Taking a bite out of mosquito-borne viruses

The mosquito-borne virus that causes an estimated 300 million dengue fever infections each year is considered one of the world’s biggest health threats. But thanks to a discovery by CALS biochemists, a promising vaccine is in the pipeline.

Arbovax, a small biotechnology company in Raleigh, is using the discovery to develop vaccines against dengue and other viral infections that insects transmit to people. So far, tests of the dengue vaccine in rodents and primates have proved promising.

The so-called host-range mutation technology that Arbovax uses was the direct – but surprising – result of research conducted by Drs. Dennis Brown and Raquel Hernandez, a husband-and-wife research team in the Department of Molecular and Structural Biochemistry. Brown is department head, and Hernandez is a research associate professor.

“Never in a million years did I think I’d be developing vaccines,” Brown recalls.

What he and Hernandez were doing was much more basic: They were creating a three-dimensional, atom-by-atom image of the Sindbis virus’ structure. The goal wasn’t to prevent disease — after all, Sindbis doesn’t even cause human illness. Instead, the researchers wanted to better understand how Sindbis’ structure influences the way the virus infects both insects and mammals.

To study the way the virus’ proteins interacted, Hernandez removed a certain piece of protein. And what she and her husband found next surprised them: The resulting mutant survived in animal cells, but it didn’t reproduce rapidly the way a normal virus would. And in insect cells, the mutant reproduced at the same rate as the wild virus.

“It became suddenly obvious,” Brown says, that the mutant could pave the way to vaccines for hundreds of disease-causing viruses that are spread by mosquitoes.

What Brown and Hernandez realized was that viruses missing the protein segment could be grown in low-cost insect cell reactors and, when injected as a vaccine into mammals, could impart immunity to the wild viruses without reproducing enough to trigger illness.  What’s more, the fact that the virus had a missing protein segment reduced the risk that the viruses would be able to revert to the infectious version.

Laboratory tests and trials in mice and monkeys have proved the couple’s idea works in the case of the virus that causes dengue fever. Arbovax’s founders chose to focus on dengue when they incorporated in 2005, because dengue is considered a growing health threat not just to the developing world but to the United States, says Malcolm Thomas, the company’s president and chief executive officer.

The World Health Organization estimates that the incidence of dengue disease has risen 30-fold in the past 50 years, and it has cropped up in recent years in the southern United States. Some scientists say that without an effective vaccine, the virus will continue to spread.

Arbovax will take testing of Brown and Hernandez’s technology to the next stage in early 2012. That’s when, Thomas says, the company will see if the technology works in non-human primates against all four virus subtypes that cause dengue fever.

If those tests go well, Thomas adds, the company will begin early-stage clinical trials in humans in 2013. Along the way, he’ll be looking for a pharmaceutical company willing to work with Arbovax to conduct late-stage clinical trials and then to manufacture and market the vaccine.

Meanwhile, Arbovax is banking on the fact that the vaccine technology can be applied not only to dengue but also to Chickungunya fever and possibly other insect-borne viruses that cause serious human diseases.

Work toward a vaccine for Chickungunya, a painful and potentially crippling illness found mainly in Africa and Asia, is taking place now and is expected to move quickly — in part because the virus that causes it is in the same family as Sindbis, and also because it has no subtypes, Thomas says.

Brown, who contracted a severe laboratory case of dengue fever years ago, knows firsthand of the need for research into potential vaccines into insect-borne diseases. He says it’s been rewarding to know that the virology and biochemistry research he and his wife have done for decades could dramatically lessen the toll that these diseases take each year.

While it would be impossible to predict how Arbovax’s trials will play out, Thomas is optimistic about his company’s chances of bringing a dengue vaccine to market. “My feeling is, it’s worked so well so far – so much better than other approaches – we feel extremely confident that this is going to work.”