Introduction and Background of the Project

Introduction

Dengue is a major global health threat, with about 50% of the world's population at risk^{1, 2}. While two live-attenuated vaccines are commercially available, they have some safety and efficacy concerns, especially for children without prior exposure to the virus. This highlights the urgent need for a safer, novel vaccine. Virus-like particle (VLP) vaccines closely resemble the real virus, triggering a strong immune response. However, they are non-infectious, making them safe also for infants and individuals with weakened immune systems. We have developed a tetravalent dengue VLP vaccine that has shown robust induction of neutralizing antibody against all four dengue serotypes in mice and monkeys³. We are now producing clinical-grade batches. Next, we will assess the vaccine’s safety, immune response, and efficacy in a Phase I clinical trial while scaling up production. Our goal of this project is to confirm its safety and efficacy and determine the optimum dose.

Project objective

This Phase I clinical trial aims to evaluate the safety, immunogenicity, and efficacy of the tetravalent DENVLP vaccine. We will assess antibody titers, neutralizing antibody levels, and antibody-dependent enhancement (ADE) following vaccination. Additionally, we will evaluate the efficacy of infection protection using a challenge strain of the dengue virus.

Objective 1: Manufacturing the DENVLP Vaccine | We will produce a high-quality, GMP-grade of the tetravalent DENVLP vaccine using our stable cell lines for dengue virus types 1-4. We will assess quality and stability.

Objective 2: Phase I Clinical Study | We will conduct a placebo-controlled Phase I trial with four groups of healthy adults (ages 18-60) to test different vaccine doses. Participants will receive three doses.

Project design

Manufacturing and IND Submission: VLP Therapeutics (VLPT) will oversee the manufacturing and regulatory submission for the tetravalent DENVLP vaccine and design the clinical trial plan. Its group company, VLP Therapeutics Japan, will conduct GMP-compliant manufacturing of the tetravalent vaccine. After manufacturing, the vaccine will undergo quality testing before submitting an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA).

Phase I Clinical Trial: A Phase I clinical trial will be conducted to evaluate the safety, immunogenicity, and efficacy of the DENVLP vaccine. The vaccine's safety and immunogenicity will be assessed, and a six-month follow-up will be conducted after vaccination. At six months, all participants will be exposed to a dengue virus challenge strain to evaluate vaccine efficacy. 

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

Dengue is one of the top 10 global health threats, according to the WHO. Despite years of research, there is no effective treatments. Various clinical trials have tested dengue vaccines, including live-attenuated, inactivated, DNA, and subunit vaccines⁴. This project represents the first clinical trial of a dengue vaccine utilizing virus-like particles (VLPs). VLPs are non-infectious viral particles that do not contain any genetic material capable of replication. When used as a vaccine, they can induce a strong immune response without causing adverse reactions related to viral replication or infection. As a result, VLP-based vaccines can be administered to infants and immunocompromised individuals, addressing a critical public health need. If this vaccine is successfully introduced to the market, we aim to make it readily available in low- and middle-income countries in dengue-endemic regions, ultimately contributing to saving lives and improving the quality of life for many people.

What sort of innovation are you bringing in your project?

The innovation of the VLP vaccine lies in its high immunogenicity and safety. This vaccine induces strong neutralizing antibodies against all four serotypes of the dengue virus (DENV) while being non-infectious, making it safe for administration to infants and immunocompromised individuals. In particular, in dengue-endemic regions, the severity rate of dengue fever is high among infants under one year of age, and the VLP vaccine has the potential to reduce this risk. Additionally, it is expected to be applied as a booster vaccine for individuals who have received a live-attenuated vaccine. In this project, we developed a novel tetravalent dengue vaccine candidate utilizing VLP technology and demonstrated in mice and non-human primates that it induces a strong neutralizing response against all serotypes without causing antibody-dependent enhancement (ADE). These support the development of a safe and effective dengue vaccine, bringing us closer to a viable solution for dengue prevention.

Role and Responsibility of Each Partner

VLPT serves as the lead research and development institution for this project, overseeing and conducting all activities, contract agreements, and collaborative research. The company is responsible for designing the project framework and conducting comprehensive data analysis.

Nagasaki University participates as a collaboration partner. Under the leadership of Professor Koichi Morita, his team contributes to this development by leveraging their extensive expertise and experience in dengue virus research. They will also conduct neutralizing antibody titer measurements for all four serotypes of the dengue VLP vaccine and perform ADE assays. Johns Hopkins University serves as a contracted institution, conducting clinical trials for the dengue vaccine. Under the guidance of Professor Anna Durbin, who has extensive experience in challenge modeling for vaccine efficacy evaluation and dengue vaccine development, the university will conduct the Phase I clinical trial.

Others (including references if necessary)

1. Cogan, J.E. Dengue and Severe Dengue. World Health Organization (2023).

2. Bhatt, S. et al. The global distribution and burden of dengue. Nature 496, 504–507 (2013).

3. Thoresen D, Matsuda K, et al. A tetravalent dengue virus-like particle vaccine induces high levels of neutralizing antibodies and reduces dengue replication in non-human primates. J Virol. 98 (2024)

4. Dutta, S. K. & Langenburg, T. A Perspective on Current Flavivirus Vaccine Development: A Brief Review. Viruses 15, (2023).

5. Halstead, S. B. et al. Dengue hemorrhagic fever in infants: research opportunities ignored. Emerg. Infect. Dis. 8, 1474–1479 (2002).