From Serendipity to Safe, Effective and Low Cost Vaccines
Against Insect-Borne Viruses

Some of the most important breakthroughs in medical science have resulted from the observations of unplanned "research" by brilliant scientists. For example, Alexander Fleming discovered penicillin after returning from holiday to find that the staphylococci in his bacterial culture dish seemed to steer clear of the mold ring that had developed in the culture while he was away. Had Fleming not kept a window open in his messy laboratory while away, penicillin might never have been discovered!

More recently, but equally serendipitously, NC State University scientists, Dr. Dennis Brown and Dr. Raquel Hernandez observed a game-changing discovery for developing vaccines against insect-borne viruses in what was essentially an experiment which produced unanticipated results!

By way of background, viruses require a host cell in order to reproduce and cause infection. The virus attaches to and enters the target cell, thereby integrating its genetic material into the cellular components and resulting in the production of multiple copies of the parent virus.

Drs. Brown and Hernandez research the mechanism of viral assembly. In 1998 they devised an experiment to determine how the virus core (the interior component of the virus particle, was able to attach to the outer virus membrane as the virus was formed. To test their hypothesis, they deleted an amino acid in the E2 membrane glycoprotein which, they hypothesized is essential in the final stages of virus assembly. The expected result was that there would be no binding to the outer membrane and therefore no viral assembly.

When tested in mammalian cells, there was indeed no viral assembly. However to the great surprise of Drs. Brown and Hernandez, the virus grew normally in insect cells. It is to their credit that these talented scientists were able to recognize the momentous potential this anomaly afforded in the field of vaccine development.

More than 100 arboviruses cause serious diseases in humans, most notably Dengue Fever, which infects between 50 and 100 million people worldwide every year with potentially fatal results. Currently, there is no vaccine or effective treatment for Dengue Fever. The Brown-Hernandez discovery enables the development of a whole family of vaccines against historically neglected, but important, diseases, vaccines that will be relatively inexpensive to produce and offer superior protection, potentially with just a single shot.

Brown and Hernandez suspected the differences between insect cell membranes and mammalian cell membranes might hold the clue. Unlike mammalian cells, insect cell membranes do not have cholesterol in them and so are thinner. Knowing this, the researchers theorized that by shortening the transmembrane domain they could create a modified virus capable of integrating into the insect membrane but not into the mammalian membrane. This theory was tested in 2001-2002 and published in 2003.

The discoveries of Drs. Brown and Hernandez have led to several patents for host range mutants and their use as a platform for vaccines against insect-borne viral diseases, such as Dengue Fever, West Nile, Japanese Encephalitis and others. The modified virus can be grown at low cost in an insect cell reactor and when injected into a mammal it produces strong immunity without disease. The resulting vaccine is a whole virus, which gives a strong, lasting immune response. In addition, the deletion strategy reduces the risk of reversion to the wild-type or infectious version, resulting in a safe product.

Arbovax, Inc. of Raleigh, North Carolina, is now commercializing the Brown-Hernandez technology. The company currently has both Dengue and Chikungunya Vaccines in pre-clinical development.