Intranasal Administration of Recombinant Influenza Vaccines in Chimeric Mouse Models to Study Mucosal Immunity

José Vicente Pérez-Girón; Sergio Gómez-Medina; Anja Lüdtke; Cesar Munoz-Fontela

doi:10.3791/52803

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Method Article

Intranasal Administration of Recombinant Influenza Vaccines in Chimeric Mouse Models to Study Mucosal Immunity

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DOI:

10.3791/52803

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June 25th, 2015

José Vicente Pérez-Girón¹ , Sergio Gómez-Medina¹ , Anja Lüdtke¹ , Cesar Munoz-Fontela¹

¹Laboratory of Emerging Viruses, Heinrich Pette Institute, Leibniz Institute for Experimental Virology

Summary

There is an overall lack of knowledge about how vaccines work. Here we propose the combined use of reverse genetics and bone marrow chimeric mice to gain insight into the early host immune responses to vaccines with a special focus on dendritic cells and T cell immunity.

Abstract

Vaccines are one of the greatest achievements of mankind, and have saved millions of lives over the last century. Paradoxically, little is known about the physiological mechanisms that mediate immune responses to vaccines perhaps due to the overall success of vaccination, which has reduced interest into the molecular and physiological mechanisms of vaccine immunity. However, several important human pathogens including influenza virus still pose a challenge for vaccination, and may benefit from immune-based strategies.

Although influenza reverse genetics has been successfully applied to the generation of live-attenuated influenza vaccines (LAIVs), the addition of molecular tools in vaccine preparations such as tracer components to follow up the kinetics of vaccination in vivo, has not been addressed. In addition, the recent generation of mouse models that allow specific depletion of leukocytes during kinetic studies has opened a window of opportunity to understand the basic immune mechanisms underlying vaccine-elicited protection. Here, we describe how the combination of reverse genetics and chimeric mouse models may help to provide new insights into how vaccines work at physiological and molecular levels, using as example a recombinant, cold-adapted, live-attenuated influenza vaccine (LAIV). We utilized laboratory-generated LAIVs harboring cell tracers as well as competitive bone marrow chimeras (BMCs) to determine the early kinetics of vaccine immunity and the main physiological mechanisms responsible for the initiation of vaccine-specific adaptive immunity. In addition, we show how this technique may facilitate gene function studies in single animals during immune responses to vaccines. We propose that this technique can be applied to improve current prophylactic strategies against pathogens for which urgent medical countermeasures are needed, for example influenza, HIV, Plasmodium, and hemorrhagic fever viruses such as Ebola virus.

Introduction

The generation of immunological memory in the absence of disease is the physiological basis of efficient vaccination¹. Recently, systems biology-based approaches have revealed that successful vaccines such as the yellow fever vaccine, induce a strong induction of innate immune responses and activation of several subsets of dendritic cells (DCs), which in turn, lead to multilineage activation of antigen-specific T cells^2,3. Since DCs are the only immune cell population with the ability to activate antigen-specific naïve T cells⁴, the study of their function during vaccination is critical to understand immune responses to vaccines a....