ChAd-MVA Prime-Boost Regimen for Hepatitis B Functional Cure
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Solution Overview
Problem
Current treatments for chronic hepatitis B, such as nucleos(t)ide analogues, do not achieve HBsAg loss or functional cure, leading to long-term therapy and risks of relapse, while new strategies like vaccines have not induced robust CD8+ T-cell responses necessary for immune control.
Innovation Solution
An immunogenic composition comprising a replication-defective chimpanzee adenoviral vector and Modified Vaccinia Virus Ankara vector, encoding hepatitis B surface and core antigens, along with an adjuvant, administered in a prime-boost regimen to stimulate HBs- and HBc-specific immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleos(t)ide analogues are used for treatment, then HBV DNA suppression is achieved, but HBsAg loss and functional cure are not achieved
Solution Approach 1:
The patent combines nucleos(t)ide analogue therapy with a novel vaccine composition containing viral vectors and adjuvants to simultaneously achieve HBV DNA suppression and HBsAg loss. The vaccine component (comprising viral vectors encoding HBs and HBc antigens with adjuvants) works synergistically with NA therapy to induce robust immune responses that drive functional cure, resolving the limitation of NA monotherapy.
Solution Approach 2:
The invention uses a composite vaccine composition integrating multiple components: viral vectors (adenoviral and poxviral), antigenic proteins (HBs and HBc), and adjuvants (AS01B or AS01E). This composite formulation enhances immunogenicity and enables both antiviral suppression and surface antigen clearance, achieving functional cure rates unattainable with single-component therapies.
2Reliability
If pegylated interferon alpha is used, then long-term immune control is induced, but sustained off-treatment control and HBsAg loss are limited
Solution Approach 1:
The patent changes the immunological parameters by using viral vector-based vaccines that induce stronger and more durable CD8+ T-cell responses compared to interferon therapy. The viral vectors (adenoviral and poxviral) deliver antigens in a manner that triggers robust cellular immunity, achieving both immune control and HBsAg loss at higher rates than PegIFNα.
Solution Approach 2:
The invention uses viral vectors as copies of the natural viral infection mechanism to deliver antigens and stimulate immunity. The adenoviral and poxviral vectors replicate the viral entry and protein expression processes in a controlled manner, inducing potent immune responses that mimic and exceed the efficacy of interferon-based therapies.
3Reliability
If NA treatment is continued long-term, then HBV DNA suppression is maintained, but patient compliance and financial costs increase
Solution Approach 1:
The patent applies preliminary action by administering the viral vector vaccine before or during early NA therapy to prime the immune system. This preliminary immunization creates memory T-cells and antibodies that will enable future discontinuation of NA therapy while maintaining suppression, reducing the need for lifelong treatment and improving compliance.
Solution Approach 2:
The invention incorporates feedback mechanisms through monitoring of HBsAg levels and immune responses during treatment. The vaccine-induced immune system provides feedback control, where rising HBsAg or viral replication triggers enhanced immune activation, enabling dynamic adjustment of therapy duration and intensity to achieve cure while minimizing treatment time.
Data Source
AI summary
The present invention relates to immunogenic compositions and combinations thereof which may find use in immunisation regimens for the treatment of chronic hepatitis B. An immunogenic composition comprises a replication-defective chimpanzee adenoviral (ChAd) vector comprising polynucleotides encoding HBs, HBc human invariant chain (hIi) fused to the HBc. Another immunogenic composition comprises a Modified Vaccinia Virus Ankara (MVA) vector comprising polynucleotides encoding HBs and HBc. Another immunogenic composition comprises recombinant HBs, C-terminal truncated recombinant HBc and an adjuvant containing MPL and QS-21.