Building the perfect dengue cure
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The search for a dengue fever vaccine
By John Duchemin
Advertiser Staff Writer
In a race against several big-time rivals, 'Aiea research company Hawaii Biotechnology Group is moving close to a vaccine for dengue fever, one of the world's most problematic tropical diseases.
Bruce Asato • The Honolulu Advertiser
Using a gene-combining technique, the company has produced a vaccine that has succeeded through several stages of a live monkey trial against dengue, a disease that afflicts between 50 million and 100 million people each year.
Hawai'i Biotech's David Clements inspects the bioreactor, left, used to breed fruit fty cells that produce the dengue vaccine
Hawaii Biotech is near the top of the world's short list of dengue vaccine developers. Its vaccine, company scientists claim, may prove not only more effective, but safer and cheaper to store than several rival vaccines, which are also entering the final stages of development.
But these rivals, including several multinational American and European firms, are no pushovers. Several have advanced with their vaccines to human trials, which are a step beyond Hawai'i Biotech's monkey tests. Some argue their methods are superior. The U.S. government is also developing a vaccine.
Dengue, however, has recently become such a problem worldwide that there's easily room for more than one vaccine, experts say. Further advances could thus bring world prestige and millions of investment dollars to Hawaii Biotech, which has received more than $28 million in grants over 18 years from grantors including the National Institutes of Health.
Observers say such attention would spill over to the rest of Hawai'i's biotechnology industry, which has been in germination for years but has not yet bloomed. Hawaii Biotech, formed by nine scientists and University of Hawai'i professors in 1982, is one of several small research companies looking to create disease vaccines, genetically improved crops and other biotech-based products in Hawai'i.
"There's nothing like a successful product to spur enthusiasm in an industry," said Dick Sherman, a biotechnology consultant from Philadelphia who has worked with Hawaii Biotech for several years. "A successful vaccine could demonstrate two things: The life sciences area could grow to maturity in Hawai'i, and a company could stay in Hawai'i, get a product that far, and presumably get it financed."
If the monkey tests, which could end sometime this year, succeed, a vaccine is still several years' worth of human trials away from the market. But in biotechnology terms, a few years is very close. Major vaccines that pass "pre-clinical" animal trials are often deemed worthy of massive investments from governments, nonprofit institutions and multinational pharmaceutical companies. For example, rival vaccine developer Acambis, a British company whose dengue vaccine is approaching human trials, has entered into a joint-venture deal with giant multinational corporation Aventis Pasteur, which itself is developing its own vaccine for dengue.
Hawaii Biotech is discussing a possible deal with Hyderabad, India-based Bharat Biotechnology International Ltd., a company with a 60,000-square-foot facility that produces millions of doses per year of hepatitis B vaccine. The company's leader, Krishna Ella, is a former student of Hawaii Biotech board member and University of Hawai'i professor Suresh S. Patil.
If a deal is reached — and Hawaii Biotech president David Watumull calls negotiations "advanced" — the Hawai'i researchers would have a corporate partner that could finance human trials, market and distribute large quantities of vaccine, and seek final drug approval from the Indian government, which would open up India's 900-million-person market to Hawaii Biotech, Watumull said.
A 21st-century disease
Dengue is little known in modern Hawai'i, but the mosquito-carried disease has become a global pandemic in the past several decades. Once limited to several tropical pockets, dengue has become more widespread as its mosquito carrier has spread throughout the world's tropical regions — thanks largely to the increased international traffic in used tires, where the mosquitoes can breed, according to the World Health Organization.
The disease has also become more virulent. Not only are outbreaks becoming larger and more frequent, but a potentially fatal dengue strain that causes internal bleeding has surfaced since the 1950s. That strain, dengue hemorrhagic fever, now kills thousands of people per year, and ranks as a leading child-killer in several Asian nations, according to the World Health Organization. More than 2.5 billion people are at risk, the WHO estimates.
That includes Hawai'i, which had three dengue outbreaks in the 20th century. The last, in 1943 and 1944, afflicted 1,500 people on O'ahu, according to the state Department of Health. That year, the military led a house-to-house spraying campaign to eradicate the carrier mosquito, ending the immediate threat.
But carrier mosquitoes survive on the islands — and the risk of dengue is real, because several people each year bring the disease from other regions including Guam and the Philippines, said George Kitaguchi, an insect specialist at the Health Department. While those infected on faraway soil are likely past the point of contagion when they arrive in Hawai'i, the state should take no chances, he said.
"These carrier mosquitoes are the common black-and-white mosquitoes, and they're all over the place," Kitaguchi said. "So as soon as someone tells us about dengue, we have to go in, isolate the people, and spray the area around where they live, so they don't transmit the disease."
Tough to crack
Despite the worldwide concern, dengue has eluded efforts to find a vaccine. The virus has four separate strains — none of which confer immunity for the other strains. Infection with one strain can also lead to more serious infections from other strains. So a dengue vaccine must fight four diseases at once — an extremely difficult task, said Paul Patek, a University of Hawai'i microbiology professor who specializes in the immune system.
"What stops one strain must stop them all, or it does no good," Patek said. "That's one of the big problems with creating a dengue vaccine."
Dengue also can hide in infected cells, ducking the body's roving antibodies and bursting out after the initial immune response fades. This sabotages the effectiveness of vaccines that merely create antibodies.
Hawaii Biotech scientists, who have worked on dengue since 1987, think they have solved these problems. In animal trials at Walter Reed Army Hospital in Washington, D.C., six rhesus monkeys injected with the Hawaii Biotech vaccine have stayed immune to dengue for nine months, said Julia Leung, Hawaii Biotech's director of development and former researcher with the Cancer Research Center of Hawai'i. The vaccine outperformed a government-designed vaccine running through the same trials, Leung said.
The results have not been published, and the researchers have not yet bombarded vaccinated monkeys with multiple dengue strains. A multiple-strain trial is scheduled to start later this year.
• Business: Commercializing biological and agricultural research advances, particularly those made in Hawai'i • Location: Hawaiian Sugar Planters' Association building, 'Aiea • Founded: In 1982 as a joint venture between HSPA and nine University of Hawai'i professors and researchers. Early work included genetic engineering to help control fruit-fly infestation of Hawai'i crops • Financing: Has been principally financed by $28 million in government and foundation research grants, but trying to build a portfolio of commercial products • Projects: Aside from dengue efforts, is researching other disease vaccines; developing a system for rapid testing of food for disease-causing microbes; compiling 'libraries' of unique organic compounds; and investigating variants of algae-produced compound astaxanthin for possible use in fighting cancer • People:
To create the vaccine, Hawaii Biotech scientists used the gene-combining technique that created the first effective vaccines for hepatitis B in the 1980s. They have snipped strands of genetic material from each strain of the dengue virus, inserted those snippets into the genes of fruit fly cells, and used those cells to produce harmless proteins that mimic parts of the dengue virus.
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When those proteins, known as "viral sub-units," are injected into an animal's bloodstream, they stimulate the body to produce virus-destroying antibodies that will recognize those proteins in case of a real dengue infection. The vaccine also includes an adjuvant, a material that stimulates the immune system and makes it more alert to cell invasion by viruses. This should help the body seek and destroy cells with hidden dengue, Hawaii Biotech hopes.
Hawaii Biotech is the only dengue vaccine developer taking the viral sub-unit approach. Other companies are using live viruses that have been rendered harmless, or "attenuated," and can stimulate the immune system without causing a disease. U.S. government researchers are working on a vaccine made of dead virus, to see if non-living viral fragments can also provoke a strong immune response.
Each method has its advantages. Sub-unit vaccines are more versatile — with no live parts, they need no refrigeration, which means they are cheaper and more useful in the impoverished tropical regions where dengue thrives, UH's Patek said.
Proponents of the live-virus approach argue their method is most reliable. Live-virus vaccines often prove more effective at penetrating cells, where dengue does much of its damage, and do a better job of consistent, long-term protection against disease, said Thomas Monath, head dengue researcher at Acambis in Cambridge, Mass. Acambis' vaccine is based on a genetically modified yellow fever virus that has been embedded with dengue marker proteins.
"Our approach mimics a very mild infection with the real disease, so you're sure to get a full, appropriate immune response," Monath said. "With sub-unit approaches, the immune responses tend to wane over time, and that makes people somewhat uncomfortable with vaccines based entirely on that technology. It may be a valid approach, but there are conceptual concerns about safety that need to be addressed in clinical trials."
The sub-unit approach, however, has been a winner in some cases — most notably the hepatitis B vaccines, which have a protection rate of more than 90 percent among adults and 95 percent among children, according to several studies.
Watumull said the results from the latest monkey trials show the Hawai'i vaccine may also hold up over time.
Monath said both approaches could ultimately prove effective, and if combined in a "cocktail" treatment, could produce a powerful treatment.
"Maybe the best result is to mix and match: start with a live-virus vaccine, have a booster with a sub-unit," he said. "Each could fill in what the other doesn't do."
