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		<p>I<lb/> t took one routine smallpox vaccination<lb/> to expose the holes in the United
			States&apos;<lb/> defences against bioterrorism. In January<lb/> 2009, the jab was given
			to 20-year-old Lance<lb/> Corporal Cory Belken of the US Marine<lb/> Corps, as it is to
			many members of the mili-<lb/>tary who are about to be deployed abroad, to<lb/> protect
			him against a potential attack with the<lb/> lethal virus. But in this case, the timing
			was<lb/> unfortunate. Two weeks after the vaccination<lb/> Belken was diagnosed with
			leukaemia; he then<lb/> underwent chemotherapy that wiped out his<lb/> immune system.
			Suddenly, the live vaccinia<lb/> virus, the milder relative of smallpox used in<lb/> the
			vaccination, was able to multiply into a<lb/> dangerous infection.<lb/></p>

		<p>Doctors turned to their only means of coun-<lb/>ter-attack: three smallpox drugs, two of
			them<lb/> experimental and developed as part of US<lb/> efforts to build up an arsenal
			against potential<lb/> bioterror agents. The marine received 30 times<lb/> the standard
			dose of the first drug, an approved<lb/> antibody, to no avail. The second, called<lb/>
			STS-246, had been used in only one person<lb/> infected with vaccinia before. By the
			time doc-<lb/>tors administered the third drug, CMX001,<lb/> Belken had developed a
			bacterial infection<lb/> that spread to his feet, brought him near death<lb/> and
			required surgeons to amputate both his<lb/> legs below the knees. Only after he received
			all<lb/> three medicines did he start to recover — and<lb/> it is still not known which
			of the drugs, if any,<lb/> eventually helped.<lb/></p>

		<p>The marine&apos;s case is just one of many<lb/> events that have raised questions about
			the<lb/> bio defence research and development enter-<lb/>prise that sprang from
			bioterror attacks in the<lb/> United States ten years ago. Shortly after the<lb/>
			terrorist attacks of 11 September 2001, anthrax<lb/> spores sent to media outlets and
			politicians<lb/> killed five people and compounded already<lb/> widespread fear and
			horror. The incidents<lb/> spurred the US government to launch a major<lb/> scientific
			effort to develop &apos;counter measures&apos;:<lb/> diagnostics, vaccines and drugs
			against poten-<lb/>tial biological threats such as smallpox and<lb/> anthrax. In a
			three-part strategy, the federal<lb/> government poured money into basic research<lb/>
			at the National Institutes of Health (NIH);<lb/> created the Biomedical Advanced
			Research<lb/> and Development Authority (BARDA) to<lb/> carry new concepts forward into
			further<lb/> development and testing; and established<lb/> BioShield, a US$5.6-billion
			programme to<lb/> purchase the finished drugs and vaccines.<lb/> But none of the links
			in this chain has worked<lb/> exactly as it was supposed to.<lb/></p>

		<p>Between 2001 and the end of this year, the<lb/> federal government will have spent $60
			bil-<lb/>lion on such biodefence efforts (see &apos; A decade<lb/> of biodefence&apos;),
			according to analyses from<lb/> the Center for Biosecurity of the University<lb/> of
			Pittsburgh Medical Center in Baltimore,<lb/> Maryland. The money has helped to
			mod-<lb/>ernize the nation&apos;s crumbling public-health<lb/> system, and BioShield has
			invested in a stock-<lb/>pile of 20 million doses of smallpox vaccine,<lb/> 28.75
			million doses of anthrax vaccine and<lb/> 1.98 million doses of four medicines to
			treat<lb/> complications of smallpox, anthrax and bot-<lb/>ulism. But few researchers or
			policy-makers<lb/> seem happy with an arsenal of six drugs that<lb/></p>

		<figure type="table">OCTOBER–NOVEMBER 200<lb/> A DECADE OF BIODEFENCE<lb/> Anthrax-laced
			letters<lb/> are sent to media<lb/> outlets and politicians,<lb/> killing ve people
			and<lb/> prompting a major FBI<lb/> investigation.<lb/> US President George W.<lb/> Bush
			signs a law creating<lb/> a list of &apos;select&apos; agents<lb/> considered to be
			the<lb/> biggest bioterror threats,<lb/> including smallpox and<lb/> anthrax
			(pictured).<lb/> Project BioShield is created: a US$5.6-billion<lb/> programme to
			purchase countermeasures against<lb/> bioterror attacks.<lb/> NOVEMBER 2004<lb/> VaxGen
			of South San Francisco, California, is awarded<lb/> some $877 million by BioShield for
			its anthrax<lb/> vaccine. The contract is cancelled in 2006 after<lb/> VaxGen fails to
			meet milestones.<lb/> DECEMBER 2006<lb/> Congress creates the Biomedical Advanced
			Research<lb/> and Development Authority (BARDA), which assumes<lb/> management of
			BioShield.<lb/> Bruce Ivins (pictured), a<lb/> scientist at the US<lb/> Army Medical
			Research<lb/> Institute of Infectious<lb/> Diseases in Fort Detrick,<lb/> Maryland,
			commits<lb/> suicide as the FBI is<lb/> preparing criminal<lb/> charges against him
			for<lb/> the anthrax attacks.<lb/> BARDA orders 45,000 doses of anthrax drug from<lb/>
			Human Genome Sciences of Rockville, Maryland. Later,<lb/> the Food and Drug
			Administration declines to approve<lb/> the drug.<lb/> US Department of Justice
			concludes that Ivins alone<lb/> was responsible for the anthrax attacks, and closes<lb/>
			the investigation.<lb/> An advisory panel<lb/> recommends trimming<lb/> the select-agent
			list to<lb/> only those posing the<lb/> very greatest risk, such<lb/> as the Ebola
			virus<lb/> (pictured).<lb/> Legislators propose reauthorizing BARDA and funding<lb/>
			BioShield at $2.8 billion for 2014–18.<lb/> JUNE 2002<lb/> JULY 2008<lb/> JULY 2009<lb/>
			FEBRUARY 200<lb/> JUNE 2000<lb/> JUNE 2000<lb/> JULY 2004<lb/></figure>

		<p>address only three of the potential threats —<lb/> even if they are among the most
			serious. &quot; The<lb/> pipeline we rely on to provide those critical<lb/>
			countermeasures — diagnostics, vaccines,<lb/> antivirals, antibiotics — is full of
			leaks, choke<lb/> points and dead ends, &quot; said Kathleen Sebelius,<lb/> US Secretary
			of Health and Human Services,<lb/> in a statement last year.<lb/></p>

		<p>Critics say that the effort has been hob-<lb/>bled by a lack of strategic thinking, focus
			and<lb/> coordination between the federal agencies<lb/> involved, and by unrealistic
			expectations of<lb/> what the money could buy. &quot; There was no<lb/> evidence that
			they looked at what our top pri-<lb/>orities are and asked, &apos;What&apos;s needed on
			the<lb/> basic-science side?&apos; , &apos;What&apos;s needed on the<lb/> development
			side?&apos; , and &apos;What&apos;s needed in the<lb/> stockpile?&apos;, &quot; says
			Andrew Pavia, an infectious-<lb/>diseases doctor at the University of Utah in<lb/> Salt
			Lake City. Until earlier this year, Pavia<lb/> served on the National Biodefense
			Science<lb/> Board, which advises the US Department of<lb/> Health and Human Services
			(DHHS) and in<lb/> March last year released a report, Where Are<lb/> The
			Countermeasures?, that was critical of the<lb/> federal biodefence effort.<lb/></p>

		<p>What is more, developing therapies for<lb/> diseases that are mercifully rare among<lb/>
			humans is a unique challenge. Drug develop-<lb/>ment is difficult at the best of times —
			and<lb/> experts say that there is simply not enough<lb/> money in biodefence to entice
			big companies<lb/> into the field. &quot; It is a bit discouraging consid-<lb/>ering
			we&apos;ve spent more than $60 billion on<lb/> this in the past decade, &quot; says
			Randall Larsen, a<lb/> member of the Commission on the Prevention<lb/> of Weapons of
			Mass Destruction Proliferation<lb/> and Terrorism, which in a January 2010
			&apos;report<lb/> card&apos; gave the nation a failing grade for its abil-<lb/>ity to
			prevent a bioterror attack from causing<lb/> huge casualties. &quot; The question is
			whether it<lb/> has been spent properly, &quot; he says.<lb/></p>

		<head>PRIORITY PATHOGENS<lb/></head>

		<p>That point is especially pressing now. The<lb/> United States is in dire financial
			straits and<lb/> may be forced to slash the research budgets<lb/> of the NIH and other
			agencies if Congress<lb/> does not agree on other spending cuts by<lb/> 23 December.
			Still, some researchers think<lb/> that ten years is simply too soon to expect
			pay-<lb/>offs from a research programme that essen-<lb/>tially started from scratch.
			&quot; There have been<lb/> some really important lessons received from<lb/> what has
			admittedly been a very large invest-<lb/>ment, &quot; says David Relman, a
			microbiologist<lb/> at Stanford University in California who has<lb/> been heavily
			involved in biodefence research<lb/> and policy. &quot; Perhaps with a more refined
			idea<lb/> of the goal, [the money] might have been<lb/> used in a more productive or
			effective way.<lb/> But at the time, we didn&apos;t really know what we<lb/> needed and
			we didn&apos;t know how hard it would<lb/> be to make any of these things that we
			needed. &quot;<lb/></p>

		<p>A pillar of the biodefence enterprise is the<lb/> US National Institute of Allergy and
			Infectious<lb/> Diseases (NIAID) in Bethesda, Maryland,<lb/> which got a $1.5-billion
			budget boost in 2003<lb/> and has so far received $14 billion for biode-<lb/>fence. It
			is there, say critics, that some early<lb/> and crucial mistakes were made.<lb/></p>

		<p>In a series of reports issued in 2002 and<lb/> 2003, the NIAID outlined its plans to
			fund<lb/> basic research aimed at the development of<lb/> treatments and vaccines for
			more than 50<lb/> &apos;priority pathogens&apos; and toxins classified into<lb/> three
			categories. Category A covers agents<lb/> considered to be the most dangerous and<lb/>
			likely to be used in an attack, such as small-<lb/>pox and anthrax. Categories B and C
			include<lb/> threats such as food-and waterborne illnesses.<lb/> (The list was similar
			to a catalogue of &apos;select<lb/> agents&apos; kept by the US Centers for Disease<lb/>
			Control and Prevention (CDC) in Atlanta,<lb/> Georgia.) The agency also built 15 labs
			across<lb/> the country — part of a building boom that<lb/> has led, so far, to the
			planning, construction<lb/> or renovation of nearly 20 labs for the study<lb/> of
			dangerous pathogens at a cost of more than<lb/> $2 billion.<lb/></p>

		<p>But some experts say that attempting to tai-<lb/>lor vaccines and treatments to
			individual path-<lb/>ogens is misguided: some of the pathogens are<lb/> difficult to
			turn into bioweapons or just aren&apos;t<lb/> very dangerous, and the costs of
			developing<lb/> a large defensive arsenal are astronomical. It<lb/> makes more sense,
			these experts say, to stock-<lb/>pile antibiotics and other medicines that could<lb/> be
			used against many pathogens. &quot; You can<lb/> look at some of the vaccine
			investments, like<lb/> for plague and [the bacterial disease] tularae-<lb/>mia, and
			wonder who decided that was the<lb/> highest priority, as opposed to developing new<lb/>
			antibiotics, &quot; says Pavia.<lb/></p>

		<p>The NIAID reorganized its biodefence<lb/> research efforts in 2007, increasing its focus
			on<lb/> &apos;broad-spectrum&apos; priorities that would work<lb/> against multiple
			pathogens. And in June this<lb/> year, a federal panel recommended trimming<lb/> and
			reorganizing the CDC&apos;s select-agent list.<lb/> But the NIAID is still funding
			research on<lb/> plague and tularaemia vaccines, and defends<lb/> the work, saying that
			research on tularae-<lb/>mia, for example, has yielded insights about<lb/> immunity that
			are relevant to other pathogens.<lb/> Michael Kurilla, director of the Office of
			Bio-<lb/>defense Research Affairs in the NIAID&apos;s Divi-<lb/>sion of Microbiology and
			Infectious Diseases,<lb/> points to recent work on a broad-spectrum<lb/> antiviral drug
			that, he says, sprang from stud-<lb/>ies of the Nipah virus, a category C bioterror<lb/>
			threat. He says that this demonstrates the value<lb/> of continued work on such
			pathogens as well<lb/> as model microbes such as the bacterium<lb/> Escherichia coli.
			&quot; If you say everyone should<lb/> study E. coli because it&apos;s like everything
			else,<lb/> you won&apos;t get those concepts that come out<lb/> of some unusual bug and
			have other applica-<lb/>tions, &quot; he says.<lb/></p>

		<p>Despite the problems with basic bio defence<lb/> research, critics see far more to
			complain<lb/> about in the later stages of the process. The<lb/></p>

		<figure>BIODEFENCE IN BILLIONS<lb/> Much US biodefence funding has had additional uses, such
			as in public health.<lb/> The government&apos;s BioShield programme buys nished drugs
			and vaccines.<lb/> Allocations of civilian biodefence funding<lb/> by scal year (US$
			billions)<lb/> 0<lb/> 1<lb/> 2<lb/> 3<lb/> 4<lb/> 5<lb/> 6<lb/> 7<lb/> 8<lb/> 9<lb/>
			Multiple-use<lb/> funding<lb/> BioShield<lb/> funding<lb/> 2001 02 03 04 05 06 07 08 09
			10 11 12<lb/> Strictly biodefence funding<lb/> (minus BioShield)<lb/></figure>

		<p>therapies can&apos;t be rigorously<lb/> tested in humans (it would be<lb/> unethical to
			infect people with<lb/> pathogens such as smallpox for<lb/> testing). And government
			agen-<lb/>cies had little idea how to go about<lb/> developing such therapies.<lb/></p>

		<p>The smallpox drugs CMX001<lb/> and STS-246 are cases in point.<lb/> CMX001 is a version
			of an estab-<lb/>lished antiviral drug called cido-<lb/>fovir that must be given as
			an<lb/> injection. In 2000, Karl Hostetler,<lb/> a chemist at the University of<lb/>
			California, San Diego, formed<lb/> Chimerix, a pharmaceutical com-<lb/>pany based in
			Research Triangle<lb/> Park, North Carolina, to develop<lb/> a cidofovir pill that could
			be taken<lb/> by mouth.<lb/></p>

		<p>In September 2003, the NIAID awarded<lb/> Chimerix a $36-million, five-year grant to<lb/>
			develop CMX001 as a treatment for small-<lb/>pox. The drug looked promising in tests
			on<lb/> mice and rabbits, and Chimerix teamed up<lb/> with the US Army Medical Research
			Institute<lb/> of Infectious Diseases in Fort Detrick, Mary-<lb/>land, to test it in
			monkeys infected with the<lb/> related virus monkey pox. But the drug didn&apos;t<lb/>
			cure the disease — owing, Chimerix said, to a<lb/> quirk of metabolism not relevant to
			humans.<lb/></p>

		<p>Meanwhile, SIGA, a pharmaceutical com-<lb/>pany based in New York, was racing ahead<lb/>
			with STS-246, a small molecule that blocks<lb/> viral maturation. In 2006, the
			company<lb/> reported that its drug protected monkeys<lb/> from monkey pox. While
			Chimerix struggled<lb/> for funding, the federal government contin-<lb/>ued to award
			money to SIGA and, in October<lb/> 2010, SIGA won a BARDA contract for STS-<lb/>246
			worth up to $2.8 billion. Chimerix pro-<lb/>tested — and SIGA&apos;s award was later
			whittled<lb/> down to $433 million.<lb/></p>

		<p>Yet the case of the sick marine in 2009<lb/> showed that fighting biothreats can take
			a<lb/> whole armamentarium of drugs. Belken&apos;s<lb/> condition didn&apos;t improve
			until CMX001 was<lb/> added to STS-246. &quot; The reality is that we need<lb/> two
			smallpox antiviral drugs, &quot; says Robert<lb/> Kadlec, a former Senate staff member
			who<lb/> helped to write the 2006 legislation that cre-<lb/>ated BARDA.<lb/></p>

		<p>The episode shows how challenging it is<lb/> to develop therapies, especially when
			there<lb/> are no good animal models or data showing<lb/> whether the drug fights
			disease in humans.<lb/> The smallpox virus infects only humans, for<lb/> example, and
			monkeypox is an imperfect<lb/> mimic. Yet authorities often need to rely on<lb/> animal
			tests when they make expensive deci-<lb/>sions about which drug to buy, and small
			bio-<lb/>defence companies can be dependent on the<lb/> funding that results from these
			decisions.<lb/></p>

		<p>&quot; The regulatory process is still evolving,<lb/> and the federal government
			doesn&apos;t have a<lb/> clear sense of what it needs, &quot; says Jim Davis,<lb/>
			executive vice-president of Human Genome<lb/> Sciences in Rockville, Mary land. &quot;
			It&apos;s frustrat-<lb/>ing for every one involved. &quot; In October 2009,<lb/> the US
			Food and Drug Administration (FDA)<lb/> decided not to approve an antibody against<lb/>
			anthrax developed by Human Genome Sci-<lb/>ences — even though BARDA had already<lb/>
			agreed to spend $326 million on the drug.<lb/> The company had thought that it had
			met<lb/> the FDA&apos;s criteria but, according to Davis, the<lb/> agency decided that
			it wanted a drug that is<lb/> more effective than the existing anthrax treat-<lb/>ment,
			ciprofloxacin.<lb/></p>

		<p>Robin Robinson, director of BARDA, says<lb/> that the agency is funding the creation of
			better<lb/> animal models. The DHHS reviewed medical<lb/> countermeasures in 2010, and
			said that it will<lb/> do more to try to help companies to bridge<lb/> the gap between
			basic research and the clinic.<lb/> The DHHS has also proposed re allocating<lb/> $170
			million in existing FDA funds to help<lb/> update regulatory review in
			biodefence.<lb/></p>

		<p>But revamping biodefence is going to take<lb/> more money — and critics say that some
			of<lb/> the $60 billion spent so far has simply been<lb/> wasted. They point to a
			$533.8-million sur-<lb/>veillance project called BioWatch, created<lb/> by the
			Department of Homeland Security,<lb/> which has deployed detectors for airborne<lb/>
			bioterror agents in 30 cities. The system has<lb/> been criticized in part because
			technicians<lb/> must manually collect the air filters and take<lb/> them to a lab for
			analysis, creating a delay of<lb/> 10–34 hours before results are in and ham-<lb/>pering
			the system&apos;s ability to provide an early<lb/> warning. In a report entitled
			BioWatch and<lb/> Public Health Surveillance, released last year,<lb/> a committee
			convened by the US National<lb/> Academies said that BioWatch faces &quot; seri-<lb/>ous
			technical and operational challenges &quot; .<lb/> The next-generation Biowatch is
			designed to<lb/> improve the programme.<lb/></p>

		<p> Much of the biodefence money didn&apos;t even<lb/> go into research, as a breakdown of
			spending<lb/> shows (see &apos;Biodefence in billions&apos;). The CDC<lb/> has received
			the most so far — $17.4 billion<lb/> — and put the vast majority<lb/> into bolstering an
			underfunded<lb/> public-health infrastructure. The<lb/> rationale is that the nation has
			lit-<lb/>tle chance of fighting a bioterror<lb/> attack without a strong system<lb/> for
			detecting, reporting and<lb/> treating any emerging infectious<lb/> disease.<lb/></p>

		<p>Most of the biodefence spend-<lb/>ing, in fact, has spin-offs into<lb/> other fields;
			even BARDA is<lb/> involved in developing medicines<lb/> against threats such as
			pandemic<lb/> flu. In all, only $11.99 billion of<lb/> the $60 billion has been spent
			on<lb/> programmes solely concerned<lb/> with biodefence. That&apos;s just over<lb/> $1
			billion per year from 2001 to<lb/> 2011.<lb/></p>

		<p>Drug-makers often say that it takes at least<lb/> $800 million and ten years to develop a
			single<lb/> drug, so a much greater investment is required<lb/> before the biodefence
			effort can yield many<lb/> new counter measures. Kadlec recommends<lb/> that the United
			States spend $10 billion a year<lb/> on bio defence in future.<lb/></p>

		<head>FUNDING CRUNCH<lb/></head>

		<p>Such sums seem unlikely to materialize.<lb/> BioShield&apos;s funding is set to expire in
			2013,<lb/> and Congress has proposed refunding it at<lb/> $2.8 billion for 2014–18 —
			about the same<lb/> as before. Cutbacks are eroding some of the<lb/> gains in
			public-health infra structure: local<lb/> health departments have lost 29,000 jobs,<lb/>
			some 19% of the workforce, over the past<lb/> three years.<lb/></p>

		<p> Now, say observers, the federal govern-<lb/>ment must take a hard look at its
			biodefence<lb/> programme and devise a more coordinated<lb/> strategy that strikes a
			balance between devel-<lb/>oping pathogen-specific countermeasures and<lb/> working on a
			more generalized resilience to<lb/> infectious disease. &quot; If the expectations
			were<lb/> that we were going to come up with a whole<lb/> armamentarium of new products
			by 2011,<lb/> that was probably unrealistic, &quot; says Relman.<lb/> &quot; It might
			make sense to pick a few [threats]<lb/> that are at the top of all possible lists, but
			then<lb/> to say, a lot of the rest of the work needs to be<lb/> in creating a fertile
			ground for innovation and<lb/> product development. &quot;<lb/></p>

		<p>&quot; We&apos;re at a point after ten years, &quot; says<lb/> Michael Osterholm,
			director of the University<lb/> of Minnesota&apos;s Center for Infectious Disease<lb/>
			Research and Policy in Minneapolis, &quot; where<lb/> we have got to start producing the
			kinds of<lb/> plans and cost estimates about what it will<lb/> take for a country like
			ours to be prepared in<lb/> a moderate way. &quot; Preparing for only the worst<lb/>
			eventualities might now be the best the nation<lb/> can do. ■ SEE COMMENT P. 153</p>


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