A Live-Attenuated Prime, Inactivated Boost Vaccination Strategy with Chimeric Hemagglutinin-Based Universal Influenza Virus Vaccines Provides Protection in Ferrets: A Confirmatory Study.

Raffael Nachbagauer,Florian Krammer,Randy Albrecht

doi:10.3390/vaccines6030047

Raffael Nachbagauer, Florian Krammer + Show 1 more

Open Access

https://doi.org/10.3390/vaccines6030047

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Journal: Vaccines	Publication Date: Jul 25, 2018
Citations: 27	License type: CC BY 4.0

Affiliation: Icahn School of Medicine at Mount Sinai

Abstract

Influenza viruses cause severe diseases and mortality in humans on an annual basis. The current influenza virus vaccines can confer protection when they are well-matched with the circulating strains. However, due to constant changes of the virus surface glycoproteins, the vaccine efficacy can drop substantially in some seasons. In addition, the current seasonal influenza virus vaccines do not protect from avian influenza viruses of human pandemic potential. Novel influenza virus vaccines that aim to elicit antibodies against conserved epitopes like the hemagglutinin stalk could not only reduce the burden of drifted seasonal viruses but potentially also protect humans from infection with zoonotic and emerging pandemic influenza viruses. In this paper, we generated influenza virus vaccine constructs that express chimeric hemagglutinins consisting of exotic, avian head domains and a consistent stalk domain of a seasonal virus. Using such viruses in a sequential immunization regimen can redirect the immune response towards conserved epitopes. In this study, male ferrets received a live-attenuated vaccine virus based on the A/Ann Arbor/6/60 strain expressing a chimeric H8/1 (cH8/1) hemagglutinin, which was followed by a heterologous booster vaccination with a cH5/1N1 formalin inactivated non-adjuvanted whole virus. This group was compared to a second group that received a cH8/1N1 inactivated vaccine followed by a cH5/1N1 inactivated vaccine. Both groups showed a reduction in viral titers in the upper respiratory tract after the A(H1N1)pdm09 virus challenge. Animals that received the live-attenuated vaccine had low or undetectable titers in the lower respiratory tract. The results support the further development of chimeric hemagglutinin-based vaccination strategies. The outcome of this study confirms and corroborates findings from female ferrets primed with a A/Leningrad/134/17/57-based live attenuated cH8/1N1 vaccine followed by vaccination with an AS03-adjuvanted cH5/1N1 split virus vaccine 10.

Highlights

Influenza viruses are a major cause of disease and mortality in the human population [1].Current influenza virus vaccines can protect from infection if they are well matched to the circulatingVaccines 2018, 6, 47; doi:10.3390/vaccines6030047 www.mdpi.com/journal/vaccinesVaccines 2018, 6, 47 virus strains
We examined the efficacy of our sequential immunization approach vaccines containing chimeric hemagglutinin to confer protection against influenza virus infection
Male ferrets prime immunized with a cH8/1N1-expressing live-attenuated influenza virus (LAIV)

Summary

Introduction

Influenza viruses are a major cause of disease and mortality in the human population [1].Current influenza virus vaccines can protect from infection if they are well matched to the circulatingVaccines 2018, 6, 47; doi:10.3390/vaccines6030047 www.mdpi.com/journal/vaccinesVaccines 2018, 6, 47 virus strains. Influenza viruses constantly mutate and evade the adaptive immune response by introducing changes in the immuno-dominant head domain of their major surface glycoprotein, hemagglutinin (HA) These changes lead to a loss of protection and can only be partially counteracted by annually updating the vaccine strains because the circulating viruses can change after a new vaccine has already been manufactured [2]. One possible way to address these issues is the development of novel vaccines that elicit antibodies against conserved viral epitopes like the HA stalk domain [3]. We have developed a vaccination strategy that uses chimeric HAs (cHA) as antigens [4] These cHAs consist of exotic avian head domains (to which humans are naïve) and the conserved HA stalk domains of seasonal influenza viruses. Repeated vaccination with cHAs and with different HA head domains and the same HA stalk domain can induce high levels of antibodies against the conserved

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