2009 saw nearly 60 years of research come together with more than five dengue vaccines in various promising stages of development. PDVI is supporting these vaccines in various ways, and PDVI-supported programs have played integral parts in the development not just of the vaccines themselves, but also the testing methodologies and trial strategies. "Our goal is to have sufficient availability of safe and effective dengue vaccines that are affordable for widespread use in developing countries to significantly lower disease incidence," said Harold Margolis, MD, Director of the Pediatric Dengue Vaccine Initiative.

PDVI's "portfolio" approach is somewhat novel in the world of vaccine development, but similar to that pursued by other product development partnerships (PDPs). Rather than choosing one candidate vaccine on which to focus its resources, PDVI has instead encouraged the development of a portfolio of promising vaccines made by different manufacturers and employing different technologies. This approach increases the chance that at least one vaccine, and probably more, will make it to market.

Additionally, the portfolio approach encourages the healthy benefits of competition: adequate production to meet the projected need, realistic prices, and the development of a variety of soundly tested technologies.

"PDVI is proud of its portfolio approach to vaccine development," noted Richard Mahoney, PhD, PDVI Director of Vaccine Access. "It has taken a lot of work to set it up, but it is paying off in terms of raising the level of activity and accelerating progress. We are confident that licensed vaccines are near at hand."

A dengue vaccine, which was a pipe dream to many just a few years ago, is rapidly becoming a reality. Following are synopses of vaccines that are the farthest along the pipeline.

At the end of 2009, at least 5 dengue vaccines were in development          

sanofi pasteur: Live-Attenuated Vaccine Candidate based on Chimerivax Technology

The vaccine that is the farthest along the development pipeline is the sanofi pasteur vaccine candidate. Currently in Phase IIb trials, the vaccine is a tetravalent vaccine (TV) built on the backbone of the yellow fever virus YF17D. It includes envelope components from all four dengue serotypes, is genetically stable, and without significant adverse reactions.

During Phase II trials in the United States, Mexico, and the Philippines, adverse effects of the vaccine were deemed mild to moderate and were transient in nature. There was no viremia reported after the initial injection. Seroconversion differed with age and, in the Philippines study, the level of seroconversion increased with each injection even though baseline levels of Flavivirus immunity were high.

Melanie Saville, Head of the Clinical Dengue Program at sanofi pasteur was quoted in the December 2009 issue of The Lancet as saying that the company is proceeding with plans for Phase III. The Phase IIb trial is underway in the Ratchaburi province of Thailand, and continued success will result in the submission of the TV vaccine to regulatory authorities, reported The Lancet.

Hawaii Biotech: Monovalent Dengue Vaccine Candidate based on Recombinant Envelope Subunits

In August 2009, Hawaii Biotech, Inc. (HBI) and St. Louis University (SLU) started a Phase I clinical study of a monovalent dengue vaccine candidate.

The study is double-blind, placebo controlled, and focuses on safety of the vaccine administered at two different doses. The subjects are also being monitored for virus-neutralizing antibody production. "This study is a precursor to the Phase I and Phase II studies we are planning for our tetravalent dengue vaccine," Beth Ann Coller, Ph.D, Senior Vice President for Research and Development at Hawaii Biotech, Inc., told The Lancet in the December 2009 issue.

The HBI vaccine candidate is the first recombinant subunit vaccine for dengue to be tested in clinical studies. The recombinant subunit approach is an alternative to live-attenuated vaccines that are under clinical evaluation. SLU has enrolled 16 participants between the ages of 18 and 45 years to participate in the study.

HBI is a privately-held biotechnology company with a focus on research and development of prophylactic vaccines.

Inviragen: DENVax Dengue-Dengue Chimera Entering Early Clinical Trials

Inviragen's DENVax candidate is based on dengue-dengue chimeric viruses that express multiple surface antigens of all four dengue subtypes. In preclinical testing, the chimeras retained safety properties and generated "potent immune responses" against the related dengue virus, according to Inviragen literature.

Inviragen, which has merged with SingVax, a vaccine company focused on infectious diseases in the Asia Pacific region, recently raised nearly US$15 million from investors to support international clinical trials in a variety of regions around the world. Since Inviragen's focus in dengue vaccine development "is to develop a vaccine that can protect against dengue after one or two easily given doses [to] best meet the needs of people at risk in endemic countries," the trials will take place in a several different forms, fashions and locations, said Dan Stinchcomb, MD, Inviragen's Chief Executive Officer.

Stinchcomb also notes that "post-merger, Inviragen has three vaccines poised to begin human clinical trials." Over the next 18 months, the clinical studies will test vaccine safety and measure immune responses of the DENVax vaccine and two others to establish "proof-of-concept" of their efficacy, Stinchcomb said. In the United States, healthy, dengue-naive individuals will receive the vaccine, along with counterparts in a high-altitude version of the study in Colombia. In Singapore, a needle-free vaccine delivery method and alternative dosing schedules will be tested. Researchers anticipate that human clinical testing of Inviragen's dengue vaccine will commence in 2010.

US NIH: DEN/DEN Chimera with Gene Deletion to enter Phase I clinical trial of tetravalent formulation in Brazil in 2010

The Butantan Institute in Sao Paulo, Brazil is undertaking further development of the US NIH dengue-dengue chimeric vaccine with gene deletions.

Butantan Institute is confident of rapid progress because the vaccine has already been safety-tested in the United States, and the Brazilian trials are intended to insure compliance with Brazil's national requirement that all safety trials be replicated in Brazil. The project is the result of a three-year negotiation between NIH and Butantan to work together to produce a lowcost product that could be supplied by the local government to the population to help prevent and control dengue. Should the vaccine prove to be safe and effective, Butantan plans to produce nearly 30 million doses and target children with the preventative vaccine.

Now, at the end of 2009, it appears that early timelines are on track, as the vaccine is scheduled to enter Phase I clinical trials in 2010.

Butantan plans to take the NIH-licensed chimeras into clinical trials after the "first of the year," said Don Francis, MD, DSc, Executive Director of Global Solutions for Infectious Diseases (GSID). This will be the first time that these vaccines have been tested in tetravalent form, said Francis. These trials will help evaluate the potential for interference among the four components.

Butantan plans to take the NIH-licensed chimeras into clinical trials after the "first of the year," said Don Francis, MD, DSc, Executive Director of Global Solutions for Infectious Diseases (GSID). This will be the first time that these vaccines have been tested in tetravalent form, said Francis. These trials will help evaluate the potential for interference among the four components.

And There's More...

Other vaccines are also under development. For example, GlaxoSmithKline (GSK) has made important progress with a traditional, live, attenuated vaccine and has taken it through successful first stage Phase II studies. At press time, GSK was reviewing its options for proceeding including a collaboration with the Oswaldo Cruz Foundation/Brazilian Ministry of Health (FIOCRUZ) in Rio de Janeiro to jointly develop a dengue vaccine.