Dengue Fever and Betacoronavirus: T cell-priming Immune Set-Point Candidates

While Dengue Fever infections are rare in the United States, they are not in other parts of the world and cause hundreds of millions of infections a year. Betacoronavirus infections are not rare—SARS-CoV-2, for example—but they can be devastating as well. What can be done to protect against these diseases?

Recently, a clinical-stage biotechnology company, Emergex, announced their collaboration with Brazil’s Instituto de Biologia Molecular do Paraná (IBMP) to co-fund Phase II and Phase III studies of Emergex’s Dengue Fever and Betacoronavirus T cell-priming therapeutic candidates in Brazil. This partnership will expand upon the recent phase I clinical trials that assessed the safety, tolerance, and effectiveness of administering DengueTcP through intradermal microneedle injection to healthy participants.

Thomas Rademacher, MD, PhD, cofounder and CEO of Emergex, is also the emeritus professor of molecular medicine at the University College London, London, England. He answered questions for Infection Control Today®(ICT®) about dengue fever and betacoronavirus and the Phase II and Phase III studies.

ICT: What are Dengue Fever and Betacoronavirus?

Thomas Rademacher, MD, PhD: Dengue fever is caused by the mosquito-borne virus, dengue, a single positive-stranded RNA virus that can be grouped into 4 genetically- and antigenically-related viruses, known as serotypes 1–4, prominent in tropical and subtropical areas. Approximately half of the world’s population (~3.9B) live in areas with a risk of dengue, which is often a leading cause of illness endemic to these areas; this population does not even include travelers from nonendemic countries, contributing overall to a high-in-demand market for protection against dengue infection. Mild dengue fever causes a high fever and flu-like symptoms, whereas severe dengue fever can be life-threatening within a few hours and often requires hospital care. Dengue is one of the most critical mosquito-borne viral diseases, with up to 400 million people worldwide infected with the dengue virus each year.

Like dengue, betacoronaviruses (one of 4 genera [Alpha, Beta, Gamma, and Delta] of coronaviruses) are positive-sense, single-stranded RNA viruses. Some recent betacoronaviruses that have appeared across the globe include Middle East Respiratory Syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the latter being responsible for causing the recent COVID-19 pandemic, resulting in more than 6 million deaths according to the World Health Organization (WHO). People with COVID-19 have reported a wide range of symptoms–ranging from mild flu-like symptoms to severe illness and death.

A unique challenge RNA viruses pose is their high mutation rates, which give rise to diverse populations of closely related variants known as “quasi-species.” Given that vaccine-induced antibodies predominantly bind to structural proteins on the virion surface, which may differ substantially between quasi-species, the use of conventional antibody-mediated vaccines (which work against bacteria/bacterial toxins) for RNA viral infections may not be the ideal approach. In a natural RNA viral infection, virus eradication on first exposure is mediated via innate and T-cell immunity. The antibody response generated in response to viral exposure during a primary infection should not be inferred to indicate their functional importance in preventing infection/disease upon secondary exposure. Limitations in efficacy and the duration of immunity provided by current vaccines highlight the requirement for costly and administratively burdensome boosters and, conversely, illuminate the need for broad and durable preventive solutions. In addition to these biological challenges, equitable distribution of conventional vaccines due to their cost and logistics remains a hurdle in many countries.

ICT: What was the announcement from Emergex?

TR: Emergex announced a multi-level collaboration agreement with the Molecular Biology Institute of Paraná (IBMP) in Brazil. Emergex and IMBP have agreed to co-fund Phase II and Phase III studies of Emergex’s dengue fever and betacoronavirus T cell-priming immune set-point candidates, known respectively as DengueTcP* and CoronaTcP*. Both clinical trial product candidates have successfully completed Phase I clinical trials in Switzerland and are nearing submission and evaluation by ANVISA, the Brazilian health regulatory agency, to begin the next phase of clinical trials. Emergex will eventually conduct clinical-stage manufacturing of the products with a planned transition to IBMP for commercial-scale manufacturing in the region. IBMP will obtain exclusive marketing and commercialization rights for the 2 candidate products in Brazil and South America.

This agreement also allows for future expansion into additional indications, including developing and commercializing Emergex’s T cell-priming set-point candidates targeting chikungunya, influenza A (including pandemic strains), and yellow fever. Additionally, Emergex announced the early equity investment by IBMP into Emergex, which has the potential for future increase pending completion of its ongoing due diligence process.

ICT: Why is it significant?

TR: Emergex’s T cell-priming immune set-point candidates are designed to provide broad and long-lasting protection (potentially up to decades). They combine 2 proprietary technologies, [1] an empirically-determined library of pathogen-derived protein fragments expressed on the surface of pathogen-infected cells (forming the MHC class I expression “ligandome” library), and [2] an ultrasmall, carbohydrate-passivated nanocluster carrier system (final diameter 5 nm) designed to deliver synthetic peptides to the skin-resident immune system via micro-needles to elicit a robust, adaptive CD8+ T cell response. Additionally, Emergex T cell-priming candidates are designed with a fully synthetic composition and have potential stability at ambient temperatures (> 3 months). This could significantly improve storage and ease of administration among diverse populations.

This collaboration, to fund clinical advancement of Phase II and III studies of Emergex Dengue Fever and Betacoronavirus T cell-priming immune set-point candidates, brings Emergex closer to effective solutions against these global infectious diseases through harnessing the natural cellular immune response. In particular, there are currently no approved antiviral treatments for dengue fever, and there are safety concerns with current vaccine strategies associated with antibody-dependent enhancement (ADE) of the disease or deployment restricted to a subset of serotypes. Phase I clinical results evaluating DengueTcP have provided proof-of-concept that the Emergex therapeutic platform can successfully induce virus-specific CD8+ T cell responses without the induction of anti-DENV antibodies, which is a favorable outcome that reduces the risk of ADE. In addition, this treatment also has the potential to protect against all dengue virus serotypes and potentially against other Flaviviridae strains, thus, protecting people from illness associated with these lethal tropical diseases.

Similarly, Emergex T cell-priming immune set-point candidate for betacoronaviruses offers the potential for long-term immune protection, thereby avoiding the need for seasonal boosting compared to current vaccine technologies, which primarily rely on an antibody immune response. In addition, the broad protection induced by CoronaTcP is less likely to be impacted by changes (mutations) in the consensus sequence of RNA viruses that lead to new variants of concern.

ICT: What is the takeaway specifically for infection preventionists and other infection prevention and control personnel?

TR: Emergex is revolutionizing the future of prevention against infectious diseases. The company’s T cell-priming immune set-point product candidates fill a gap in global infectious disease coverage beyond current standards in its intended efficacy, longevity, sustainability, safety, and versatility. Aside from the induction of robust virus-specific T cell responses, there are several key advantages of the Emergex approach: [1] These candidates are designed for administration via a novel micro-needle skin-mounted patch, intended to reduce the burden and logistics associated with conventional vaccine administration in both developed and emerging country contexts; [2] they are inexpensive to manufacture, intended for governments, philanthropies, and other pharmaceutical companies for distribution; and [3] their simple design lends itself to potential rapid manufacture in the face of emerging pandemics. Their potential to be shelf stable at ambient temperatures further enables easy transportation to remote parts of the world where they are needed most, a global catalyst in responding to RNA viral infections.

ICT: What are the next steps?

TR: Emergex will continue to pursue collaborative arrangements with governments, philanthropies, international health care agencies, and select pharmaceutical companies (for defined geographic regions), which will empower that partner with first rights to commercialization in a given territory or field, thus aiding in the development and distribution of its T cell-priming immune set-point candidates.

* Trademark application submitted.