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September 16, 2005

Influenza: The Levee Is Too WeakMike the Mad Biologist

Regardless of who is to blame in New Orleans, there were two widely recognized facts:
  1. The levees would collapse during a sufficiently strong storm.
  2. Weather forecasters thought that New Orleans was due for a big storm that would breach the levees. It wasn't considered a matter of if, but when.
Despite all the warnings, nothing was done. The same thing is happening with avian influenza. While some disagree, the experts think that an avian influenza pandemic is a real possibility, and are furiously sounding the alarm (e.g., the NIH is not typically an alarmist organization, and is actually a rather cautious bunch).

If Bush wants some redemption for New Orleans, he could act on the influenza problem (and many of the solutions in non-pandemic years could be used to reduce the ~36,000 deaths per year in the U.S. from 'regular' influenza). There are several things he could do:
  1. Increase production capacity and stockpiles of antivirals. Lest you think this is the creeping hand of socialism, we already have a Strategic National Stockpile for all sorts of drugs.
  2. Increase the influenza vaccine production capacity. We're going to need a lot more chicken eggs and incubators.
  3. Refine the influenza vaccine. Right now, there is an H5N1 vaccine, but it requires two shots at high doses. Obviously, the more vaccine you need person, the more vaccine you need to produce. We need a better vaccine.
  4. Refine the production process. Currently, vaccine production is a long and laborious process involving innoculating chicken eggs. This means it takes a long time to begin production. The CDC every year makes an educated guess as to what the most likely influenza viruses will be months in advance because it takes so long to actually produce the vaccine. We need to develop the capacity to genetically engineer bacteria that produce parts of the virus that can be recognized by the immune system and stimulate a response (this is not far fetched; it is currently under study). Such a technology would enable producing massive amounts of vaccine quickly (and is also rapidly 'scalable'), as well as rapid shifting of the type of vaccine produced to meet changing threats.
  5. Internationally coordinate the response to influenza. Don't let Bolton near this. Why not get Clinton (Mr., not the Senator) involved in this? Whatever other faults he might have, he's liked internationally and he's a damn quick study. His talents are being wasted on Red Cross fundraising (people were going to do that anyway–a rare moment of optimism from the Mad Biologist).
Of course, doing all of this would require leadership and courage. He might actually have to spend some of that 'political capital' he was so fond of. He could start by convincing Sen. Stevens (R-Pork Barrel) to stop building bridges from nowhere to nowhere in the middle of nowhere, and instead spend some money on public health. Yeah, that will happen... Maybe if Halliburton went into the vaccine business...

Anyway, here's what some of the experts think (excerpted from ASM News Sept. 2005; subscription only):
Antiviral Drug Supplies Remain Thin, Vaccines Not Ready
“The number of human and animal H5N1 infections has been increasing,” says Osterholm, director of the University of Minnesota Center for Infectious Disease Research and Policy. “Small clusters of cases suggest that the virus may have come close to sustained human-to-human transmission, and H5N1 continues to evolve in the virtual genetic reassortment laboratory provided by the unprecedented number of people, pigs, and poultry in Asia.”
The chief concern is that H5N1 may be undergoing mutations consistent with an antigenic shift that will make human-to-human transmission efficient and a pandemic highly likely, if not outright inevitable. If those genetic changes occur in the virus, much of the world's population will be vulnerable because they lack immunity-unless an appropriate vaccine can be rapidly developed and made widely available.

Another deterrent to a pandemic would be to build a sufficient supply of antiviral drugs to treat the sick before such a vaccine is available. But supplies of such drugs are far from adequate . “This is a very real and, in my view, imminent threat that requires urgent action,” says Frederick Hayden, professor of internal medicine and pathology at the University of Virginia in Charlottesville, who soon will join the World Health Organization (WHO) in establishing a research network in Southeast Asia to study avian flu and other emerging pathogens. “ We really need a response that involves building the national stockpile of antivirals, and we need to continue to fast track the development of a vaccine .”

Virus May Be Shifting to a Human-to-Human Transmission Mode

While investigators could not prove that human-to-human transmissions are occurring, they expressed concerns--shared by local clinicians--that the pattern of disease changed in a manner consistent with this possibility . These changes further suggest that emerging H5N1 viruses are more infectious for humans.

Some public health officials say that the impact of a pandemic cannot be overemphasized. Osterholm, for example, thinks such a pandemic will damage the world economy. For instance, trade and travel would slow—in response to the effects of the virus and an effort to curtail its spread--while domestic transportation also would be reduced to contain local outbreaks. “The arrival of pandemic influenza would trigger a reaction that would change the world overnight,” he says. “Even if the U.S. is better prepared, there still will be substantial collateral damage here because of the collapse of the global economy.”

Influenza pandemics occurred in 1918, 1957, and 1968, with significant morbidity and mortality, killing hundreds of thousands of Americans, including more than a half-million in the 1918 pandemic. The mortality rate among patients infected with H5N1 influenza is more than 50%, nearly 10-fold higher than mortality rates during the 1918 pandemic, according to the Infectious Diseases Society of America (IDSA). Figures from the Centers for Disease Control and Prevention predict that even a “mild” flu pandemic could kill up to 250,000 Americans if the nation is ill prepared.

Some Experts Urge Stockpiling Drugs, Other Measures

Recently, IDSA president Walter E. Stamm sent a letter to Health and Human Services (HHS) Secretary Michael Leavitt warning that the growing number of cases in Southeast Asia warrants an urgent and immediate increase in the pace of the U.S. response. “
Our nation and the world remain unprepared for a pandemic of even modest severity,” he wrote. Moreover, “When the next pandemic hits, antivirals will be our only defense for at least the six to nine months it takes to make new vaccine. But right now, if Asia's bird flu or another strain turns into a pandemic, we'll be caught nearly empty-handed .”...

So far, the U.S. government has stockpiled only a little more than 2 million treatment courses of oseltamivir (Tamiflu), the neuraminidase inhibitor that has proved effective against H5N1 in tests, and is at least partly protective when administered to H5N1-infected mice. IDSA officials recommend stockpiling up to 84 million courses of this drug to treat the ill and as many as 40 million courses as preventive treatments for essential health care workers and emergency responders.

NIAID Director Anthony Fauci says there are plans to add to the antiviral drug stockpile, although “I cannot tell you the exact number, since it is under discussion,” he says, adding: “
The supply of Tamiflu is limited, since there is only one manufacturer (Roche), thus we couldn't get 300 million doses if we wanted to.” He also points out that “the clinical efficacy of Tamiflu in pandemic influenza is still uncertain. It is true that H5N1 is sensitive to Tamiflu, but the clinical experience with Tamiflu is with ordinary seasonal flu where it merely decreases by 1 to 2 days the symptomatic period. We do not know whether it will be a life-saving therapy in serious pandemic flu .”

Hayden acknowledges that oseltamivir has been used only in a small number of H5N1 patients in Asia--and used late--but says that other evidence from following seasonal human flu outbreaks indicates that a two-day reduction in symptoms among patients suffering from H5N1 flu could make a dramatic difference in the face of a growing pandemic. He estimates its use could cut hospitalizations by half, meaning a significant reduction in flu-related complications and deaths. “We need a much more robust stockpile than we have now, enough to treat at least 25% of the population,” he says. “Unfortunately, we are way behind right now .”

Stamm from IDSA points out that substantial antiviral stockpiles are being planned in the United Kingdom, France, Germany Australia, Japan, South Korea, New Zealand, Canada, and other countries.
He further says that the lag time involved in producing the required volume of such drugs coupled with the high demand from other nations will put the United States at a severe disadvantage unless the federal government acts quickly .

“We are concerned that resource limitations as well as uncertainties about the evidence are driving policy,” Stamm says. “The cost of a pandemic to the U.S. economy will be several hundred billion dollars, and direct medical care costs alone are likely to exceed $100 billion. In this setting, an antiviral stockpile will almost certainly be cost saving.”

IDSA estimates that it could cost up to $1 billion to purchase an adequate supply of drugs, “yet we have spent far more to protect Americans against threats such as anthrax or smallpox attack, which are far less likely,” Stamm says. “Measured against tens of thousands of American lives saved the cost of an antiviral response will be a bargain.

Other Plans, Other Complications Regarding Antiviral Drugs

Further complicating readiness efforts in the face of this impending shortage of oseltamivir,
the H5N1 virus appears to be resistant to amantadine and its sister drug rimantadine, two other drugs that ordinarily can be effective against influenza . Chinese farmers, acting in violation of international livestock guidelines, used amantadine widely in recent years to suppress flu outbreaks in poultry--a practice that may have abetted the development of resistance. In any case, the resistance to these lower-priced antiviral drugs means that they likely will not help in treating infected humans in the event of a pandemic...

H5N1 Vaccine Promising at High Dosages in First Clinical Trial

...Fauci points to another problem, namely fragility of the vaccine production industry. “Even with a six-month lead and maximized vaccine production, capacity is currently the limiting step; even at maximal production globally, there would not be enough pandemic vaccine,” he says. “For this reason, scientists, industry, health care workers, government officials, and the public need to address the fragile vaccine enterprise in a global manner--through research resources, industry incentives, and public education. One approach may be to address interpandemic influenza and pandemic influenza as a single challenge--the solutions of one can complement the solutions of the other.”

Posted by dymaxion at September 16, 2005 12:16 PM

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