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The Soul of a New Vaccine
By DONALD G. McNEIL Jr., The New York Times, December 11, 2007
ROCKVILLE, Md. — The sign on the wall reads “Emergency Response Procedures for a Mosquito Release.”
Among them are “Do Not Leave the Room or Open Any Doors!!!” and “Do Not Panic!”
Everything in the room is white, including the lab coats and surgical masks — for sterility, yes, but also the better to see a mosquito. Hanging next to the sign, in vivid Coast Guard orange, is the last line of defense, a brace of fly swatters.
This room, the mosquito dissection lab, in an unassuming biotech park in the Washington suburbs, is at the heart of one of the most controversial ideas in vaccine science.
Sanaria Inc. (meaning “healthy air,” a play on the Italian “mal’aria” or “bad air”) is making a vaccine the old-fashioned way, more or less as Louis Pasteur did.
Avoiding modern recombinant DNA technology that injects tiny fragments of parasite protein to prime an immune response, Sanaria uses the whole parasite, extracted by hand from the mosquito’s salivary glands, and weakened so it cannot multiply.
Pasteur weakened rabies and anthrax bacilli by air drying them. Sanaria uses gamma rays.
Because the world now fights malaria — ineptly — with nets, insecticides and drugs, a vaccine is desperately needed.
As many as 70 experimental ones exist around the world; eight rival projects are being supported by the Malaria Vaccine Initiative, which was created in 1999 with money from the Gates Foundation.
Sanaria’s is the sole vaccine using the whole parasite. Injected into a capillary, it rides the bloodstream to the liver and starts making proteins. But after about three days, it stops, and it never floods the blood with copies of itself.
Radiation-weakened parasites have protected many lab mice and a handful of humans, but making a vaccine that can be mass produced is a huge challenge.
The lucrative market is made up of tourists and the world’s military forces. The larger goal is to protect the 3,000 children who die of malaria each day.
“We’ve got a lot of work to do, and we’re extremely mindful of the fact that the road to success is filled with potholes,” said the founder of Sanaria, Dr. Stephen L. Hoffman, a former chief of malaria research for the Navy.
Before he died two years ago, Dr. Maurice R. Hilleman, who invented 40 human and animal vaccines, called the Sanaria plan “the best show in town.”
Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, which gave Sanaria some of its early research money, said he was enthusiastic. “I have as much confidence in this as I do in any candidate,” he said, acknowledging that major problems remained to be solved.
Peering through microscopes and wielding tweezers and a fine needle in surgeon-steady hands, six workers snick the heads off anopheles mosquitoes, tease out the transparent salivary glands and pop them into little vials. After the glands and saliva proteins are dissolved, the parasites will be frozen at extremely low temperatures. When enough batches are ready, clinical trials overseen by the Navy will begin.
One recent morning, a reporter and photographers were allowed to view the last “engineering run” in the dissection room.
Nearby, in a room protected by five doors air pressurized to prevent escapes, mosquitoes are being raised from sterilized eggs and fed infected blood.
On harvesting day, they are wheeled to the gamma-ray kiln in red picnic coolers, each batch in a plastic pipe the size of a gelato container.
Just before dissection, they are popped into a freezer for a few minutes to stop their flying. The little pile of chilled mosquitoes is shaken into a dish of ethanol and divided into six portions.
The ethanol kills them without killing the parasites, explained B. Kim Lee Sim, the head of manufacturing. The dissectors work rapidly and with little talk, dismembering 80 females an hour.
“We need to get some music in here,” Dr. Sim said.
The males, which do not drink blood, “are just leftovers on the plate, waiting to get incinerated in the biohazard waste,” said Richard Stafford, chief of quality control.
Anyone with good eyesight and steady hands can be trained. “It’s not as difficult as it would seem to a person who doesn’t do it,” said Sumana Chakravarty, head of the team.
The idea that parasites weakened by radiation could be a vaccine has been around since 1967, when Dr. Ruth S. Nussenzweig of the New York University Medical School showed that it worked in mice.
In the ’70s, she and others showed that it could work in humans. Fourteen volunteers were vaccinated with weakened parasites and later exposed to malarial mosquitoes. Thirteen were protected, one so well that he then worked for three years in rural Ghana without taking any antimalaria drugs.
But the research never proceeded, for the same reason that the number of tests was so small: It was impractical.
The parasites could not survive outside mosquitoes. So the “vaccination” had to be delivered by mosquito bite, not needle. And because just one parasite at a time fits down a proboscis, each bite delivers just a few.
To be sure of receiving enough material, volunteers endured 1,000 bites from irradiated mosquitoes, which took weeks. In the ’80s, said Dr. John G. McNeil, scientific director of the vaccine initiative, the decoding of the mosquito genome opened new routes to make vaccines from bits of parasite surface protein that could be brewed quickly.
Early ventures did not work out. In 1987, Dr. Hoffman was one of six volunteers to be injected with an experimental vaccine, FSV-1, and then “challenged” by infected mosquitoes. He was so confident that he flew to San Diego for a medical conference.
“In the middle of giving a presentation,” he recalled. “I had a rigor, uncontrolled shaking and chills. It took 36 hours to find the parasites, but I had malaria.”
That vaccine, however, helped lead to the candidate now farthest along in African trials, RTS,S/AS02A, tentatively named Mosquirix, which has partly protected young children.
But nothing other than the whole parasite yet offers anything like 90 percent protection. So in 2002 Dr. Hoffman founded Sanaria and obtained $15 million in backing from the infectious disease institute, the Army and the Institute for One World Health. But $29 million from the Gates Foundation last year finally allowed the building of a real assembly line.
There were many hurdles. Sanaria had to work out how to raise sterile mosquitoes, to supercharge them with far more parasites than nature does, to dissolve saliva proteins to avoid allergic reactions and to freeze and thaw parasites without exploding them.
“This is the evolution of the efforts of five years of very dedicated scientists working together,” Dr. Sim said. “It’s a robust, repeatable, reliable process.”
Some scientists say the challenges remain insurmountable. At a recent meeting of the American Society for Tropical Medicine and Hygiene, Dr. Zarifah Reed, a parasite specialist in the World Health Organization’s vaccine research initiative, said she was troubled that the mosquitoes had to be raised on human blood, which cannot be sterilized.
Even though mosquitoes do not inject one person’s blood into another, there is the theoretical risk of passing on a virus, a prion or some other pathogen, she said.
Dr. Pierre Druilhe, a malaria expert at the Pasteur Institute in France and the inventor of a rival vaccine that he said was rejected for a Gates grant, was even more scathing.
“Even calling it a vaccine is a compliment,” he said. “It has no chance of offering protection. It is like Captain Ahab in the movie trying to kill Moby Dick with his knife.”
Besides the sterilization problem, he said, there was the risk that underirradiated parasites would cause malaria or that weakened parasites would not reach the liver. Cryogenically frozen vaccines, he added, will never be practical at sites with poor refrigeration.
Sanaria’s defenders said these were legitimate questions, but ones that had answers.Dr. Fauci, of the infectious disease institute, said the company had consulted the Food and Drug Administration about every aspect of sterility, “so quite frankly, I’m not impressed by that objection.”
Dr. Myron M. Levine, director of the center for vaccine development at the University of Maryland School of Medicine, said that any successful vaccine “would be used in places where kids’ chances of dying of malaria are much greater than any theoretical risk of dying from a rare blood problem.”
How big a dose is needed and where it is injected are questions for the trials, the doctors said. And although cryogenic storage may be impractical in Africa now, such problems can be solved with money, Dr. Levine said, adding, “Those are the easiest ones.”
Dr. Druilhe, in his critique, also said Dr. Hoffman was raising millions of dollars with unreal promises to sell Sanaria to private investors and cash out.
Dr. Hoffman, obviously seething, responded: “Pierre and I are friends and colleagues, but we don’t think alike about how to get to the end of the game. But let me ask a rhetorical question. If, as he says, this is never going to be a vaccine, who am I going to sell it to?”
Until then, he said, “I do what I do, and if it works, it works.”
Warming Trends: In Duck Blinds, Visions of Global Warming
By WILLIAM YARDLEY, The New York Times, December 11, 2007
RICH HILL, Mo. — After 32 years of hunting ducks in the wetlands of Missouri, Chuck Geier knows when temperatures will drop and waters will freeze. That means he also knows when the birds will fly and hunting will be best.
Except that much of what he knows is now in question.
“It used to be by Dec. 6, this place was frozen,” said Mr. Geier, 51, a national sales manager for a telecommunications company. “That’s not true anymore.”
From the “prairie potholes” of Canada and the upper Midwest to the destination states of Arkansas and Louisiana, the rhythms of the cross-continental migratory bird route known as the Mississippi Flyway are changing.
In Missouri, where the average winter temperature has been rising, hunters say birds are arriving later and sticking around longer before bolting for warmer redoubts. Elsewhere, wetlands are not freezing over the way they once did.
As hunters point their shotguns toward the sky and fire, a question echoes in the spent powder: what is up with the ducks?
“People say it’s cycles, every five to seven years, but it’s just been too long,” Mr. Geier said of the warming trend, which he traces to the late 1990s. “It’s a wake-up call.”
Five-year averages for “duck use” days on some conservation areas in Missouri show peaks that come a week or more later in the year than do the 30-year averages. Hunters have said in state surveys they want later hunting seasons, reflecting the later arrival of major weather systems that move birds into the state.
In Missouri, the average winter temperature this decade has been about 35 degrees, roughly 2 degrees higher than the previous peak around 1930.
“We’re having milder falls, later winters,” said Dave Erickson, chief of the wildlife division for the Missouri Department of Conservation. “What we don’t know is if the trend that affects migration and the hunters’ desire for a longer hunting season is a temporary fixture or a permanent fixture.”
Sure science is elusive. Scientists and state wildlife officials say there is not clear-cut data to support the reports of changes in duck behavior, but the patterns are familiar. They note that various other animal species, including songbirds, frogs and foxes, are developing different patterns for breeding and migration.
“We’re seeing northern range shifts of lots of birds and butterflies,” said Camille Parmesan, a professor of conservation biology at the University of Texas and a member of the United Nations panel that was awarded the Nobel Peace Prize for its work documenting climate change.
Many hunters, wildlife officials and scientists say the changes have added new mystery to waterfowl migration and to how to manage it. Against an uncertain future, state wildlife agencies and conservation groups that cultivate waterfowl populations are re-examining some longstanding conservation approaches and questioning whether business as usual needs to change.
Why, after all, some wildlife experts ask, should money still be poured into cultivating traditional breeding grounds like the prairie potholes of the upper Midwest if some climate forecasts prove true and those areas get too dry for ducks?
“The birds will not be there if you don’t have the same kind of general patterns of moisture and grasslands to nest in,” said Alan Wentz, who oversees conservation programs for Ducks Unlimited, a group that works to conserve and restore wetlands.
Similar questions are being raised elsewhere.
Some experts on Pacific salmon argue for diverting conservation resources away from areas where water temperatures are forecast to become too warm for survival. Some big game experts say deer and elk in many Western states might not leave higher elevations for traditional hunting areas because the weather will be milder. Anecdotal evidence suggests that this is already happening. Other animals, like moose in northwest Minnesota, are disappearing from some of the southern latitudes that they have traditionally inhabited.
Matt Hogan, the executive director of the Association of Fish and Wildlife Agencies, which represents state wildlife divisions, said the prospect of climate change was presenting wildlife with a new kind of threat. The association devoted part of its annual meeting in September to climate change and wildlife management.
“I know what I can do to mitigate this housing subdivision, but how do I mitigate that?” Mr. Hogan said of climate change. “A lot of it is saying, ‘O.K., what do I have to do to address this?’”
Concern is widespread. Consensus is not.
Many hunters are fond of calling themselves the original environmentalists. But in a sport with a distinct rural identity, many are not about to get behind Al Gore.
Some are just as quick to blame farming practices of big agricultural companies or government feeding programs for changes in duck behavior. In many areas, wildlife have also changed their behavior when their habitat has been damaged by development and when it has been improved by conservation efforts, like converting farmland to forests.
“We were conservationists before ‘green’ was even a popular word,” said Allen Morris, known as Horntagger, who lives in Jackson, Mo. “We have sacrificed and used money for licenses to save land for the wildlife, but in the mainstream media, you never hear about it.”
Mr. Morris dismissed “so-called global warming” as having no impact on hunting. Some biologists are divided, too. National conservation groups typically are more inclined to say climate change is already affecting wildlife and hunting.
“This actually is happening,” said Douglas B. Inkley, a senior scientist at the National Wildlife Federation and an author of “The Waterfowler’s Guide to Global Warming.”
“The evidence is there,” Mr. Inkley said, noting bird migration, changes in amphibian behavior and even impacts on lobsters in warming Atlantic waters. “We have both the scientific and we have the anecdotal, and then on top of that we have the theoretical based on climate models.”
Virginia Burkett, the chief scientist for global change research at the United States Geological Survey and a member of the United Nations panel that shared the Nobel Peace Prize with Mr. Gore, said scientists have already tracked changes in the breeding and migration patterns of many species because of warming, although they have not focused on game animals.
Red foxes are moving north, Ms. Burkett said. More than two dozen types of birds are nesting earlier. Three species of warbler are expected to move completely out of the United States. Squirrels in Canada and frogs in the United States have had their breeding patterns affected.
Ms. Burkett, a former director of the Louisiana Department of Wildlife and Fisheries, said that while development and land-use changes have had the most impact on wildlife in the past, “the affect of climate is much more likely to be a player in the loss of wildlife in the coming decades.”
She warned against wildlife managers using previous patterns to manage for the future.
“Relying on historical data alone,” she said, “can lead to mal-adaptation and the setting of seasons and bag limits that may no longer sustain populations, for both fish and wildlife.”
Even if climate change hurts habitat in some places, it could improve it in others. For all the uncertainty, times are good right now for many hunters, depending on where and when they hunt. Here in west-central Missouri, the ducks come late, but with the prairie potholes now wet after a long drought and with aggressive feeding programs in place on farms and wetlands, they come in abundance. Hunting seasons once restricted to 30 days by the federal government have been extended to 60.
By 10 a.m. on a recent morning in the Schell-Osage Conservation Area, Bob Wafel was one bird short of the daily limit imposed by the state. His black Labrador, Gunner, licked blood from the feathers of the five dead ducks that lay limp in the blind.
Mr. Wafel, 55, a barber from nearby Appleton City, lighted a cigar. “I think weather goes through cycles,” he said, “and I think you’ll have them warmer cycles.” Later, after bagging his sixth bird and with the optimism of a man who rises at 2 a.m. on winter mornings to sit in a dark, muddy, freezing hunting blind, Mr. Wafel added, “Maybe the cycle we’re going through now was before anybody kept track of the weather.”
Teenage Birth Rate Rises for First Time Since ’91
By GARDINER HARRIS, The New York Times, December 6, 2007
WASHINGTON, Dec. 5 — The birth rate among teenagers 15 to 19 in the United States rose 3 percent in 2006, according to a report issued Wednesday, the first such increase since 1991. The finding surprised scholars and fueled a debate about whether the Bush administration’s abstinence-only sexual education efforts are working.
The federal government spends $176 million annually on such programs. But a landmark study recently failed to demonstrate that they have any effect on delaying sexual activity among teenagers, and some studies suggest that they may actually increase pregnancy rates.
“Spending tens of million of tax dollars each year on programs that hurt our children is bad medicine and bad public policy,” said Dr. David A. Grimes, vice president of Family Health International, a nonprofit reproductive health organization based in North Carolina.
Robert Rector, a senior research fellow with the Heritage Foundation, said that blaming abstinence-only programs was “stupid.” Mr. Rector said that most young women who became pregnant were highly educated about contraceptives but wanted to have babies.
President Bush noted the long decline in teenage pregnancy rates in his 2006 State of the Union address, saying, “Wise policies such as welfare reform, drug education and support for abstinence and adoption have made a difference in the character of our country.”
The White House did not respond to requests for comment Wednesday.
In a speech last year, Senator Hillary Rodham Clinton said that rates of teenage pregnancy declined during the Clinton administration because of a focus on family planning.
Teenage birth rates are driven by rates of sex, contraception and abortion. In the 1990s, teenage sex rates dropped and condom use rose because teenagers were scared of AIDS, said Dr. John S. Santelli, chairman of the department of population and family health at Columbia University.
But recent advances in AIDS treatments have lowered concerns about the disease, and AIDS education efforts, which emphasized abstinence and condom use, have flagged.
Perhaps as a result, teenage sex rates have risen since 2001 and condom use has dropped since 2003. Abortion rates have held steady for a decade, although numbers from 2005 and 2006 are not available.
Kristin A. Moore, a senior scholar at Child Trends, a nonprofit children’s research organization, said the increase in the teenage birth rate was particularly alarming because even the 2005 rate was far higher than that in other industrialized countries.
“It’s really quite disappointing because we weren’t close to reaching our goal,” Dr. Moore said.
The lone bright spot in Wednesday’s report, issued by the Centers for Disease Control and Prevention, was that the birth rate for girls 14 and under dropped to 0.6 percent per 1,000 from 0.7 percent. Birth rates rose 3 percent among teenagers ages 15 to 17 and 4 percent among those ages 18 and 19.
The largest increase came among black teenagers, but increases were also seen among whites, Hispanics and American Indians. Birth rates among Asian teenagers continued to drop.
Unmarried childbearing reached a record high in 2006, according to the disease control centers, with unmarried mothers now accounting for 38.5 percent of all births. Births among teenagers and unmarried women tend to lead to poor outcomes for their children.
Helping to prevent these pregnancies was the reason advocates pushed for the wide availability of the morning-after pill known as Plan B. The Food and Drug Administration approved sales of Plan B without a prescription in August 2006, too late to have any effect on that year’s birth rate.
Mr. Rector of the Heritage Foundation said that teenage and unmarried birth rates were driven by the same factors: young women with little education who are devoted to mothering but see no great need to be married.
“We should be telling them that for the well-being of any child, it’s critically important that you be over the age of 20 and that you be married,” he said. “That message is not given at all.”
Dr. Santelli of Columbia said that many abstinence-only educational efforts tended to emphasize that contraceptives often fail. “They scare kids about contraception,” he said.
The report also found that the Caesarean delivery rate continued its rise, increasing 3 percent in 2006 to 31.1 percent of all births, a record. In recent years, women who have had one birth by Caesarean have often been discouraged from having subsequent births vaginally. And there is some evidence that a growing number of women are requesting Caesareans to avoid pain or vaginal stretching.
The American College of Obstetricians and Gynecologists published a position paper last month stating that some Caesareans-upon-request should be discouraged. Women who have multiple Caesarean births are more likely to suffer uterine rupture and other serious consequences.
Dr. Robert Freeman, a professor of obstetrics and gynecology at the University of California, Irvine, said that managed-care companies no longer discouraged Caesareans and malpractice fears often led doctors to opt for Caesarean at the first hint of trouble.
“These numbers are bad news,” Dr. Freeman said, “and I think it’s only going to get worse.”
For the first time since 1971, the nation’s overall fertility rate rose past the replacement rate, increasing 2 percent in 2006 to 2,101 births per 1,000 women. Women of almost every age had more children last year than the year before, except girls under 15 and women over 45.
Essay: A Growing Debate Over Folic Acid in Flour
By DARSHAK M. SANGHAVI, M.D., The New York Times, December 4, 2007
Every year, an estimated 200,000 children around the world are born with crippling defects of the spinal column. Many are paralyzed or permanently impaired by spina bifida; some, with a condition called anencephaly (literally, “no brain”), survive in a vegetative state.
It is a stubborn and terrible problem, in the developed and developing worlds alike. But many experts believe it could be greatly eased by a simple government measure: requiring that flour be fortified with the dietary supplement folic acid, which has been shown to prevent these neural tube defects if taken by expectant mothers from before conception through the first trimester.
The debate over folic acid is a familiar one, and Americans could be excused for thinking it was over. Since 1998, the federal government has required that almost all flour be fortified with the supplement.
But in fact, the requirement has meant women receive an average extra dose of just 100 micrograms of folic acid a day — far below the levels that have been shown in studies to prevent spina bifida and other neural tube defects. For more than a decade, the Food and Drug Administration has resisted calls to require that the amount be doubled.
To Dr. Godfrey Oakley, the former director of birth defects research for the Centers for Disease Control and Prevention, it is a baffling situation. “Until this day the F.D.A. still obstructs folic acid supplementation,” he said. “It’s like making a vaccine against polio with only one strain instead of four.”
The debate is intensifying. In the past two years, the American Medical Association, the March of Dimes and several pediatric societies have called on the food and drug agency to reconsider. The only country now adding the amount recommended by experts like Dr. Michael Katz, the medical director of the March of Dimes, is Chile.
Folic acid’s promise emerged 40 years ago, when British obstetricians realized that spina bifida often occurred when mothers had a form of anemia caused by folic acid deficiency. Then, in a 1991 British study of mothers of children with spina bifida, Dr. Nicholas Wald, the lead investigator, found such extraordinary results that he stopped the trial prematurely. When the women took folic acid daily before their next conception and through the first trimester of pregnancy, spina bifida recurrences fell 72 percent.
“That was the most important scientific data I’d heard in my career,” Dr. Oakley said.
In 1992, the Public Health Service called for all menstruating women to take a daily folic acid pill. (Folic acid helps only if taken before the fetus’s nervous system forms, which is before women realize they’re pregnant.)
But when few women followed that advice, the C.D.C. prevailed on the food and drug agency to hold hearings on folic acid fortification. That led to the federal requirement in effect today, though the food and drug agency was never enthusiastic about it. Dr. David A. Kessler, the food and drug commissioner at the time, told me recently that the issue “was probably the hardest decision I had on my tenure on the commission.”
“Adding a biologically active ingredient to the food supply of 300 million people is a very weighty issue,” Dr. Kessler said. “You can’t experiment on the American people.”
For critics of the idea, the first problem was that the recommended doses of folic acid were large, dwarfing the amount found in the average person’s diet. The second worry was that too much folic acid could mask symptoms of vitamin B12 deficiency and perhaps lead to irreversible brain damage in older people.
More recently, some researchers have pointed out that the rate of colon cancer rose slightly in the late 1990s, after the folic acid requirement took effect. But colon cancer rates have since fallen, suggesting the increase was a statistical anomaly.
Skeptics remain. Dr. James Mills, a foe of increased fortification at the National Institutes of Health, concludes that most women’s folate levels are already high enough to avoid preventable neural tube defects. He says there is no way the population’s safety can be guaranteed with higher fortification levels, and asks, “How would you design a study to determine if this is safe?”
Yet the folic acid requirement has had clear benefits. Within a year of the limited fortification, the C.D.C. reported, neural tube defect rates fell 20 percent, and no reports of widespread toxic effects emerged.
And there is good reason to think that requiring more fortification may prevent more birth defects. Blood levels of folate among women have been declining, according to a C.D.C. study released last January, perhaps because of worsening obesity and the popularity of low-carbohydrate diets.
The United States has a long history of accepting food fortification for public health. Iodine in salt has been shown to prevent many cases of mental retardation; while almost one-third of the world’s population has no access to iodized salt, Americans have been ingesting it since 1924. Similarly, additives like vitamin D in milk to prevent rickets, iron in flour to prevent anemia and fluoride in water to prevent cavities have been widespread in the developed world for half a century. Ultimately every public health intervention, including fortification, widespread vaccination and banning trans fats, involves a leap of faith, since no study can ever prove safety beyond the shadow of a doubt. One can show only that unintended harm is very unlikely.
From this perspective, the fact that 300 million Americans have already been exposed to folic acid in flour constitutes one of the world’s largest medical trials — one that suggests fortification is safe. And new benefits have emerged: in June, the American Heart Association reported that folic acid prevented common birth defects of the heart, and the journal Lancet reported that more folic acid might reduce strokes in adults by 18 percent.
Ideally, the authorities would address every concern before any intervention. But this approach causes public health paralysis.
Dr. Oakley bemoans the lack of incentives to prevent birth defects. For example, efforts to include package inserts in tampons or oral contraceptives to educate women about folic acid have not been adopted.
By comparison, he pointed to the introduction of a new vaccine two decades ago that led to the near eradication of Hemophilus meningitis in children.
“The vaccine-industrial complex works like a charm,” Dr. Oakley said. But with folic acid, things are slow: “Nobody’s making any money off this.”
Darshak Sanghavi is a pediatric cardiologist at the University of Massachusetts Medical School and the author of “A Map of the Child: A Pediatrician’s Tour of the Body.”
By DONALD G. McNEIL Jr., The New York Times, December 11, 2007
ROCKVILLE, Md. — The sign on the wall reads “Emergency Response Procedures for a Mosquito Release.”
Among them are “Do Not Leave the Room or Open Any Doors!!!” and “Do Not Panic!”
Everything in the room is white, including the lab coats and surgical masks — for sterility, yes, but also the better to see a mosquito. Hanging next to the sign, in vivid Coast Guard orange, is the last line of defense, a brace of fly swatters.
This room, the mosquito dissection lab, in an unassuming biotech park in the Washington suburbs, is at the heart of one of the most controversial ideas in vaccine science.
Sanaria Inc. (meaning “healthy air,” a play on the Italian “mal’aria” or “bad air”) is making a vaccine the old-fashioned way, more or less as Louis Pasteur did.
Avoiding modern recombinant DNA technology that injects tiny fragments of parasite protein to prime an immune response, Sanaria uses the whole parasite, extracted by hand from the mosquito’s salivary glands, and weakened so it cannot multiply.
Pasteur weakened rabies and anthrax bacilli by air drying them. Sanaria uses gamma rays.
Because the world now fights malaria — ineptly — with nets, insecticides and drugs, a vaccine is desperately needed.
As many as 70 experimental ones exist around the world; eight rival projects are being supported by the Malaria Vaccine Initiative, which was created in 1999 with money from the Gates Foundation.
Sanaria’s is the sole vaccine using the whole parasite. Injected into a capillary, it rides the bloodstream to the liver and starts making proteins. But after about three days, it stops, and it never floods the blood with copies of itself.
Radiation-weakened parasites have protected many lab mice and a handful of humans, but making a vaccine that can be mass produced is a huge challenge.
The lucrative market is made up of tourists and the world’s military forces. The larger goal is to protect the 3,000 children who die of malaria each day.
“We’ve got a lot of work to do, and we’re extremely mindful of the fact that the road to success is filled with potholes,” said the founder of Sanaria, Dr. Stephen L. Hoffman, a former chief of malaria research for the Navy.
Before he died two years ago, Dr. Maurice R. Hilleman, who invented 40 human and animal vaccines, called the Sanaria plan “the best show in town.”
Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, which gave Sanaria some of its early research money, said he was enthusiastic. “I have as much confidence in this as I do in any candidate,” he said, acknowledging that major problems remained to be solved.
Peering through microscopes and wielding tweezers and a fine needle in surgeon-steady hands, six workers snick the heads off anopheles mosquitoes, tease out the transparent salivary glands and pop them into little vials. After the glands and saliva proteins are dissolved, the parasites will be frozen at extremely low temperatures. When enough batches are ready, clinical trials overseen by the Navy will begin.
One recent morning, a reporter and photographers were allowed to view the last “engineering run” in the dissection room.
Nearby, in a room protected by five doors air pressurized to prevent escapes, mosquitoes are being raised from sterilized eggs and fed infected blood.
On harvesting day, they are wheeled to the gamma-ray kiln in red picnic coolers, each batch in a plastic pipe the size of a gelato container.
Just before dissection, they are popped into a freezer for a few minutes to stop their flying. The little pile of chilled mosquitoes is shaken into a dish of ethanol and divided into six portions.
The ethanol kills them without killing the parasites, explained B. Kim Lee Sim, the head of manufacturing. The dissectors work rapidly and with little talk, dismembering 80 females an hour.
“We need to get some music in here,” Dr. Sim said.
The males, which do not drink blood, “are just leftovers on the plate, waiting to get incinerated in the biohazard waste,” said Richard Stafford, chief of quality control.
Anyone with good eyesight and steady hands can be trained. “It’s not as difficult as it would seem to a person who doesn’t do it,” said Sumana Chakravarty, head of the team.
The idea that parasites weakened by radiation could be a vaccine has been around since 1967, when Dr. Ruth S. Nussenzweig of the New York University Medical School showed that it worked in mice.
In the ’70s, she and others showed that it could work in humans. Fourteen volunteers were vaccinated with weakened parasites and later exposed to malarial mosquitoes. Thirteen were protected, one so well that he then worked for three years in rural Ghana without taking any antimalaria drugs.
But the research never proceeded, for the same reason that the number of tests was so small: It was impractical.
The parasites could not survive outside mosquitoes. So the “vaccination” had to be delivered by mosquito bite, not needle. And because just one parasite at a time fits down a proboscis, each bite delivers just a few.
To be sure of receiving enough material, volunteers endured 1,000 bites from irradiated mosquitoes, which took weeks. In the ’80s, said Dr. John G. McNeil, scientific director of the vaccine initiative, the decoding of the mosquito genome opened new routes to make vaccines from bits of parasite surface protein that could be brewed quickly.
Early ventures did not work out. In 1987, Dr. Hoffman was one of six volunteers to be injected with an experimental vaccine, FSV-1, and then “challenged” by infected mosquitoes. He was so confident that he flew to San Diego for a medical conference.
“In the middle of giving a presentation,” he recalled. “I had a rigor, uncontrolled shaking and chills. It took 36 hours to find the parasites, but I had malaria.”
That vaccine, however, helped lead to the candidate now farthest along in African trials, RTS,S/AS02A, tentatively named Mosquirix, which has partly protected young children.
But nothing other than the whole parasite yet offers anything like 90 percent protection. So in 2002 Dr. Hoffman founded Sanaria and obtained $15 million in backing from the infectious disease institute, the Army and the Institute for One World Health. But $29 million from the Gates Foundation last year finally allowed the building of a real assembly line.
There were many hurdles. Sanaria had to work out how to raise sterile mosquitoes, to supercharge them with far more parasites than nature does, to dissolve saliva proteins to avoid allergic reactions and to freeze and thaw parasites without exploding them.
“This is the evolution of the efforts of five years of very dedicated scientists working together,” Dr. Sim said. “It’s a robust, repeatable, reliable process.”
Some scientists say the challenges remain insurmountable. At a recent meeting of the American Society for Tropical Medicine and Hygiene, Dr. Zarifah Reed, a parasite specialist in the World Health Organization’s vaccine research initiative, said she was troubled that the mosquitoes had to be raised on human blood, which cannot be sterilized.
Even though mosquitoes do not inject one person’s blood into another, there is the theoretical risk of passing on a virus, a prion or some other pathogen, she said.
Dr. Pierre Druilhe, a malaria expert at the Pasteur Institute in France and the inventor of a rival vaccine that he said was rejected for a Gates grant, was even more scathing.
“Even calling it a vaccine is a compliment,” he said. “It has no chance of offering protection. It is like Captain Ahab in the movie trying to kill Moby Dick with his knife.”
Besides the sterilization problem, he said, there was the risk that underirradiated parasites would cause malaria or that weakened parasites would not reach the liver. Cryogenically frozen vaccines, he added, will never be practical at sites with poor refrigeration.
Sanaria’s defenders said these were legitimate questions, but ones that had answers.Dr. Fauci, of the infectious disease institute, said the company had consulted the Food and Drug Administration about every aspect of sterility, “so quite frankly, I’m not impressed by that objection.”
Dr. Myron M. Levine, director of the center for vaccine development at the University of Maryland School of Medicine, said that any successful vaccine “would be used in places where kids’ chances of dying of malaria are much greater than any theoretical risk of dying from a rare blood problem.”
How big a dose is needed and where it is injected are questions for the trials, the doctors said. And although cryogenic storage may be impractical in Africa now, such problems can be solved with money, Dr. Levine said, adding, “Those are the easiest ones.”
Dr. Druilhe, in his critique, also said Dr. Hoffman was raising millions of dollars with unreal promises to sell Sanaria to private investors and cash out.
Dr. Hoffman, obviously seething, responded: “Pierre and I are friends and colleagues, but we don’t think alike about how to get to the end of the game. But let me ask a rhetorical question. If, as he says, this is never going to be a vaccine, who am I going to sell it to?”
Until then, he said, “I do what I do, and if it works, it works.”
Warming Trends: In Duck Blinds, Visions of Global Warming
By WILLIAM YARDLEY, The New York Times, December 11, 2007
RICH HILL, Mo. — After 32 years of hunting ducks in the wetlands of Missouri, Chuck Geier knows when temperatures will drop and waters will freeze. That means he also knows when the birds will fly and hunting will be best.
Except that much of what he knows is now in question.
“It used to be by Dec. 6, this place was frozen,” said Mr. Geier, 51, a national sales manager for a telecommunications company. “That’s not true anymore.”
From the “prairie potholes” of Canada and the upper Midwest to the destination states of Arkansas and Louisiana, the rhythms of the cross-continental migratory bird route known as the Mississippi Flyway are changing.
In Missouri, where the average winter temperature has been rising, hunters say birds are arriving later and sticking around longer before bolting for warmer redoubts. Elsewhere, wetlands are not freezing over the way they once did.
As hunters point their shotguns toward the sky and fire, a question echoes in the spent powder: what is up with the ducks?
“People say it’s cycles, every five to seven years, but it’s just been too long,” Mr. Geier said of the warming trend, which he traces to the late 1990s. “It’s a wake-up call.”
Five-year averages for “duck use” days on some conservation areas in Missouri show peaks that come a week or more later in the year than do the 30-year averages. Hunters have said in state surveys they want later hunting seasons, reflecting the later arrival of major weather systems that move birds into the state.
In Missouri, the average winter temperature this decade has been about 35 degrees, roughly 2 degrees higher than the previous peak around 1930.
“We’re having milder falls, later winters,” said Dave Erickson, chief of the wildlife division for the Missouri Department of Conservation. “What we don’t know is if the trend that affects migration and the hunters’ desire for a longer hunting season is a temporary fixture or a permanent fixture.”
Sure science is elusive. Scientists and state wildlife officials say there is not clear-cut data to support the reports of changes in duck behavior, but the patterns are familiar. They note that various other animal species, including songbirds, frogs and foxes, are developing different patterns for breeding and migration.
“We’re seeing northern range shifts of lots of birds and butterflies,” said Camille Parmesan, a professor of conservation biology at the University of Texas and a member of the United Nations panel that was awarded the Nobel Peace Prize for its work documenting climate change.
Many hunters, wildlife officials and scientists say the changes have added new mystery to waterfowl migration and to how to manage it. Against an uncertain future, state wildlife agencies and conservation groups that cultivate waterfowl populations are re-examining some longstanding conservation approaches and questioning whether business as usual needs to change.
Why, after all, some wildlife experts ask, should money still be poured into cultivating traditional breeding grounds like the prairie potholes of the upper Midwest if some climate forecasts prove true and those areas get too dry for ducks?
“The birds will not be there if you don’t have the same kind of general patterns of moisture and grasslands to nest in,” said Alan Wentz, who oversees conservation programs for Ducks Unlimited, a group that works to conserve and restore wetlands.
Similar questions are being raised elsewhere.
Some experts on Pacific salmon argue for diverting conservation resources away from areas where water temperatures are forecast to become too warm for survival. Some big game experts say deer and elk in many Western states might not leave higher elevations for traditional hunting areas because the weather will be milder. Anecdotal evidence suggests that this is already happening. Other animals, like moose in northwest Minnesota, are disappearing from some of the southern latitudes that they have traditionally inhabited.
Matt Hogan, the executive director of the Association of Fish and Wildlife Agencies, which represents state wildlife divisions, said the prospect of climate change was presenting wildlife with a new kind of threat. The association devoted part of its annual meeting in September to climate change and wildlife management.
“I know what I can do to mitigate this housing subdivision, but how do I mitigate that?” Mr. Hogan said of climate change. “A lot of it is saying, ‘O.K., what do I have to do to address this?’”
Concern is widespread. Consensus is not.
Many hunters are fond of calling themselves the original environmentalists. But in a sport with a distinct rural identity, many are not about to get behind Al Gore.
Some are just as quick to blame farming practices of big agricultural companies or government feeding programs for changes in duck behavior. In many areas, wildlife have also changed their behavior when their habitat has been damaged by development and when it has been improved by conservation efforts, like converting farmland to forests.
“We were conservationists before ‘green’ was even a popular word,” said Allen Morris, known as Horntagger, who lives in Jackson, Mo. “We have sacrificed and used money for licenses to save land for the wildlife, but in the mainstream media, you never hear about it.”
Mr. Morris dismissed “so-called global warming” as having no impact on hunting. Some biologists are divided, too. National conservation groups typically are more inclined to say climate change is already affecting wildlife and hunting.
“This actually is happening,” said Douglas B. Inkley, a senior scientist at the National Wildlife Federation and an author of “The Waterfowler’s Guide to Global Warming.”
“The evidence is there,” Mr. Inkley said, noting bird migration, changes in amphibian behavior and even impacts on lobsters in warming Atlantic waters. “We have both the scientific and we have the anecdotal, and then on top of that we have the theoretical based on climate models.”
Virginia Burkett, the chief scientist for global change research at the United States Geological Survey and a member of the United Nations panel that shared the Nobel Peace Prize with Mr. Gore, said scientists have already tracked changes in the breeding and migration patterns of many species because of warming, although they have not focused on game animals.
Red foxes are moving north, Ms. Burkett said. More than two dozen types of birds are nesting earlier. Three species of warbler are expected to move completely out of the United States. Squirrels in Canada and frogs in the United States have had their breeding patterns affected.
Ms. Burkett, a former director of the Louisiana Department of Wildlife and Fisheries, said that while development and land-use changes have had the most impact on wildlife in the past, “the affect of climate is much more likely to be a player in the loss of wildlife in the coming decades.”
She warned against wildlife managers using previous patterns to manage for the future.
“Relying on historical data alone,” she said, “can lead to mal-adaptation and the setting of seasons and bag limits that may no longer sustain populations, for both fish and wildlife.”
Even if climate change hurts habitat in some places, it could improve it in others. For all the uncertainty, times are good right now for many hunters, depending on where and when they hunt. Here in west-central Missouri, the ducks come late, but with the prairie potholes now wet after a long drought and with aggressive feeding programs in place on farms and wetlands, they come in abundance. Hunting seasons once restricted to 30 days by the federal government have been extended to 60.
By 10 a.m. on a recent morning in the Schell-Osage Conservation Area, Bob Wafel was one bird short of the daily limit imposed by the state. His black Labrador, Gunner, licked blood from the feathers of the five dead ducks that lay limp in the blind.
Mr. Wafel, 55, a barber from nearby Appleton City, lighted a cigar. “I think weather goes through cycles,” he said, “and I think you’ll have them warmer cycles.” Later, after bagging his sixth bird and with the optimism of a man who rises at 2 a.m. on winter mornings to sit in a dark, muddy, freezing hunting blind, Mr. Wafel added, “Maybe the cycle we’re going through now was before anybody kept track of the weather.”
Teenage Birth Rate Rises for First Time Since ’91
By GARDINER HARRIS, The New York Times, December 6, 2007
WASHINGTON, Dec. 5 — The birth rate among teenagers 15 to 19 in the United States rose 3 percent in 2006, according to a report issued Wednesday, the first such increase since 1991. The finding surprised scholars and fueled a debate about whether the Bush administration’s abstinence-only sexual education efforts are working.
The federal government spends $176 million annually on such programs. But a landmark study recently failed to demonstrate that they have any effect on delaying sexual activity among teenagers, and some studies suggest that they may actually increase pregnancy rates.
“Spending tens of million of tax dollars each year on programs that hurt our children is bad medicine and bad public policy,” said Dr. David A. Grimes, vice president of Family Health International, a nonprofit reproductive health organization based in North Carolina.
Robert Rector, a senior research fellow with the Heritage Foundation, said that blaming abstinence-only programs was “stupid.” Mr. Rector said that most young women who became pregnant were highly educated about contraceptives but wanted to have babies.
President Bush noted the long decline in teenage pregnancy rates in his 2006 State of the Union address, saying, “Wise policies such as welfare reform, drug education and support for abstinence and adoption have made a difference in the character of our country.”
The White House did not respond to requests for comment Wednesday.
In a speech last year, Senator Hillary Rodham Clinton said that rates of teenage pregnancy declined during the Clinton administration because of a focus on family planning.
Teenage birth rates are driven by rates of sex, contraception and abortion. In the 1990s, teenage sex rates dropped and condom use rose because teenagers were scared of AIDS, said Dr. John S. Santelli, chairman of the department of population and family health at Columbia University.
But recent advances in AIDS treatments have lowered concerns about the disease, and AIDS education efforts, which emphasized abstinence and condom use, have flagged.
Perhaps as a result, teenage sex rates have risen since 2001 and condom use has dropped since 2003. Abortion rates have held steady for a decade, although numbers from 2005 and 2006 are not available.
Kristin A. Moore, a senior scholar at Child Trends, a nonprofit children’s research organization, said the increase in the teenage birth rate was particularly alarming because even the 2005 rate was far higher than that in other industrialized countries.
“It’s really quite disappointing because we weren’t close to reaching our goal,” Dr. Moore said.
The lone bright spot in Wednesday’s report, issued by the Centers for Disease Control and Prevention, was that the birth rate for girls 14 and under dropped to 0.6 percent per 1,000 from 0.7 percent. Birth rates rose 3 percent among teenagers ages 15 to 17 and 4 percent among those ages 18 and 19.
The largest increase came among black teenagers, but increases were also seen among whites, Hispanics and American Indians. Birth rates among Asian teenagers continued to drop.
Unmarried childbearing reached a record high in 2006, according to the disease control centers, with unmarried mothers now accounting for 38.5 percent of all births. Births among teenagers and unmarried women tend to lead to poor outcomes for their children.
Helping to prevent these pregnancies was the reason advocates pushed for the wide availability of the morning-after pill known as Plan B. The Food and Drug Administration approved sales of Plan B without a prescription in August 2006, too late to have any effect on that year’s birth rate.
Mr. Rector of the Heritage Foundation said that teenage and unmarried birth rates were driven by the same factors: young women with little education who are devoted to mothering but see no great need to be married.
“We should be telling them that for the well-being of any child, it’s critically important that you be over the age of 20 and that you be married,” he said. “That message is not given at all.”
Dr. Santelli of Columbia said that many abstinence-only educational efforts tended to emphasize that contraceptives often fail. “They scare kids about contraception,” he said.
The report also found that the Caesarean delivery rate continued its rise, increasing 3 percent in 2006 to 31.1 percent of all births, a record. In recent years, women who have had one birth by Caesarean have often been discouraged from having subsequent births vaginally. And there is some evidence that a growing number of women are requesting Caesareans to avoid pain or vaginal stretching.
The American College of Obstetricians and Gynecologists published a position paper last month stating that some Caesareans-upon-request should be discouraged. Women who have multiple Caesarean births are more likely to suffer uterine rupture and other serious consequences.
Dr. Robert Freeman, a professor of obstetrics and gynecology at the University of California, Irvine, said that managed-care companies no longer discouraged Caesareans and malpractice fears often led doctors to opt for Caesarean at the first hint of trouble.
“These numbers are bad news,” Dr. Freeman said, “and I think it’s only going to get worse.”
For the first time since 1971, the nation’s overall fertility rate rose past the replacement rate, increasing 2 percent in 2006 to 2,101 births per 1,000 women. Women of almost every age had more children last year than the year before, except girls under 15 and women over 45.
Essay: A Growing Debate Over Folic Acid in Flour
By DARSHAK M. SANGHAVI, M.D., The New York Times, December 4, 2007
Every year, an estimated 200,000 children around the world are born with crippling defects of the spinal column. Many are paralyzed or permanently impaired by spina bifida; some, with a condition called anencephaly (literally, “no brain”), survive in a vegetative state.
It is a stubborn and terrible problem, in the developed and developing worlds alike. But many experts believe it could be greatly eased by a simple government measure: requiring that flour be fortified with the dietary supplement folic acid, which has been shown to prevent these neural tube defects if taken by expectant mothers from before conception through the first trimester.
The debate over folic acid is a familiar one, and Americans could be excused for thinking it was over. Since 1998, the federal government has required that almost all flour be fortified with the supplement.
But in fact, the requirement has meant women receive an average extra dose of just 100 micrograms of folic acid a day — far below the levels that have been shown in studies to prevent spina bifida and other neural tube defects. For more than a decade, the Food and Drug Administration has resisted calls to require that the amount be doubled.
To Dr. Godfrey Oakley, the former director of birth defects research for the Centers for Disease Control and Prevention, it is a baffling situation. “Until this day the F.D.A. still obstructs folic acid supplementation,” he said. “It’s like making a vaccine against polio with only one strain instead of four.”
The debate is intensifying. In the past two years, the American Medical Association, the March of Dimes and several pediatric societies have called on the food and drug agency to reconsider. The only country now adding the amount recommended by experts like Dr. Michael Katz, the medical director of the March of Dimes, is Chile.
Folic acid’s promise emerged 40 years ago, when British obstetricians realized that spina bifida often occurred when mothers had a form of anemia caused by folic acid deficiency. Then, in a 1991 British study of mothers of children with spina bifida, Dr. Nicholas Wald, the lead investigator, found such extraordinary results that he stopped the trial prematurely. When the women took folic acid daily before their next conception and through the first trimester of pregnancy, spina bifida recurrences fell 72 percent.
“That was the most important scientific data I’d heard in my career,” Dr. Oakley said.
In 1992, the Public Health Service called for all menstruating women to take a daily folic acid pill. (Folic acid helps only if taken before the fetus’s nervous system forms, which is before women realize they’re pregnant.)
But when few women followed that advice, the C.D.C. prevailed on the food and drug agency to hold hearings on folic acid fortification. That led to the federal requirement in effect today, though the food and drug agency was never enthusiastic about it. Dr. David A. Kessler, the food and drug commissioner at the time, told me recently that the issue “was probably the hardest decision I had on my tenure on the commission.”
“Adding a biologically active ingredient to the food supply of 300 million people is a very weighty issue,” Dr. Kessler said. “You can’t experiment on the American people.”
For critics of the idea, the first problem was that the recommended doses of folic acid were large, dwarfing the amount found in the average person’s diet. The second worry was that too much folic acid could mask symptoms of vitamin B12 deficiency and perhaps lead to irreversible brain damage in older people.
More recently, some researchers have pointed out that the rate of colon cancer rose slightly in the late 1990s, after the folic acid requirement took effect. But colon cancer rates have since fallen, suggesting the increase was a statistical anomaly.
Skeptics remain. Dr. James Mills, a foe of increased fortification at the National Institutes of Health, concludes that most women’s folate levels are already high enough to avoid preventable neural tube defects. He says there is no way the population’s safety can be guaranteed with higher fortification levels, and asks, “How would you design a study to determine if this is safe?”
Yet the folic acid requirement has had clear benefits. Within a year of the limited fortification, the C.D.C. reported, neural tube defect rates fell 20 percent, and no reports of widespread toxic effects emerged.
And there is good reason to think that requiring more fortification may prevent more birth defects. Blood levels of folate among women have been declining, according to a C.D.C. study released last January, perhaps because of worsening obesity and the popularity of low-carbohydrate diets.
The United States has a long history of accepting food fortification for public health. Iodine in salt has been shown to prevent many cases of mental retardation; while almost one-third of the world’s population has no access to iodized salt, Americans have been ingesting it since 1924. Similarly, additives like vitamin D in milk to prevent rickets, iron in flour to prevent anemia and fluoride in water to prevent cavities have been widespread in the developed world for half a century. Ultimately every public health intervention, including fortification, widespread vaccination and banning trans fats, involves a leap of faith, since no study can ever prove safety beyond the shadow of a doubt. One can show only that unintended harm is very unlikely.
From this perspective, the fact that 300 million Americans have already been exposed to folic acid in flour constitutes one of the world’s largest medical trials — one that suggests fortification is safe. And new benefits have emerged: in June, the American Heart Association reported that folic acid prevented common birth defects of the heart, and the journal Lancet reported that more folic acid might reduce strokes in adults by 18 percent.
Ideally, the authorities would address every concern before any intervention. But this approach causes public health paralysis.
Dr. Oakley bemoans the lack of incentives to prevent birth defects. For example, efforts to include package inserts in tampons or oral contraceptives to educate women about folic acid have not been adopted.
By comparison, he pointed to the introduction of a new vaccine two decades ago that led to the near eradication of Hemophilus meningitis in children.
“The vaccine-industrial complex works like a charm,” Dr. Oakley said. But with folic acid, things are slow: “Nobody’s making any money off this.”
Darshak Sanghavi is a pediatric cardiologist at the University of Massachusetts Medical School and the author of “A Map of the Child: A Pediatrician’s Tour of the Body.”
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Date: 2007-12-11 11:27 pm (UTC)no subject
Date: 2007-12-12 02:19 pm (UTC)