Vaccination With Viral Vectors Expressing Chimeric Hemagglutinin, NP and M1 Antigens Protects Ferrets Against Influenza Virus Challenge.

Meagan McMahon,Daniel Stadlbauer,Randy A Albrecht,Mario Aramouni,Wen-Chun Liu,Teresa Lambe,Sarah C Gilbert,Florian Krammer,Vincent Pavot,Guha Asthagiri Arunkumar

doi:10.3389/fimmu.2019.02005

Abstract

Seasonal influenza viruses cause significant morbidity and mortality in the global population every year. Although seasonal vaccination limits disease, mismatches between the circulating strain and the vaccine strain can severely impair vaccine effectiveness. Because of this, there is an urgent need for a universal vaccine that induces broad protection against drifted seasonal and emerging pandemic influenza viruses. Targeting the conserved stalk region of the influenza virus hemagglutinin (HA), the major glycoprotein on the surface of the virus, results in the production of broadly protective antibody responses. Furthermore, replication deficient viral vectors based on Chimpanzee Adenovirus Oxford 1 (ChAdOx1) and modified vaccinia Ankara (MVA) virus expressing the influenza virus internal antigens, the nucleoprotein (NP) and matrix 1 (M1) protein, can induce strong heterosubtypic influenza virus-specific T cell responses in vaccinated individuals. Here, we combine these two platforms to evaluate the efficacy of a viral vectored vaccination regimen in protecting ferrets from H3N2 influenza virus infection. We observed that viral vectored vaccines expressing both stalk-targeting, chimeric HA constructs, and the NP+M1 fusion protein, in a prime-boost regimen resulted in the production of antibodies toward group 2 HAs, the HA stalk, NP and M1, as well as in induction of influenza virus-specific—IFNγ responses. The immune response induced by this vaccination regime ultimately reduced viral titers in the respiratory tract of influenza virus infected ferrets. Overall, these results improve our understanding of vaccination platforms capable of harnessing both cellular and humoral immunity with the goal of developing a universal influenza virus vaccine.

Highlights

Influenza A virus infections cause significant morbidity and mortality in the human population globally on an annual basis [1, 2]
Our results show that vaccination with all viral vectors (NP + matrix 1 (M1), chimeric HAs (cHAs) or cHA-NP + M1) and the virus-matched trivalent influenza vaccine (TIV) reduced viral titers in the nasal washes at both days 1 (Figure 2A) and 3 (Figure 2B) post-challenge infection when compared to naïve controls
In this study we show that viral vectors expressing cHAs, NP and M1 influenza antigens can induce both broad anti-HA antibodies and IFN-γ cellular immune responses in ferrets that are protective against influenza virus infection

Summary

Introduction

Influenza A virus infections cause significant morbidity and mortality in the human population globally on an annual basis [1, 2]. Novel vaccine platforms are being developed to refocus the immune response toward the immuno-subdominant HA stalk [13] One of these platforms involves sequential vaccination with chimeric HAs (cHAs), where the stalk domain of the HA remains the same, but a different head construct is used at each vaccination. Using this strategy we have previously demonstrated that vaccinating animals with the same HA stalk (but different HA heads) over consecutive immunizations, results in the production of robust antibody responses toward the stalk domain [6, 14]. These stalk antibodies have the potential to be cross-reactive within and across influenza virus HA subtypes due to the high level of conservation in the stalk domain [15]

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Conclusion