Pandemic Flu in Boarding Schools

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<p>[Technology</a> Review: Breakthrough Flu Drug Might Already Exist](<a href=“http://www.technologyreview.com/biomedicine/24084/]Technology”>http://www.technologyreview.com/biomedicine/24084/)</p>

<p>Fragments of known drugs could lead to a more robust antiviral for H1N1 and other flu variants.
By Lauren GravitzTuesday, December 08, 2009</p>

<p>The flu virus is a wily target, constantly mutating to avoid attack from the immune system and from antiviral drugs like Tamiflu. But in research presented Sunday at the annual meeting of the American Society for Cell Biology (ASCB) in San Diego, scientists announced a new method for fighting pandemic influenzas such as H1N1 (swine) and H5N1 (avian).</p>

<p>Structurally sound: The neuraminidase protein of the H1N1 virus is particularly adept at mutating to avoid attack. In this crystal structure, the mutations that allow it to resist Tamiflu and other antiviral drugs are visible as multicolored stick structures.
Credit: Daniel Dadon and Jacob Durrant</p>

<p>The approach involves using massive amount of computer power to simulate never-before-seen conformations of a virus. Using the method, researchers at the University of California at San Diego have not only identified a new molecular target for influenza drugs, they have also found drugs already approved by the U.S. Food and Drug Administration that just might hit the target perfectly.</p>

<p>The target in question is a single, large protein called neuraminidase–one of two major proteins present on the surface of the influenza virus–that allows newly replicated viruses to be released into their host. Because most pandemic versions share the same neuraminidase subtype, N1, the protein is an ideal drug target.</p>

<p>Most molecular imaging or modeling focuses on determining the arrangement of atoms in a molecule’s crystal structure–a lengthy, energy-intensive process that provides a precise way to capture the molecule’s shape but only in one conformation, frozen at a single moment in time. In contrast, the new “relaxed complex” method models the virus protein molecule in a state that provides a better understanding of how the protein behaves and even revealing conformations that rarely occur.</p>

<p>Biochemist Andrew McCammon and undergraduate lab member Daniel Dadon used a sophisticated computer program to simulate all possible conformations–27 in all–of the H1N1 virus’s flexible neuraminidase protein. Rather than forcing the protein into a single crystal structure’s conformation, “[we] got a movie of how the protein would behave in nature,” Dadon says. “It’s like frames from a film, rather than a single photograph.”</p>

<p>Dadon aligned each of those 27 neuraminidase conformations and found that all of them had a binding site that remained unchanged, a single spot that could act as a prime inhibitor target. The researchers then looked at a library of drugs already approved by the FDA. After breaking molecular models of the drugs down into small fragments, they ran them through a colossal search algorithm in order to find those molecules with the highest affinity for the neuraminidase binding site.</p>

<p>“If you start with compounds that are FDA-approved, it may be a faster way to find good drug leads,” says Rommie Amaro, who specializes in pharmaceutical and computer sciences at the University of California at Irvine. “There’s a long process to get a drug reviewed, and the molecules have to be metabolically okay for people to ingest. So instead of starting with random leads from a chemical library, if you start with compounds that are FDA-approved, you could already have the more harmful compounds weeded out.”</p>

<p>The process gave Dadon 15 hits, all with a higher binding affinity for H1N1 than any of the antivirals already approved for use against flu. Because all 15 of those compounds had a single substructure in common, Dadon looked for molecules already being produced by chemical and drug companies that contained that substructure. He found six of them, and all are currently being tested against H1N1 by collaborators in Australia.</p>

<p>The flu virus mutations known to resist antiviral drugs appear to occur in an altogether different binding site than the one Dadon and his colleagues discovered. Such a distinction is important, especially as reported cases of H1N1 resistance to Tamiflu are on the rise. If any of the researchers’ six molecules prove successful, the resulting drug could provide a second line of attack to be used where current antivirals fail.</p>

<p>McCammon used an earlier version of the same method to discover novel inhibitors for a key HIV enzyme. But the technique is still relatively obscure in the drug-discovery world. “The relaxed complex method is not widely used because of the amount of computing time that it requires,” says Wilfred Li, a bioinformatics specialist at UCSD’s San Diego Supercomputing Center.</p>

<p>Li also notes that such studies are quite computationally expensive. “This study really stresses the need for a better computing infrastructure so more proteins can be studied in this fashion. These techniques can be used to develop new, interesting, and more potent inhibitors.”</p>

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<p>[Unexpected</a> weakness in H1N1’s method for evading detection by the immune system](<a href=“Unexpected weakness in H1N1's method for evading detection by the immune system | ScienceDaily”>Unexpected weakness in H1N1's method for evading detection by the immune system | ScienceDaily)</p>

<p>ScienceDaily (Dec. 10, 2009) — The H1N1 influenza virus has been keeping a secret that may be the key to defeating it and other flu viruses as well.</p>

<p>Researchers at Rice University and Baylor College of Medicine (BCM) have found what they believe is a weakness in H1N1’s method for evading detection by the immune system.</p>

<p>Comparing its genetic sequences going all the way back to the virus’s first known appearance in the deadly “Spanish flu” outbreak of 1918, they discovered a previously unrealized role of receptor-binding residues in host evasion, which effectively becomes a bottleneck that keeps the virus in check.</p>

<p>Rice’s Jianpeng Ma and graduate student Jun Shen and BCM’s Qinghua Wang compared the sequences of more than 300 strains of H1N1 to track its evolution; they reported their results in a recent online edition of the scientific journal PLoS ONE.</p>

<p>The researchers were looking in particular at hemagglutinin (HA), the protein “hook” that allows the virus to attach itself to and infect host cells. It’s long been known that five regions of H1N1’s HA serve as antigenic sites, the protein fragments that trigger the body’s immune system. These antigenic sites, first mapped in 1981, shuffle their amino-acid sequences in the endless cat-and-mouse game that viruses play to survive.</p>

<p>The researchers discovered several key residues involved in both antigenic sites and the receptor-binding site, the part of the protein that attaches to a cell and allows the virus to invade.</p>

<p>The common belief has been that the receptor binding could not change. “The site is known, but no one thought it was involved in the immune system. In order to recognize the receptor, that particular region has to be robust,” Ma said. “But it turns out this region is not only variable, but also interacts with the immune system.”</p>

<p>For a virus to evade antibodies, all five antigenic sites would have to disguise themselves by mutating. The new finding led the researchers to believe the receptor-binding residues would also have to mutate, but not so much that the binding no longer works. “If the binding is abolished, the virus dies,” said Ma, a Rice professor in bioengineering with a joint appointment at BCM.</p>

<p>Such dual-function residues are a likely bottleneck for the virus, he said, because they’re under the tightest restrictions. Thus, they could be easier to track over time and may chart a path to predict future mutations that will aid in vaccine design.</p>

<p>“It becomes a weak link and provides us with a window into the virus that we can monitor,” Ma said. “The virus’s bottleneck is our opportunity.”</p>

<p>Wang, an assistant professor of biochemistry and molecular biology at BCM who has long studied the structure and function of HA, has been involved in the project since it began and is now working to verify the results in vitro. She hopes confirming the computations will lead to more efficiency in creating vaccines not only for H1N1 but also for other strains of the flu.</p>

<p>“An underlying implication is that this may not be restricted to H1N1,” Wang said. “It may apply to other influenza viruses as well. If studying viral evolution can help predict what will cause a severe problem in humans, you can actually pre-stock vaccines, which will save time.”</p>

<p>The research was supported by the National Institutes of Health, National Science Foundation, Welch Foundation, the Welch Chemistry and Biology Collaborative Grant from the John S. Dunn Gulf Coast Consortium for Chemical Genomics and the Rice Faculty Initiatives Fund</p>

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<p>[Op-Ed</a> Contributor - What We Learned From H1N1’s First Year - NYTimes.com](<a href=“http://www.nytimes.com/2010/04/13/opinion/13wenzel.html?scp=2&sq=h1n1&st=cse]Op-Ed”>http://www.nytimes.com/2010/04/13/opinion/13wenzel.html?scp=2&sq=h1n1&st=cse)</p>

<p>Op-Ed Contributor
What We Learned From H1N1’s First Year</p>

<p>By RICHARD P. WENZEL
Published: April 12, 2010</p>

<p>Richmond, Va.</p>

<p>ONE year ago today, a government worker in Oaxaca, Mexico, became the first person to die of swine flu. At the bedsides of other men and women struggling to stay alive in Mexican critical care units, we clinicians noticed early on that this novel H1N1 flu virus diverged from influenza’s usual pattern of activity in striking ways. It began in the Northern Hemisphere, not in Asia, and in mid-spring, not late fall or winter. It also had a worrying predilection for children and young adults, not the elderly and newborns.</p>

<p>In the months after those first deaths, the virus ignited a global pandemic. While the epidemic never became as deadly as we initially feared, it was not as mild as some experts now believe. What’s more, it exposed some serious shortcomings in the world’s public health response.</p>

<p>Those who now describe the pandemic as mild base their conclusion primarily on what, at first, seems like a mortality rate in the United States similar to those seen after seasonal influenza. But my colleagues in developing countries would strongly object.</p>

<p>Though we lack reliable death rates from country to country, certainly no one who helped care for the large number of critically ill patients in Mexico could conclude that the flu in the United States was as severe as in developing countries that lacked our resources.</p>

<p>Here, the vaccine arrived later than estimated, and only about 80 million Americans received it — not nearly enough, but a far higher proportion of the population than in many developing countries. In fact, only 26 of 94 poor countries in need of the protective H1N1 vaccine have even received it so far.</p>

<p>We also cannot count as mild any virus that was so devastating for young adults, along with pregnant women, obese patients and minorities.</p>

<p>Worse yet, this virus made itself particularly hard for clinicians to identify. Whereas doctors associate fever and cough with outbreaks of influenza, one-third of patients admitted to hospitals and up to half of infected outpatients in this pandemic had no fever, yet they were infectious.</p>

<p>And because it is likely that only patients with fever were tested for the presence of the virus, we greatly underestimated the number of people infected. A telling report from Britain showed that when children were tested in cross sectional surveys after the first wave of infection, one in three had antibodies to the virus, meaning that they had been infected — this was 10 times more people than estimated from clinical surveillance.</p>

<p>H1N1 posed huge infection-control problems, especially in hospitals. This was because it was found not only on hard surfaces in the environment, which is common to all influenza strains, but in the stool of patients, a feature of avian influenza.</p>

<p>Public health groups emphasized the necessity of frequent hand-washing, which surely helped reduce transmission. But those groups also disagreed on other preventatives: for instance, the World Health Organization and Society for Health Care Epidemiologists of America recommended the relatively inexpensive surgical mask, whereas the Centers for Disease Control and Prevention argued for the N-95 respirator mask.</p>

<p>In our own country, the virus struck at a time when Americans seemed particularly skeptical about our government and large institutions. The C.D.C. faced an uphill battle to characterize the trajectory of the pandemic, to define its impact, to offer suggestions and to convince a wary public to get vaccinated.</p>

<p>At times, health officials erred in their recommendations. C.D.C. authorities often said that ill children and adults could go back to school or work 24 hours after their fever disappeared — even though young children are contagious for up to three weeks and adults for 5 to 7 days.</p>

<p>It is not an easy task, but our public health authorities need to become clearer about the lexicon of uncertainty — what they know and don’t know about a pandemic. They also need to be transparent about how they devise their recommendations, which often have to balance between infection control and the daily activities of offices and schools. And we need to identify which social distancing techniques truly help control pandemics — for example, does the closing of schools and malls minimize the spread of viruses from infected children to adults?</p>

<p>One year after its appearance, we continue to have many unanswered questions about the virus. Will the novel H1N1 agent become a persistent seasonal virus? Can we produce vaccine more quickly by moving to a cell-based rather than egg-based method? Can we possibly identify the Holy Grail of influenza vaccination, finding a virus target common to all influenza A strains so that we can administer a single vaccination at 10-year intervals?</p>

<p>Even as we work to solve these enigmas, we can try to prepare better for future pandemics. First, we need to approach disease control not as individual nations, but as a global community. In this, Mexico has already set an excellent example. Only 10 days passed between Mexican health authorities’ recognition of a possible new epidemic and their announcement of it, a sharp contrast to the many months in 2003 between the outbreak of SARS in China and its public declaration.</p>

<p>Mexico’s transparency was a policy decision made with full recognition of the unfavorable economic consequences from H1N1, now estimated to have cost almost 1 percent of the gross domestic product. Thanks to that decision, we had an edge in fighting this virus. We should find ways to financially reward early reporting of novel infectious agents, while doing a better job of sharing resources and agreeing on common containment strategies.</p>

<p>Second, we should rely not just on governments for reporting but on the cooperative efforts of international health organizations as well. These groups should set up better sentinel reporting systems in places where new swine or avian variants are most likely to occur — wherever people and pigs or birds live closely together — so that they can identify new virus progeny quickly.</p>

<p>Eventually, we’ll also need to encourage farmers in developing countries to follow agricultural and safety practices that make it less likely that viruses will jump species.</p>

<p>One predicts influenza at his own peril, but it is likely that H1N1 will continue to cause sporadic cases. In some highly susceptible, unvaccinated populations it may even produce local outbreaks.</p>

<p>But the struggle between people and pathogens is a part of life itself. We cannot continue to be surprised every time a new virus emerges. Instead, we must use the lessons we’ve learned during the year since H1N1 arrived to develop more effective public health responses.</p>

<p>Richard P. Wenzel is a professor of internal medicine and a specialist in infectious diseases at Virginia Commonwealth University.</p>