Biologics for dengue prevention: up-to-date

ABSTRACT

Introduction

Dengue is a worsening global public health problem. The vector-viral-host interactions driving the pathogenesis of dengue are multi-dimensional. Sequential dengue virus (DENV) infections with different DENV types significantly increase the risk of severe disease. Treatment is supportive in nature as there are no licensed anti-DENV antivirals or immuno-therapeutics. A single dengue vaccine has widely been licensed with two others in advanced clinical development. Dengvaxia® has been licensed in numerous countries but uptake has been slow as a result of safety signals noted in the youngest recipients and those who were dengue naïve at the time of vaccination.

Areas covered

In this review, the current state of dengue vaccine and antiviral drug development will be discussed as well as new developments in controlled human infection models to support product development.

Expert opinion

The world needs a safe and efficacious tetravalent dengue vaccine capable of protecting multiple different populations across a broad age range and different flavivirus immunologic backgrounds. Safe and effective antivirals are also needed to prevent or attenuate dengue disease in the unvaccinated, in cases of vaccine failure, or in high-risk populations.

KEYWORDS:

• Dengue
• DENV
• vaccine
• antiviral

Article highlights

• Dengue is a worsening global public health problem afflicting tropical and subtropical regions

• Infection may be subclinical or result in severe disease with coagulation dysregulation, plasma leakage, shock, and potentially death.

• Dengue pathogenesis is incompletely understood but there is strong evidence pre-existing immunity to one dengue serotype significantly increases the risk of severe disease when sequentially infected by a different serotype more than two years later.

• A single dengue vaccine has been licensed but uptake has been slow due to a safety signal observed in seronegative vaccine recipients; two other vaccines are in advanced clinical development with one poised to receive regulatory approvals.

• Dengue therapeutics target either viral replication or the immunopathologic mechanisms of disease but the therapeutic window is narrow introducing a significant development challenge but opening the door to consider prophylaxis indications.

• A dengue human infection model represents an innovative tool to de-risk dengue vaccine and drug development programs by providing an early look into the potential for clinical benefit.

Declaration of interest

SJ Thomas is an academic and executes clinical trials and other research related to dengue. The funding for these is provided by federal and sponsored funding. These relationships are between his University and the funder. He currently has funding related to dengue from Janssen, Merck, Atea, NIH, and CDMRP. He also sits on advisory boards and review committees related to dengue countermeasure development. In some cases, he is compensated for his time and effort with monies, equity, or both. Current personal relationships of this variety include Merck (chair, scientific ad committee, dengue vaccines, financial comp.), PrimeVax (member, scientific ad board, dengue use in immuno-oncology, equity), Island Pharma (member, scientific ad board, dengue drug, equity), and Takeda (member, advisory board, dengue vaccines, financial comp; chair, dengue case adjudication committee, dengue vaccine, financial comp). He also participates in similar advisory and committee positions for non-dengue related countermeasure development work. He states that none of the work above relates to the submitted manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are an employee of Takeda Vaccines. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.