PHOTO: SANOFI PASTEUR/FLICKR
A pediatric trial of a dengue vaccine produced mixed results.
TROPICAL DISEASES
Dengue vaccine trial poses public health quandary Experimental vaccine fell short against key strain By Dennis Normile
A
s scientists and public health officials mull over the puzzling results of the first large efficacy trial of a vaccine for dengue, one thing is clear: “There are complexities we’ve never seen in any other vaccines,” says Annelies Wilder-Smith, a public health specialist at Nanyang Technological University (NTU) in Singapore. The vaccine, the fruit of decades of public and private sector efforts, reduced the incidence of the mosquito-borne disease overall by 56.5% and, perhaps more significant, cut cases of dengue hemorrhagic fever, a severe form of the disease, by 88.5%. But the vaccine provided only limited protection against dengue 2, one of the four serotypes of the virus, and, mysteriously, it worked best in people who had already recovered from one dengue infection and among older children. Reported online on 11 July in The Lancet, these results will likely leave public health officials in dengue-endemic countries grappling with whether to include the Sanofi Pasteur vaccine in national immunization programs. Its cost, the logistics of delivering three doses over the course of a year,
SCIENCE sciencemag.org
and its limited efficacy in regions where the dengue 2 serotype predominates must all be considered. And because the vaccine works best in preventing second infections, its value in subtropical nations where dengue is not yet firmly entrenched is even more questionable. Joachim Hombach, senior adviser to the World Health Organization (WHO) on immunization and vaccines in Geneva, Switzerland, says the results can “clearly translate” into public health benefits. But each country will have to carefully study the costs, risks, and benefits in light of its own epidemiological situation, he adds. No one ever thought developing a vaccine for a disease as complicated and poorly understood as dengue would be easy. The four virus serotypes, all spread by the Aedes aegypti mosquito, are found throughout the tropics, but one strain or another often predominates in different regions and at different times. A first infection with any of the serotypes typically causes a mild fever, rash, and muscle and joint pain. Patients then have lifelong immunity to that serotype. But infection with a second serotype raises the risk of a little-understood phenomenon called antibody-dependent enhancement, which can cause dengue 25 JULY 2014 • VOL 345 ISSUE 6195
Published by AAAS
367
Downloaded from www.sciencemag.org on August 25, 2014
to $600,000 a year (plus another 50% for overhead costs) that will replace an investigator’s project-based grants. (NIH’s average R01 covers $282,000 a year in direct costs for 4.3 years.) NCI expects that if it adds 50 of these Outstanding Investigator Awards a year for 7 years, the program will total $317 million a year, or about 16% of the $2 billion that NCI now spends on research grants. At NIGMS, a people award would replace a standard NIGMS project grant, offering $150,000 to $750,000 a year in direct funding for 5 years. But Lorsch says that unlike NCI and HHMI awards, the so-called Maximizing Investigators’ Research Award his institute plans to pilot-test would be intended not just for high-risk research or for “a perceived elite,” but also for “regular outstanding researchers.” Several other NIH institutes are also planning people awards, Rockey says. But other funders’ experiences could make them cautious. For example, NIH Director Francis Collins noted in a meeting earlier this month that the United Kingdom’s Wellcome Trust, which 3 years ago shifted roughly $180 million in annual project grant funding to people awards (Science, 13 November 2009, p. 921), is now “rethinking” the program. Collins says Wellcome officials are concerned about the “graying” of its investigators—one risk of basing awards on reputation. Asked for comment, a Wellcome Trust representative pointed to a blog post last week from Director Jeremy Farrar saying that he plans to increase opportunities for early- and mid-career investigators. Lorsch says NIGMS will give early-stage investigators a boost by judging them through a separate review process that will examine their graduate and postdoctoral records; the institute may also set targets to make sure enough young investigators are funded. But Rockey raises another concern: As an institute funds more long-term awards, the amount of money that turns over each year will go down, which could mean fewer awards overall. Institutes will “need to balance their portfolios,” she says. Howard Garrison, deputy executive director for policy at the Federation of American Societies for Experimental Biology in Bethesda, Maryland, said his group’s members are still discussing NIH’s plans. “I suspect that views will be mixed,” he says, citing “concern about how funding ‘people instead of projects’ will affect younger scientists.” But he adds: “More and more people are frustrated by the continuous struggle for funding, and there is a growing acceptance of the idea that we need to do something different.” ■
NEWS | I N D E P T H
2.5 billion people
50–100 million dengue infections
500,000 people with severe dengue 2.5%
368
ENERGY POLICY
Oil sands fight heats up in U.S. Environmentalists oppose federal lease in Utah By David Malakoff
T
he battle over oil sands is moving to U.S. soil. Soon, the U.S. Bureau of Land Management (BLM) plans to offer private firms the chance to exploit tar-soaked sandstones beneath 8.5 square kilometers of federal land on Asphalt Ridge, a sagebrush-speckled outcrop near the small town of Vernal, Utah. If successful, the lease sale would open a new frontier in U.S. energy production, easing industry access to land in Utah that could hold up to 19 billion barrels of oil; that’s in addition to the nation’s roughly 30 billion barrels of conventional oil reserves. The prospect of developing Utah’s vast, untapped deposits alarms environmentalists and conservation scientists, who point to Canada’s burgeoning oil sands operations to argue that extraction takes an unacceptable toll on land, water, and global climate. A coalition of environmental groups is vowing to challenge the Asphalt Ridge lease and other similar sales. “Tar sands leasing on federal lands is absolutely the wrong policy if you are serious about preventing the worst effects of climate change,” says Taylor McKinnon, director of energy at the Grand Canyon Trust in Flagstaff, Arizona. “The greenhouse emissions and environmental impacts will be enormous.” sciencemag.org SCIENCE
25 JULY 2014 • VOL 345 ISSUE 6195
Published by AAAS
PHOTO: TAYLOR MCKINNON/GRAND CANYON TRUST/ECOFLIGHT
hemorrhagic fever, with debilitating fain Thailand: In spite of the PRNT results, tigue, internal bleeding, and occasionally the tetravalent vaccine provided almost no death. WHO puts the annual death toll at protection against the dengue 2 virus. By 20,000. But the costs of caring for the estithen, Sanofi Pasteur had already launched mated 500,000 patients with severe dengue two large, randomized, double-blind phase yearly “represents an enormous strain to III trials: the one just reported, involving society, to the economy, to the health care more than 10,000 children in five Southsystem, and may drive households into poveast Asian countries, and another involving erty,” Hombach says. more than 20,000 subjects in five countries The burden has been steadily growing in Latin America. Results of the second along with the global move to cities, where trial will be announced later this year. flowerpots, discarded tires, and construcIn the current trial, efficacies for the four tion site puddles create breeding sites for serotypes range from 75% or better against the opportunistic mosquito. Before 1970, serotypes 3 and 4 down to just 35% for only nine countries had experienced seserotype 2. The variation is unsettling news vere dengue epidemics; now the disease is for other groups developing dengue vacendemic in more than 100 countries, and cines, most of which have shown some eviepidemics have increased in frequency and dence of weakness to one of the serotypes. severity. “Most public health officials in All are using PRNT to guide their work—a Southeast Asia will tell you that dengue is strategy that is now in question. “Positive their biggest concern,” says Duane Gubler, findings on PRNT are a poor surrogate of a dengue expert at the Duke-NUS Graduate immunity,” says Eng Eong Ooi, a dengue Medical School in Singapore. There are no researcher at Duke-NUS. Researchers are dengue medications. working on more accurate tests, but none Efforts to develop a vaccine stretch back is ready for use yet, he says. to the 1940s. From the Another mystery is outset, researchers bewhy the Sanofi Pasteur lieved that to avoid envaccine was more eflive in dengue-endemic countries hancement a dengue (more than 40% of the world’s population) fective in people who vaccine would have to had already been exbe tetravalent, providposed to dengue. That ing balanced protection finding means that “for against all four serodengue-naive travelers types. This has proved this vaccine is of little occur worldwide each year challenging. Among the use,” says NTU’s Wilderpioneers was a group Smith. Gubler thinks it at Mahidol University will still be of value in in Bangkok that tried dengue-endemic counto create a live attenutries, “because most ated vaccine by paspersons in those counrequire hospitalization each year saging all four virus tries have already exserotypes in culture perienced at least one until weakened ones dengue infection” and emerged. Sanofi Pasteur could be protected from of people with partnered with Mahidol severe disease. severe dengue die to work on the vaccine Sanofi Pasteur exin the mid-1990s but pects the vaccine to Source: World Health Organization abandoned the effort in “have a real impact on 2004 when it could not properly attenuate this disease,” says Guillaume Leroy, head one serotype. The company then switched of the company’s dengue program in Lyon, strategies, using a proven yellow fever live France, and is aggressively moving forward. attenuated vaccine as a backbone on which The company built a $400 million facility to insert the genes for the envelope and in Neuville-sur-Saône, France, capable of membrane proteins from each of the seroproducing 100 million doses of its vaccine types. The four resulting chimeric vaccines per year. But the company is putting off a were tested for safety individually and then decision on pricing until after the results of combined to create the current candidate the second efficacy trial are available later and tested further. A standard in vitro assay this year. used to predict immunity, called the plaque Endemic countries will then be faced reduction neutralization test (PRNT), sugwith a difficult decision on whether to use gested the vaccine would provide roughly a partially effective vaccine or wait for other equal protection against all four serotypes. dengue vaccines in the pipeline. Says WilderBut in September 2012, discouraging Smith: “It will be very interesting to see how news came from a small phase IIb trial countries react to this possible vaccine.” ■
A pediatric trial of a dengue vaccine produced mixed results.
TROPICAL DISEASES
Dengue vaccine trial poses public health quandary Experimental vaccine fell short against key strain By Dennis Normile
A
s scientists and public health officials mull over the puzzling results of the first large efficacy trial of a vaccine for dengue, one thing is clear: “There are complexities we’ve never seen in any other vaccines,” says Annelies Wilder-Smith, a public health specialist at Nanyang Technological University (NTU) in Singapore. The vaccine, the fruit of decades of public and private sector efforts, reduced the incidence of the mosquito-borne disease overall by 56.5% and, perhaps more significant, cut cases of dengue hemorrhagic fever, a severe form of the disease, by 88.5%. But the vaccine provided only limited protection against dengue 2, one of the four serotypes of the virus, and, mysteriously, it worked best in people who had already recovered from one dengue infection and among older children. Reported online on 11 July in The Lancet, these results will likely leave public health officials in dengue-endemic countries grappling with whether to include the Sanofi Pasteur vaccine in national immunization programs. Its cost, the logistics of delivering three doses over the course of a year,
SCIENCE sciencemag.org
and its limited efficacy in regions where the dengue 2 serotype predominates must all be considered. And because the vaccine works best in preventing second infections, its value in subtropical nations where dengue is not yet firmly entrenched is even more questionable. Joachim Hombach, senior adviser to the World Health Organization (WHO) on immunization and vaccines in Geneva, Switzerland, says the results can “clearly translate” into public health benefits. But each country will have to carefully study the costs, risks, and benefits in light of its own epidemiological situation, he adds. No one ever thought developing a vaccine for a disease as complicated and poorly understood as dengue would be easy. The four virus serotypes, all spread by the Aedes aegypti mosquito, are found throughout the tropics, but one strain or another often predominates in different regions and at different times. A first infection with any of the serotypes typically causes a mild fever, rash, and muscle and joint pain. Patients then have lifelong immunity to that serotype. But infection with a second serotype raises the risk of a little-understood phenomenon called antibody-dependent enhancement, which can cause dengue 25 JULY 2014 • VOL 345 ISSUE 6195
Published by AAAS
367
Downloaded from www.sciencemag.org on August 25, 2014
to $600,000 a year (plus another 50% for overhead costs) that will replace an investigator’s project-based grants. (NIH’s average R01 covers $282,000 a year in direct costs for 4.3 years.) NCI expects that if it adds 50 of these Outstanding Investigator Awards a year for 7 years, the program will total $317 million a year, or about 16% of the $2 billion that NCI now spends on research grants. At NIGMS, a people award would replace a standard NIGMS project grant, offering $150,000 to $750,000 a year in direct funding for 5 years. But Lorsch says that unlike NCI and HHMI awards, the so-called Maximizing Investigators’ Research Award his institute plans to pilot-test would be intended not just for high-risk research or for “a perceived elite,” but also for “regular outstanding researchers.” Several other NIH institutes are also planning people awards, Rockey says. But other funders’ experiences could make them cautious. For example, NIH Director Francis Collins noted in a meeting earlier this month that the United Kingdom’s Wellcome Trust, which 3 years ago shifted roughly $180 million in annual project grant funding to people awards (Science, 13 November 2009, p. 921), is now “rethinking” the program. Collins says Wellcome officials are concerned about the “graying” of its investigators—one risk of basing awards on reputation. Asked for comment, a Wellcome Trust representative pointed to a blog post last week from Director Jeremy Farrar saying that he plans to increase opportunities for early- and mid-career investigators. Lorsch says NIGMS will give early-stage investigators a boost by judging them through a separate review process that will examine their graduate and postdoctoral records; the institute may also set targets to make sure enough young investigators are funded. But Rockey raises another concern: As an institute funds more long-term awards, the amount of money that turns over each year will go down, which could mean fewer awards overall. Institutes will “need to balance their portfolios,” she says. Howard Garrison, deputy executive director for policy at the Federation of American Societies for Experimental Biology in Bethesda, Maryland, said his group’s members are still discussing NIH’s plans. “I suspect that views will be mixed,” he says, citing “concern about how funding ‘people instead of projects’ will affect younger scientists.” But he adds: “More and more people are frustrated by the continuous struggle for funding, and there is a growing acceptance of the idea that we need to do something different.” ■
NEWS | I N D E P T H
2.5 billion people
50–100 million dengue infections
500,000 people with severe dengue 2.5%
368
ENERGY POLICY
Oil sands fight heats up in U.S. Environmentalists oppose federal lease in Utah By David Malakoff
T
he battle over oil sands is moving to U.S. soil. Soon, the U.S. Bureau of Land Management (BLM) plans to offer private firms the chance to exploit tar-soaked sandstones beneath 8.5 square kilometers of federal land on Asphalt Ridge, a sagebrush-speckled outcrop near the small town of Vernal, Utah. If successful, the lease sale would open a new frontier in U.S. energy production, easing industry access to land in Utah that could hold up to 19 billion barrels of oil; that’s in addition to the nation’s roughly 30 billion barrels of conventional oil reserves. The prospect of developing Utah’s vast, untapped deposits alarms environmentalists and conservation scientists, who point to Canada’s burgeoning oil sands operations to argue that extraction takes an unacceptable toll on land, water, and global climate. A coalition of environmental groups is vowing to challenge the Asphalt Ridge lease and other similar sales. “Tar sands leasing on federal lands is absolutely the wrong policy if you are serious about preventing the worst effects of climate change,” says Taylor McKinnon, director of energy at the Grand Canyon Trust in Flagstaff, Arizona. “The greenhouse emissions and environmental impacts will be enormous.” sciencemag.org SCIENCE
25 JULY 2014 • VOL 345 ISSUE 6195
Published by AAAS
PHOTO: TAYLOR MCKINNON/GRAND CANYON TRUST/ECOFLIGHT
hemorrhagic fever, with debilitating fain Thailand: In spite of the PRNT results, tigue, internal bleeding, and occasionally the tetravalent vaccine provided almost no death. WHO puts the annual death toll at protection against the dengue 2 virus. By 20,000. But the costs of caring for the estithen, Sanofi Pasteur had already launched mated 500,000 patients with severe dengue two large, randomized, double-blind phase yearly “represents an enormous strain to III trials: the one just reported, involving society, to the economy, to the health care more than 10,000 children in five Southsystem, and may drive households into poveast Asian countries, and another involving erty,” Hombach says. more than 20,000 subjects in five countries The burden has been steadily growing in Latin America. Results of the second along with the global move to cities, where trial will be announced later this year. flowerpots, discarded tires, and construcIn the current trial, efficacies for the four tion site puddles create breeding sites for serotypes range from 75% or better against the opportunistic mosquito. Before 1970, serotypes 3 and 4 down to just 35% for only nine countries had experienced seserotype 2. The variation is unsettling news vere dengue epidemics; now the disease is for other groups developing dengue vacendemic in more than 100 countries, and cines, most of which have shown some eviepidemics have increased in frequency and dence of weakness to one of the serotypes. severity. “Most public health officials in All are using PRNT to guide their work—a Southeast Asia will tell you that dengue is strategy that is now in question. “Positive their biggest concern,” says Duane Gubler, findings on PRNT are a poor surrogate of a dengue expert at the Duke-NUS Graduate immunity,” says Eng Eong Ooi, a dengue Medical School in Singapore. There are no researcher at Duke-NUS. Researchers are dengue medications. working on more accurate tests, but none Efforts to develop a vaccine stretch back is ready for use yet, he says. to the 1940s. From the Another mystery is outset, researchers bewhy the Sanofi Pasteur lieved that to avoid envaccine was more eflive in dengue-endemic countries hancement a dengue (more than 40% of the world’s population) fective in people who vaccine would have to had already been exbe tetravalent, providposed to dengue. That ing balanced protection finding means that “for against all four serodengue-naive travelers types. This has proved this vaccine is of little occur worldwide each year challenging. Among the use,” says NTU’s Wilderpioneers was a group Smith. Gubler thinks it at Mahidol University will still be of value in in Bangkok that tried dengue-endemic counto create a live attenutries, “because most ated vaccine by paspersons in those counrequire hospitalization each year saging all four virus tries have already exserotypes in culture perienced at least one until weakened ones dengue infection” and emerged. Sanofi Pasteur could be protected from of people with partnered with Mahidol severe disease. severe dengue die to work on the vaccine Sanofi Pasteur exin the mid-1990s but pects the vaccine to Source: World Health Organization abandoned the effort in “have a real impact on 2004 when it could not properly attenuate this disease,” says Guillaume Leroy, head one serotype. The company then switched of the company’s dengue program in Lyon, strategies, using a proven yellow fever live France, and is aggressively moving forward. attenuated vaccine as a backbone on which The company built a $400 million facility to insert the genes for the envelope and in Neuville-sur-Saône, France, capable of membrane proteins from each of the seroproducing 100 million doses of its vaccine types. The four resulting chimeric vaccines per year. But the company is putting off a were tested for safety individually and then decision on pricing until after the results of combined to create the current candidate the second efficacy trial are available later and tested further. A standard in vitro assay this year. used to predict immunity, called the plaque Endemic countries will then be faced reduction neutralization test (PRNT), sugwith a difficult decision on whether to use gested the vaccine would provide roughly a partially effective vaccine or wait for other equal protection against all four serotypes. dengue vaccines in the pipeline. Says WilderBut in September 2012, discouraging Smith: “It will be very interesting to see how news came from a small phase IIb trial countries react to this possible vaccine.” ■
