humoral Immune System Reveal How Imprinting Can Affect Responses to Influenza HA Stalk with Implications for the Design of Universal Vaccines
AID  - 10.1101/346726
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 346726
4099  - http://biorxiv.org/content/early/2018/06/13/346726.short
4100  - http://biorxiv.org/content/early/2018/06/13/346726.full
AB  - Antigenic drift of the H1N1 virus results in significant reduction in vaccine efficacy and often necessitates the production of new vaccines that more closely antigenically match the circulating strains. Efforts to develop a vaccine resistant to antigenic drift are ongoing and the HA stalk region of the influenza H1N1 virus has emerged as a potential target for vaccines due to its conservation across antigenically drifted strains. Studies of the 2009 pandemic H1N1 vaccine as well as candidate pandemic avian influenza vaccines have demonstrated that it is possible to boost antibody towards the stalk region, but for reason that are unclear, only in individuals who had not been exposed to antigenically similar viruses. Here we use stochastic simulations of a humoral immune system model to provide theoretical insights into how repeated exposure to influenza vaccines increases stalk-specific antibodies. We found that pre-existing memory B cells are the greatest contributor to stalk-specific antibody boosting and that pre-existing antibody negatively interferes with this boosting. Additionally, we found that increases in cross-reactivity after heterologous boosting occur in both head and stalk specific antibody populations. Moreover, pre-existing memory B cells focus antibody responses towards the stalk region in a manner dependent on the antigenic dissimilarities between other antigenic sites, even when these dissimilarities are minimal. Finally we show stalk-specific antibody can be boosted by repeat exposure to homologous antigen, but this boosting is limited. These finding provide needed insights into universal vaccine regimens, especially those aimed at boosting stalk-specific antibody responses using prime and boost strategies.