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Exploring the impact of inoculum dose on host immunity and morbidity to inform model-based vaccine design

By Andreas Handel, Yan Li, Brian McKay, Kasia A. Pawelek, Veronika Zarnitsyna, Rustom Antia

Posted 22 May 2018
bioRxiv DOI: 10.1101/328559 (published DOI: 10.1371/journal.pcbi.1006505)

Background: Vaccination is an effective method to protect against infectious diseases. An important consideration in any vaccine formulation is the inoculum dose, i.e., amount of antigen or live attenuated pathogen that is used. Higher levels generally lead to better stimulation of the immune response but might cause more severe side effects and allow for less population coverage in the presence of vaccine shortages. Determining the optimal amount of inoculum dose is an important component of rational vaccine design. A combination of mathematical models with experimental data can help determine the impact of the inoculum dose. Methods: We designed mathematical models and fit them to data from influenza A virus (IAV) infection of mice and human parainfluenza virus (HPIV) of cotton rats at different inoculum doses. We used the model to predict the level of immune protection and morbidity for different inoculum doses and to explore what an optimal inoculum dose might be. Results: We show how a framework that combines mathematical models with experimental data can be used to study the impact of inoculum dose on important outcomes such as immune protection and morbidity. We find that the impact of inoculum dose on immune protection and morbidity depends on the pathogen and both protection and morbidity do not always increase with increasing inoculum dose. An intermediate inoculum dose can provide the best balance between immune protection and morbidity, though this depends on the specific weighting of protection and morbidity. Conclusions: Once vaccine design goals are specified with required levels of protection and acceptable levels of morbidity, our proposed framework which combines data and models can help in the rational design of vaccines and determination of the optimal amount of inoculum.

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