Introduction and Background of the Project

Introduction

Dengue is one of the most serious public health problems worldwide. 50% of the world’s population are at risk of dengue. Despite decades of effort, there is no effective treatment and the currently one licensed vaccine is recommended for use only in those ≥ 9 years of age. The current vaccine has been associated with a safety risk in those who were seronegative to dengue at the time of vaccination. Therefore, there is an urgent need for next-generation vaccines.

Virus-like particle (VLP)-based vaccines are an attractive approach. VLP vaccines have shown to be safe and highly immunogenic because they mimic the conformation of the authentic virus but lack the viral genome. Notably, VLP vaccines can be administered to all populations including the most vulnerable population of infants and children. 

Project objective

In collaboration with Nagasaki University and National Institute of Infectious diseases, Japan (NIID), VLP Therapeutics has developed a novel dengue VLP vaccine using our unique technology. In an ongoing project, we have demonstrated the efficacy of our dengue VLP vaccine in preclinical studies including non-human primates. Here we will produce this VLP vaccine to conduct and lay the groundwork for clinical trials. The long-term goal of this project is to commercialize the first flavivirus VLP vaccine.

Project design

This project involves constructing VLP dengue vaccines across all four Dengue serotypes; establishing master cell banks and manufacturing vaccines, prepare an IND package and a clinical development plan.

How can your partnership (project) address global health challenges?

Dengue is one of the most serious public health problems worldwide, with 50% of the world’s population at risk of dengue. Currently there is no effective vaccine to protect against dengue infection. VLP vaccine can be a highly effective novel vaccine and be administered to all populations.

What sort of innovation are you bringing in your project?

VLP vaccines represent a new approach to dengue vaccines since all other vaccines in development are live attenuated vaccines. Administration of live attenuated vaccines to infants is considered to be risky, and these populations are very vulnerable to dengue infection.

Role and Responsibility of Each Partner

VLP Therapeutics: As the primary contractor on this project, VLP Therapeutics is responsible for overall project coordination and oversight as well as Dengue VLP construction.

National Institute of Infectious Disease (NIID): NIID will set up and perform animal experiments to confirm vaccine production for clinical trials. 

Nagasaki University: Nagasaki University will perform analyses of all studies from the animal studies performed at NIID.

Latham Biopharm Group: Latham will provide program management services which includes overseeing the timelines and coordination across all project participants.

ohns Hopkins University (JHU): With the assistance of Professor Anna Durbin, JHU will help prepare the pre-IND and IND packages and a clinical development plan.

Final Report

1. Project objective:

The objective of this project was to advance the development of a novel tetravalent dengue VLP (DENVLP) vaccine to produce by producing GMP-grade vaccine doses for use in a Phase I trial. Key subsidiary objectives included developing the GMP manufacturing processes needed to produce lots of all four serotype VLPs at sufficient scale, developing the release criteria and analytical methods to verify the sterility, identity and potency of vaccine doses, conducting further preclinical studies necessary for regulatory submission and selection of an adjuvant, and final regulatory submission to the FDA in preparation for a clinical trial.

2. Project design:

Research-grade mammalian cell banks which constitutively express one serotype of dengue VLP were transferred from VLP Therapeutics to a GMP-certified CDMO(s) for initial development of upstream and downstream manufacturing methods at a sufficient scale, followed by production and release of GMP-grade master cell banks (MCBs), with oversight from VLPT and Latham Biopharma Group. Further preclinical studies performed by VLPT, Nagasaki University, the National Institute for Infectious Disease, and the Japan Institute for Health Security were used for regulatory filing and also resulted in publication of a manuscript describing vaccine efficacy in non-human primates.

3. Results, lessons learned:

The G2018-103 project encountered numerous obstacles to in achieving its project objectives, and the project’s partners are deeply appreciative to the GHIT foundation for their patience and support as the project navigated these difficulties. Challenges included the development of the research-grade and GMP-grade cell banks for the expression of DENVLPs of all four serotypes, transitioning from a monovalent to tetravalent test article for first-in-human studies, and migration to a new GMP-grade certified CDMO.

The first and most significant challenge for the project was the generation of all four GMP compliant MCBs for stable expression of each drug substance. Several cell banks lost the stable DENVLP-expressing phenotype during the prolonged passaging required to achieve production-scale volumes, necessitating full redesigns of the DENVLP-expressing sequences, re-cloning of stable cell lines, qualification of the new GMP-grade master cell banks, and verification that the new DENVLPs generated an equivalent serotype-specific immunogenicity in preclinical models. Despite these challenges, the project partners were ultimately successful in meeting their objectives and gained valuable insights into the contribution of various structural features to both DENVLP expression and serotype-specific immunogenicity.

While the project partners dealt with the obstacles to MCB generation described above, they resolved, with GHIT support, to begin manufacturing a cGMP-grade monovalent DENVLP drug product so that the knowledge gained could further the ultimate project objectives. Based on nonclinical data which demonstrated that each serotype-specific DENVLP was responsible for the majority of the neutralizing antibody titer to a live dengue virus of the same serotype, the project partners sought to use monovalent DENVLP vaccine for the first-in-human trials, with a goal to demonstrate safety and efficacy across a range of doses at lower cost. Ultimately, the authors were persuaded by GHIT and other co-investing partners to pursue a clinical development plan that began phase I with a tetravalent DENVLP vaccine. This transition corresponded with a transition to a new, Japan-based CDMO for generation of the cGMP drug substances required for the final product. The authors appreciate the GHIT foundations continuous guidance and support in navigating each of these challenges.