Incorporation of membrane-bound, mammalian-derived immunomodulatory proteins into influenza whole virus vaccines boosts immunogenicity and protection against lethal challenge

Andrew S Herbert,Roy Sundick,Paul C Roberts,Lynn Heffron

doi:10.1186/1743-422x-6-42

Andrew S Herbert, Roy Sundick + Show 2 more

Open Access

https://doi.org/10.1186/1743-422x-6-42

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Abstract

BackgroundInfluenza epidemics continue to cause morbidity and mortality within the human population despite widespread vaccination efforts. This, along with the ominous threat of an avian influenza pandemic (H5N1), demonstrates the need for a much improved, more sophisticated influenza vaccine. We have developed an in vitro model system for producing a membrane-bound Cytokine-bearing Influenza Vaccine (CYT-IVAC). Numerous cytokines are involved in directing both innate and adaptive immunity and it is our goal to utilize the properties of individual cytokines and other immunomodulatory proteins to create a more immunogenic vaccine.ResultsWe have evaluated the immunogenicity of inactivated cytokine-bearing influenza vaccines using a mouse model of lethal influenza virus challenge. CYT-IVACs were produced by stably transfecting MDCK cell lines with mouse-derived cytokines (GM-CSF, IL-2 and IL-4) fused to the membrane-anchoring domain of the viral hemagglutinin. Influenza virus replication in these cell lines resulted in the uptake of the bioactive membrane-bound cytokines during virus budding and release. In vivo efficacy studies revealed that a single low dose of IL-2 or IL-4-bearing CYT-IVAC is superior at providing protection against lethal influenza challenge in a mouse model and provides a more balanced Th1/Th2 humoral immune response, similar to live virus infections.ConclusionWe have validated the protective efficacy of CYT-IVACs in a mammalian model of influenza virus infection. This technology has broad applications in current influenza virus vaccine development and may prove particularly useful in boosting immune responses in the elderly, where current vaccines are minimally effective.

Highlights

Influenza epidemics continue to cause morbidity and mortality within the human population despite widespread vaccination efforts
Establishment of CYT-IVAC producer cell lines for the production of Cytokine-Bearing Influenza Vaccines (CYTIVACs) We have previously described an in vitro cell culture platform that allows for the direct incorporation of membrane-bound forms of chicken-derived cytokines into virus particles [22]
Preparation of these cytokine-bearing influenza virus vaccines, or CYT-IVACs, requires that the cytokine or immunomodulator of choice be both anchored in the virion membrane, and efficiently packaged into virions as they are released from the infected host cell

Summary

Introduction

Influenza epidemics continue to cause morbidity and mortality within the human population despite widespread vaccination efforts. This, along with the ominous threat of an avian influenza pandemic (H5N1), demonstrates the need for a much improved, more sophisticated influenza vaccine. Influenza epidemics continue to cause morbidity and mortality within the human population. Epidemics affect 5–20% of the population leading to over 200,000 hospitalizations and up to 36,000 deaths annually in the United States [1]. Recent studies have documented that HPAI can cross the avian-human species barrier and infect humans, leading to disease and high mortality (50%) [2,3,4]. Continual yearly outbreaks of influenza and the looming threat of a potential influenza pandemic illustrate the growing need for improved influenza vaccines

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