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

Abstract

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. We illustrate the concept of using data and models to inform inoculum dose determination for vaccines, wby fitting a mathematical model to data from influenza A virus (IAV) infection of mice and human parainfluenza virus (HPIV) infection of cotton rats at different inoculum doses. We use the model to map inoculum dose to the level of immune protection and morbidity and to explore how such a framework might be used to determine an optimal inoculum dose. 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. Our findings illustrate that the impact of inoculum dose on immune protection and morbidity can depend on the specific pathogen and that both protection and morbidity do not necessarily increase monotonically with increasing inoculum dose. Once vaccine design goals are specified with required levels of protection and acceptable levels of morbidity, our proposed framework can help in the rational design of vaccines and determination of the optimal amount of inoculum. An important component of vaccines is the amount of pathogen inoculum, dead or alive, that is included in the vaccine. This inoculum dose, sometimes also referred to as antigen dose, needs to be large enough to induce good protective immunity. However, one usually also wants to keep the dose low to reduce costs, maximize the number of vaccine doses available, and minimize potential vaccine side effects. The inoculum dose is currently chosen based on limited data from clinical trials. In this study, we set up a framework that combines data with mathematical models to illustrate how such a combination could lead to better and more efficient determination of an optimal inoculum dose for vaccines.