Hepatitis B Vaccine Using CpG Immunostimulatory Sequences

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Solution Overview

Problem

Current hepatitis B vaccines are hindered by a lengthy administration regimen and poor compliance due to the need for multiple doses over several months, and they fail to induce a potent immune response in hypo-responsive populations, such as diabetic individuals and those with renal failure or high-risk behaviors, resulting in low seroprotective antibody levels.

Innovation Solution

A method involving the administration of a hepatitis B surface antigen (HBsAg) combined with an immunostimulatory sequence (ISS) comprising an unmethylated cytosine-phosphate-guanosine (CpG) motif, given in two separate doses, followed by a booster, to elicit a seroprotective immune response in individuals with glucose metabolism disorders, including diabetics, within a shorter timeframe.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Speed

If current HBV vaccines are administered using the standard regimen, then the immune response is induced, but the administration takes six to twelve months with three or four doses, resulting in poor compliance and delayed protective immunity

Engineering Contradiction:

ImproveSpeed of immune response inductionVSAvoidTime for vaccination regimen completion

Core Design Contradiction:

SpeedVSLoss of time

Solution Approach 1:

The vaccine formulation includes immunostimulatory sequences (ISS) with CpG motifs that pre-activate immune pathways, enabling faster immune response without requiring multiple doses over extended periods. This preliminary immune system priming allows protective immunity to be achieved within weeks rather than months

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention changes the immunogenic parameters by incorporating ISS at specific concentrations (e.g., 1-100 μg per dose) and using modified nucleotide sequences (unmethylated CpG motifs) that enhance immune stimulation. These parameter changes accelerate the immune response kinetics while maintaining safety

Inventive Principle:

Principle #35Parameter changes

2Reliability

If current HBV vaccines are administered to hypo-responsive populations, then some immune response is achieved, but seroprotective antibody levels remain low in 30-60% of recipients, particularly in those over 40 years of age and subjects with renal failure or diabetes

Engineering Contradiction:

ImproveReliability of seroprotective responseVSAvoidAdaptability to hypo-responsive populations

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The vaccine formulation uses locally optimized components including specific ISS sequences (e.g., 5'-TCG-3' or 5'-CGTTCG-3' motifs) and HBsAg concentrations tailored to overcome immune suppression in hypo-responsive populations. This local quality enhancement ensures reliable seroprotective responses even in diabetic individuals and those with renal failure

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention creates a composite vaccine formulation combining HBsAg with immunostimulatory sequences (ISS) containing unmethylated CpG motifs. This composite structure provides both the antigenic stimulus and the immunomodulatory enhancement needed to achieve reliable seroprotective responses in hypo-responsive populations that fail to respond adequately to standard vaccines

Inventive Principle:

Principle #40Composite materials

3Ease of manufacture

If HBsAg is adsorbed to alum in current vaccines, then the vaccine is stable and manufacturable, but the immune response is insufficient and requires multiple doses over extended periods

Engineering Contradiction:

ImproveEase of vaccine productionVSAvoidReliability of immune response

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The invention enhances the alum-adjuvanted HBsAg formulation by incorporating immunostimulatory sequences (ISS) with unmethylated CpG motifs. This composite approach maintains the manufacturing simplicity of alum adsorption while significantly improving immune response reliability through the addition of ISS that activate innate immune pathways

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The invention modifies the formulation parameters by adding ISS at optimized concentrations (e.g., 1-100 μg per dose) with specific nucleotide sequences (e.g., 5'-TCG-3' or 5'-CGTTCG-3'). These parameter changes enhance immunogenicity while preserving the ease of manufacture associated with alum adsorption technology

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach significantly increases the seroprotective antibody response in diabetic and other hypo-responsive populations, achieving higher titers and sustained protection with fewer doses, thereby improving vaccine compliance and efficacy in high-risk groups.

Implementation Method 1

the immunogenic composition comprises a hepatitis B surface antigen (HBsAg) and an immunostimulatory sequence (ISS) of from 8 to 50 nucleotides in length comprising an unmethylated cytosine-phosphate-guanosine (CpG) motif

Methodology Applied

Scientific EffectCpG motif immunostimulation:

Data Source

PatentUS10314907B2Methods and compositions for eliciting an immune response against hepatitis B virus

Publication Date: 2019.06.11 DYNAVAX TECHNOLOGIES CORPORATION

AI summary

The present invention relates to immunization of hypo-responsive groups of individuals. In particular, the present invention provides methods and compositions for eliciting a potent immune response to hepatitis B virus in individuals in need thereof.