Will New Vaccine, Better Science Deliver in Time to Stop the Next Pandemic Flu?

The US Department of Health and Human Services (DHHS) under the Bush Administration has begun to sketch out a blueprint - made public in November - for responding to the threat of pandemic flu. Roughly $4.7 billion out of a bit more than $7 billion in proposed spending is intended for vaccine development. That is much more than is earmarked for public health measures in the United States or in countries where the evolution of an easily transmitted and deadly flu is likely to occur first - and where some public health officials believe a pandemic might still be prevented from arising. The US Congress, too, is considering how it would prefer to spend billions for flu fighting. The source of this sudden urgency among policymakers is a bird flu - the avian influenza virus known as H5N1. Without really becoming human flu, H5N1 nonetheless already has claimed more than 60 human lives since 1997. That toll is more than half of the people known to have been infected. H5N1, therefore, meets two of the three criteria for a flu strain with potential to cause pandemic death: It's already deadly, and it's new to humans. How, when and even if it will acquire changes that make it easily transmissible among humans - and thereby capable of quickly spanning the globe - are open questions. In other words, the threat is real, but nobody knows just how real. Is a strategy weighted heavily toward vaccine development the best bet? Vaccine Race Has Begun Leave aside for the moment the vaccine-production infrastructure issues that have resulted in frequent regional shortages of vaccine for the seasonal flu, a comparatively predictable foe that arrives on schedule each year. Leave aside also the public health challenge of how to quickly get vaccine from the pharmaceutical plant injected into humans. What you're left with is that the scientific and clinical success of vaccine development itself is unclear. In part, success may depend on how much time there is to prepare. "In general, once a solution is identified - even if it's not a great solution - people channel a lot of money and time into that solution," says UCSF virologist Raul Andino. "That can inhibit the investigation of other solutions that are perhaps less developed, but that in the end may be the best to pursue." In a pinch, there may appear to be no better choice than to devote the bulk of resources to rushing a traditional, inactivated flu virus vaccine into production, and to shoring up the strategy by stockpiling existing antiviral medicines. See story here. Whether the vaccines will have a real impact on the pandemic is anybody's guess," Andino says. The vaccines currently under development are targeting an H5N1 strain that is nearly two years old. Initial reports indicate that one such vaccine elicits an immune response in humans, but that getting such a response requires about 12 times the vaccine dose normally used in the vaccines produced each year to combat seasonal flu. New studies are being launched in which a type of "adjuvant" - an irritant that amplifies immune response - is included in vaccine formulations. Seasonal flu vaccine is updated every year to keep up with genetic drift in circulating flu strains. Even without vaccination, the immune systems of most people might have some slight degree of immunologic memory to call upon to fight seasonal influenza strains, because related forms have been circulating in humans for a long time. H5N1 is likely to change significantly before it becomes easily transmissible among humans, and a vaccine produced from a strain that had circulated in birds years earlier might offer little or no protection. No one will have prior immunity. It is almost certain that any H5N1 vaccine would have to be continually updated, according to Andino, in a process similar to the way the seasonal flu vaccine is updated each year. "You can stockpile whatever you want this year, but it's probably not going to help you next year," he says. A goal of US policymakers is to establish a "surge" capability to produce enough vaccine for the US population within six months. If it is necessary to wait until a deadly, easily transmitted, human version of H5N1 is identified and isolated before an effective vaccine can be made, it is not clear that it would be possible to contain spread of the virus before it sweeps the globe. There are other production issues. In the short term, there will not be enough H5N1 vaccine of any sort, even if such a vaccine works to prevent illness and transmission of disease. In a November statement to the Foreign Relations Committee of the US Senate, Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, noted, "Current domestic capacity for the manufacturing of influenza vaccine can meet only a small fraction of the need projected for a pandemic response." The nation currently makes its seasonal flu vaccine using outdated technology, growing virus in chicken eggs in a time-consuming process. Some deadly avian strains, such as the one that killed about 40 million people in the 1918-1919 pandemic, cannot be grown in eggs - it kills them. Through a technology called reverse genetics, attenuated influenza virus vaccine strains can be developed, and these vaccine strains can be grown in mammalian cells in culture. However, the commercial production of any such vaccine is complicated by intellectual property and licensing issues. While reverse genetics might one day be used to obtain a new vaccine supply within six months, it will be several years before an adequate number of facilities to produce vaccine this way could go on line, according to Fauci, and success is not guaranteed. {pagebreak}

Fundamental Science Proposed

There is no agreement among experts as to when - or even if - H5N1 itself will become a human pandemic. But many are saying that a new, uncommonly deadly, easily transmissible human influenza with pandemic potential is certain to emerge eventually. If there are more years to prepare, there will be more time to better understand flu and the human immune response to it, and to develop more innovative vaccines, antivirals and new drugs to combat it. So far, there has been no inspirational call to arms for research scientists - nothing like a Manhattan Project, or JFK's request to ask oneself "what you can do for your country." What may emerge is a series of bureaucratically communicated solicitations for research proposals. But there is almost certain to be a large pool of research money available. Fauci has said that there is $400 million included in the proposed DHHS plan for the study of fundamental science questions related to flu, the sorts of questions researchers like to address at academic medical centers such as UCSF. There is a precedent in the nation's bioterrorism research program. After 9/11, millions of dollars became available to study diseases that had once been the cornerstone of the nation's biological warfare research program, with a few economically important diseases thrown in. Unfortunately, there was no space for flu researchers on that gravy train and, in Andino's opinion, the science that was funded was not always good science. "Flu, in my opinion, was a very important pathogen missing on the biodefense list," Andino says. When more money is made available to study a particular problem, good scientists do not necessarily switch scientific fields to study that problem, Andino explains. Instead, more money may be made available to lower-achieving scientists who already are working in the field. "Good scientists in general have already developed a way to address the problems they are most interested in," Andino says. "Shifting focus is risky." Andino is not a flu expert, but he has the experience of switching his focus of study from picornoviruses to flavoviruses. He says that he and his student now are "doing fine," but that there were a few lean years when he first switched fields. Andino is studying how genetic variants in the viral population that infects a single individual can play synergistic roles and contribute to the overall survival of the viral population and to the spread of infection. Most virus research and vaccine development focus only on the most abundant genetic variant. For his part, Andino hopes any new flu research initiative draws some of the best scientists who do not today work on flu. "I would rather you give some of that money to good scientists who may not previously have worked on flu directly, but who may contribute to conceptualizing new ways to view the flu problem," he says. Potential for Collaboration "Sometimes programs are put together in a way that is nothing like a group that develops naturally," Andino says. Even so, he is excited about the potential of collaborative research organizations such as the California Institute for Quantitative Biomedical Research, or QB3, to conceivably play a dynamic role in flu research at UCSF. Andino also believes UCSF could benefit from hiring a flu virologist whose work might be central to a collaborative UCSF effort. I think QB3 is bringing something very interesting to the scene - technology-based science with ties to industry. It could be positioned in the middle, bringing together virologists, epidemiologists, immunologists, x-ray crystallographers, experts in bioinformatics, mathematicians - people from many different disciplines who all recognize when there is a great contribution to be made." Links: UCSF to Host Scientific Symposium on Pandemic Flu on Dec. 12]