The Design and Development of a Multi-HBV Antigen Encoded in Chimpanzee Adenoviral and Modified Vaccinia Ankara Viral Vectors; A Novel Therapeutic Vaccine Strategy against HBV.

Senthil K Chinnakannan,Sarah Sebastian,Timothy A Donnison,Mala K Maini,Lian Ni Lee,Eleanor Barnes,M Azim Ansari,Paul Klenerman,Tamsin N Cargill,Tom Evans,Claire Hutchings

doi:10.3390/vaccines8020184

Abstract

Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are urgently required. To develop a therapeutic HBV vaccine that can induce high magnitude T cells to all major HBV antigens, we have developed a novel HBV vaccine using chimpanzee adenovirus (ChAd) and modified vaccinia Ankara (MVA) viral vectors encoding multiple HBV antigens. ChAd vaccine alone generated very high magnitude HBV specific T cell responses to all HBV major antigens. The inclusion of a shark Invariant (SIi) chain genetic adjuvant significantly enhanced the magnitude of T-cells against HBV antigens. Compared to ChAd alone vaccination, ChAd-prime followed by MVA-boost vaccination further enhanced the magnitude and breadth of the vaccine induced T cell response. Intra-cellular cytokine staining study showed that HBV specific CD8+ and CD4+ T cells were polyfunctional, producing combinations of IFNγ, TNF-α, and IL-2. In summary, we have generated genetically adjuvanted ChAd and MVA vectored HBV vaccines with the potential to induce high-magnitude T cell responses through a prime-boost therapeutic vaccination approach. These pre-clinical studies pave the way for new studies of HBV therapeutic vaccination in humans with chronic hepatitis B infection.

Highlights

Chronic hepatitis B virus infection (CHBV) is a massive global health burden affecting 257 million people worldwide with an estimated 887,000 annual deaths due to liver cirrhosis and hepatocellular carcinoma (HCC) (WHO 2018)
ChAdOx1/ChAdOx2 and modified vaccinia Ankara (MVA); shark class-II invariant chain (SIi), PreC, core, Pmut, N∆PreS1, and PreS2 were generated under a CMV (ChAd) or F11 (MVA) promoter to induce HBV specific T cells, whilst tissue plasminogen activator (TPA), C∆PreS1 and surface was generated separately using
To design the HBV immunogen, we focused on HBV genotype C, highly prevalent in Asia

Summary

Introduction

Chronic hepatitis B virus infection (CHBV) is a massive global health burden affecting 257 million people worldwide with an estimated 887,000 annual deaths due to liver cirrhosis and hepatocellular carcinoma (HCC) (WHO 2018). Available antiviral drugs suppress viral replication, but fail to suppress viral transcription and translation or eliminate covalently closed circular DNA (cccDNA), Vaccines 2020, 8, 184; doi:10.3390/vaccines8020184 www.mdpi.com/journal/vaccines. Vaccines 2020, 8, 184 the viral DNA template. Cessation of therapy results in viral rebound such that antiviral therapy is often continued indefinitely [1,2]. Treatment does not eliminate the risk of developing HCC [3,4,5]. There is an urgent need to develop effective therapeutic strategies to cure chronic HBV infection and to replace the current strategy of long-term antiviral treatment. If infection persists, HBV specific T cells develop an exhausted phenotype and lose their full cytotoxic and proliferative functions [6]. Therapeutic vaccination, with the aim of inducing high-magnitude functional HBV

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