Colorado biotech’s latest milestones exemplify big-picture progress toward a dengue vaccine

The tropical disease dengue fever isn’t something we hear or worry about much in the U.S. So when virologists at the Centers for Disease Control and Prevention recently published study findings that a rare 2010 dengue outbreak in Florida came not from abroad but from a unique, local strain of the virus that’s evolved its own genetic code, ears started perking up.

Dengue is the most common mosquito-borne viral disease, transmitted via the Aedes mosquito in tropical and subtropical areas of the world. Symptoms range from mild fever and flu-like symptoms to potentially lethal hemorrhagic fevers. Although it’s recently caused some alarm in a small part of the U.S., for nearly 60 years it’s been considered a global health problem, designated as endemic in Puerto Rico and many popular tourist destinations in Latin America and Southeast Asia. According to the World Health Organization, about half the world’s population is at risk.

Although early detection and access to medical care keeps fatality rates below 1 percent, health experts and organizations have long pushed for preventive measures. Dr. Harold Margolis, chief of the CDC’s Dengue Branch, said that preventing dengue fever means breaking at least part of the transmission cycle. “The problem has been that pretty much everything that’s been tried so far on the mosquito side has not worked,” he said.

That’s put pressure on the medical community to develop a way to give humans immunity from the infection. The problem with that is dengue fever can actually be caused by any of four distinct but related serotypes of the virus. Creating a vaccine that provides immunity against all four of them has posed a challenge to researchers and pharmaceutical companies, especially since there are no good animal model of the disease to test on, Margolis said.

Sanofi, the leader in the development of a dengue vaccine, has advanced its candidate to phase 3 trials involving more than 30,000 people. But results from its phase 2 trial showed that it failed to protect from DEN-2, the serotype that happened to be most present in the region where the trials were being done. GlaxoSmithKline and Merck are also developing vaccines, but are a few years behind, having recently begun phase 1 studies. Another candidate being developed by the National Institutes of Health recently completed a phase 1 trial.

Somewhere in the middle of those big organizations is (relatively) small, Colorado-based Inviragen, which has just reached an important milestone in developing its own dengue vaccine, DENVax. It’s completed the first stage of its phase 2 study, in which it evaluated the vaccine for the first time in multiple age groups of people who live in dengue-endemic areas like Puerto Rico, Colombia, Singapore and Thailand.

Now that its delivered preliminary safety data from the study, Inviragen has been cleared to start the second stage of the trial in which it will test for safety and immunogenicity in 200 children.

One thing worth noting about Inviragen’s two-dose recombinant vaccine is that the CDC scientists who started work on it years ago began with a backbone of a weakened DEN-2 virus that had previously been shown to be safe and generated an immune response. They then built the other three vaccines by replacing the structural genes of DEN-2 with the genes of DEN-1, DEN-3 and DEN-4 viruses. In preclinical tests, those chimeric vaccine viruses demonstrated safety and potent immune responses.

“The reason we’re somewhat optimistic was that the virus Sanofi failed to protect was dengue 2, and that’s what we started with,” CEO Dan Stinchcomb said. “Our responses are strongest there.”

Inviragen began operations in 2005 and licensed the technology from the CDC. If the second stage of this phase 2 study goes as planned, the young company is looking at potential efficacy studies — a milestone only Sanofi has recently crossed — to begin next year. Stinchcomb said those studies would likely take about two years to complete.

The simplicity of the vaccine should also make it relatively inexpensive to manufacture and offer in a tiered pricing structure, Stinchcomb added. “We’re quite hopeful that we’ll be able to manufacture it in the realm where it can be used widely for public health.”

But a vaccine developed in a similar fashion by the National Institutes of Health is also about to enter phase 2 studies. In phase 1, TV003 was well tolerated by healthy volunteers and appeared to induce an immune response against each of the dengue viruses. A phase 2 trial is set to begin soon.

To be clear, all of these vaccines and developers have a long way to go, Margolis said. But seeing this kind of clinical activity, and the advances in diagnostics that have come along with it, is encouraging. It’s been enabled in part by funding from an initiative of Bill & Melinda Gates called the Pediatric Dengue Vaccine Initiative, established in 2001 to better define the burden of dengue and support R&D efforts toward a vaccine. Margolis, formerly director of the initiative, said that none of the vaccines currently in trials were even near clinical development when money first became available to them in 2003. By 2007, he said, there were five.

Inviragen, for one, has been able to round up nearly $30 million in grant and research funding from numerous organizations following a $15 million series A from private investors upon its founding.

In addition to the WHO, CDC and PDVI, other organizations have also emerged to to support the progress of a dengue vaccine. In preparation of a presumed rollout of at least one vaccine in the next several years, the Dengue Vaccine Initiative has been established to build on PDVI’s work by laying the groundwork for the introduction of a dengue vaccine in endemic areas.

[Mosquito photo from BigStock Photos]