Stanford researchers tackling H1N1 virus on variety of fronts

- By Bruce Goldman

STANFORD, Calif. - A vaccine against the H1N1 influenza strain, which has crossed over from pigs to people in recent months, probably won't be available before this autumn. But ongoing research at the Stanford University School of Medicine promises to help public-health authorities come to grips with future influenza pandemics - and may prove to be useful against this one.

A common theme in this research is that it pays to look not just at the virus itself, but also to our responses, at all levels, to viral attack: how immune responses vary among individuals, what sorts of medical innovation could help to prevent pandemics entirely and how we should organize the collective public-health response to pandemics when they do occur.

While it's still too early to draw conclusions, so far the H1N1 outbreak has proved fairly mild, at least in the United States, said Mark Davis, PhD, director of the Stanford Institute for Immunity, Transplantation and Infection. "The next one could be more devastating." Even typical seasonal influenza strains kill some 36,000 Americans each year, he noted.

Davis and several Stanford colleagues have assembled a facility, called the Human Immune Monitoring Core, in which blood samples are subjected to thousands of assays - for immune cell counts, such as cells' ability to respond to different types of stimuli, levels of circulating immunity-related proteins in the blood and more. (A key source of samples is a study of older vs. younger people's response to the standard seasonal flu vaccine, led by Davis and Cornelia Dekker, MD, professor of pediatrics and medical director of the Stanford-Lucile Packard Children's Hospital vaccine program.) The goal is to figure out how these myriad molecular and cellular measures vary with the quality of an individual's responses to the vaccines, said Davis, who is also the Burt and Marion Avery Family Professor of microbiology and immunology.

"We're trying to define, at the molecular and cellular levels, what a normal response looks like," he said. "When you give people a flu vaccine, some respond vigorously, others not as much. We hope to find the parameters that predict who will respond well and who's at risk."

Davis said he thinks the expertise and data he and his colleagues are accumulating may also prove useful in guiding the development of future influenza vaccines. "We've tended to use vaccines based on what has worked historically and without knowing much about the way they interact with the immune system. They usually work, but sometimes they don't. New vaccines are here, but which is best? We think we can help get the answer."

The National Institutes of Health recently contacted Davis and asked him to propose - within 24 hours - additional projects that might relate to the H1N1 strain. He did, with the help of other Stanford colleagues, suggesting that "instead of looking only at vaccinated people, we can look at people who have actually contracted the H1N1 strain, to see how their molecular and cellular responses correlate with their overall ability to cope with the infection."

When a new vaccine targeting the H1N1 strain is available, perhaps as early as this September, "we'll be there monitoring responses to that, too," Davis said.

Even if that vaccine does arrive on schedule, there's no guarantee it will prevent future pandemics, and public-health authorities will have to remain vigilant. A couple of years ago, Nayer Khazeni, MD, an instructor in pulmonary & critical care medicine and an associate at Stanford's Center for Health Policy, developed with colleagues a mathematical model of a pandemic influenza outbreak in a place like New York City, based on the H5N1 or "avian flu" virus that is still causing concern among national and global health authorities. The team included graduate student David Hutton of the School of Engineering's department of management science and engineering, and Alan Garber, MD, PhD, and Douglas Owens, MD, both professors of medicine.

These researchers have since been adapting their model to predict both the course of the new H1N1 viral strain and how that course could be altered by various interventions, such as vaccination and antiviral drugs, Khazeni said. "We're able to compare different interventions and ask: Will it be cost-effective? Will it save lives?"

One intervention Khazeni said deserves careful study is the use of surgical masks, which block relatively large droplets of mouth or nasal secretions, vs. so-called respirators, which are more sophisticated (and commensurately more expensive) masks with much smaller pore sizes, so that even some aerosols are blocked. "This is sort of mind-boggling when I tell people who don't study influenza, but we don't know how influenza is transmitted," she said. "If it's by large droplets, surgical masks might work; if via aerosols, the more expensive respirators might be more effective." Khazeni and her Stanford co-investigators intend to compare the cost-effectiveness of the two types of masks.

Another area Khazeni is scrutinizing is the long-term use of antivirals as prophylactics. "Historically, most pandemic waves - peaks of infection in a given community - have lasted for about six to eight weeks. So, to be maximally effective for prevention, antivirals would also have to be given for six to eight weeks. But most clinical trials of prophylactic antiviral use have given the drugs only for several days." To investigate long-term prophylaxis, Khazeni's team has been conducting a meta-analysis: a mathematically rigorous teasing out of statistical and clinical significance (or the lack thereof) by pooling data from many trials whose outcomes, in individual trials, may have been too uncertain to draw firm conclusions about effectiveness and safety. Results of this analysis should be available fairly soon, she said.

Any large-scale influenza pandemic is going to leave hospitals short on a critical device: the ventilator, which assists breathing in instances of severe respiratory distress. Government studies have estimated a national shortage of almost 750,000 ventilators in the event of a serious influenza pandemic, said Matthew Callaghan, MD, a postdoctoral scholar in medicine who is affiliated with Stanford's Biodesign Program, a joint venture between the schools of Engineering and Medicine. Yet standard hospital models cost from $30,000 to $60,000 apiece, he said. "Even the stripped-down, portable ventilators found in ambulances cost between $4,000 and $6,000 apiece."

A Stanford team led by Callaghan - and including Joelle Faulkner, who is another biodesign fellow, medical student Dhruv Boddupalli and mechanical engineering graduate student William Bishop - has produced prototypes of a ventilator, relatively free of bells and whistles, that can be assembled from off-the-shelf components. It is tailored for a specific indication, acute respiratory distress, and would sell for as little as $300 to $600 per unit, Callaghan said. "We set out to create a device specifically made for stockpiling in the event of a pandemic. You don't need the functionality of the $50,000 model," he said. "It's cheap enough that, we envision, every hospital would be able to stockpile hundreds of these machines." They'd be disposable - one patient, one ventilator - with a shelf-life of about three years. The device, developed in part with funding from the Coulter Foundation and the National Collegiate Inventors and Innovators Alliance, is scheduled to go into animal testing (ironically, in pigs, whose lungs are similar to those of humans) in June.

Of course, the ideal is to have an effective enough vaccine and enough supplies of it so that no one will need ventilators. One challenge is that with a pandemic virus, where there has been no past human exposure, very high vaccine doses and a booster shot are required to induce an immune response. That in turn necessitates manufacturing huge amounts of vaccine material to cover an entire population for each new strain. Yet, Khazeni noted, current incarnations of the seasonal influenza vaccine don't use any adjuvants - substances that, added to many other vaccines in use today, stimulate immune response in general and therefore make the vaccines more potent, regardless of the particular infectious agent they're targeting.

David Lewis, MD, professor of pediatric infectious diseases, is collaborating with a biotechnology company, Burlingame-based Juvaris Biotherapeutics (on whose scientific advisory board Lewis serves), and Christopher Miller, DVM, PhD, a researcher at the University of California-Davis, to develop a new influenza vaccine that includes a novel adjuvant that appears to boost the power of existing vaccines. "There are many reasons that we believe this approach has great promise," Lewis said, "including the fact that it's very potent at augmenting not only B-cell or antibody-mediated immunity, but also the other, cellular branch of the immune system" that many vaccinologists think greatly enhance our bodies' ability to combat infectious agents even after they've invaded our cells. Lewis said he expects the new adjuvant to enter a Juvartis-sponsored phase-2 clinical trial this fall in conjunction with an influenza vaccine for older people. Although the approach won't be tested in time for use in the coming H1N1 vaccine, it could make a big difference in future responses to influenza pandemics.

Khazeni holds out hope that in a few years a "universal flu vaccine," now in early-stage human trials, will be available. Instead of targeting highly mutable surface features of the virus that change from season to season, and even within a single season, this vaccine takes aim at features that remain the same in every viable viral strain. "If it works, instead of getting a new shot every year, you'd need just one shot or two, plus maybe an occasional booster, that would protect you for your entire life," said Khazeni. "There'd never be a pandemic again."

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