Why the dengue vaccine has eluded science for decades

A virus perhaps like no other, dengue has baffled science for decades. The disease has spread rapidly across developing countries, laboratories have laboured over it for almost 90 years, yet the world remains without an effective dengue vaccine. The root of the problem is that dengue, unlike other viruses, has four different strains, each with their own genotypes. Scientists have been trying to crack how to use all four forms of the living but weakened virus types into a working vaccine.

According to scientists from the India chapter of the International Centre for Genetic Engineering and Biotechnology (ICGEB), that very approach, that worked for every other viral disease, has held science back. On the cusp of producing a dengue vaccine that could actually work, created through a wildly different method, Dr. Naveen Khanna of the ICGEB told dna that pharmaceutical industry globally is finally leaving behind the tried and tested methods of a live attenuated vaccine (LAV), where the weakened virus produces antibodies boosting one's immunity.

"The dengue virus creates two types of antibodies when they enter the system," explained Dr. Khanna, "the few protective antibodies that completely neutralise the virus, and the many pathogenic, bad antibodies". Each dengue strain creates its own type of good and bad antibodies.

These 'bad' antibodies are at the heart of the puzzle. No one knows how, said Khanna, but when they come into contact with the one of the other three strains of the virus, they somehow invite them into the human body and allow them to flourish. Called antibody dependent enhancement (ADE) of the infection, this is why the second bout of dengue is always more dangerous than the first. It is also why Sanofi Pasteur's vaccine Dengvaxia, released last year as the first dengue vaccine, is limited in scope. If given to someone unexposed to any dengue strain, it will create the pathogenic antibodies, leaving that person vulnerable to a more virulent form of the disease. Hence, Dengvaxia cannot be given to children or people over the age of 45, with weaker immune systems.

This is also the reason GlaxoSmithKline (GSK) in a recent paper admitted that their LAV vaccine candidate did not produce the desired result, "a durable humoral immune response". Khanna told dna that GSK was leaving that line of research after 30 years of work. Dengvaxia took 22 years, said Khanna.

For Khanna's vaccine, created with the support of the Department of Biotechnology, "less is more". Instead of a mishmash of all four strains of dengue, Khanna isolated "receptor binding domain" of each strain, a component of the virus that acts like its master key to entering any cell. "Take away that key and the virus will stand outside," described Khanna. Linking these 'keys' together with a hepatitis B protein, that has the inherent ability to take the ideal virus like shape, Khanna has created a new chimera protein for his vaccine.

This, according to his pre-clinical trials, has produced minimal pathogenic antibodies in mice and monkeys; promising early results. What sounds so simple took six people 10 years to create, and will need another six or seven of work and clinical trials to reach completion.