A Bird Flu Manhattan Project?
Vaccination to prevent viral and bacterial diseases is modern medicine's most cost-effective intervention. Vaccines to prevent the expected avian flu pandemic could save the lives of millions—if vaccine R&D were not in such a sorry state, as the result of an unfortunate confluence of biology and public policy.Several kinds of policies are responsible for our vaccine quagmire. The Vaccines for Children Program, for example, was a do-gooder innovation of the Clinton administration that disrupted market forces and dealt a blow to vaccine producers. Established in 1994, it created a single-buyer system for children's vaccines, making the government by far the largest purchaser of childhood vaccines—at a mandated, extortionate discount of 50 percent. And, as discussed below, regulators have been tough on vaccines, especially those that use the most innovative technology.We are woefully short of capacity for the production of a vaccine against a pandemic strain of flu, which cannot actually begin until we have it in hand and have performed various genetic manipulations so that it doesn't kill the chicken embryos in which flu vaccines currently are grown. An optimistic estimate is that there is sufficient flu vaccine capacity worldwide for approximately 450 million people—but that calculation assumes that two intramuscular inoculations of 15 micrograms each would confer protection, whereas recently developed experimental vaccines against H5N1 required two doses of 90 micrograms. That suggests that the true capacity might be closer to enough for only 75 million people. (The world's population is over six billion.)Another worry is that when a pandemic strain of H5N1 avian flu appears, virtually all of the world's flu vaccine development and production capacity might shift to producing a vaccine against it, which will leave us vulnerable to the non-pandemic strain(s) that causes the usual annual, or seasonal, flu. (The annual flu bug kills, on average, 36,000 Americans each year—even when we have an effective, widely used vaccine.) As Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, has observed, "The biggest challenge unequivocally is vaccine production capacity."Remedying that won't be easy: Currently, it requires five to six years (and a massive investment) to build and validate a new manufacturing plant to the satisfaction of regulators. Moreover, the currently available vaccines are made using half-century-old technology—cultivation of live virus in scores of millions of fertilized chicken eggs.There is some good news concerning vaccines, however, emanating from research laboratories. Several recent advances suggest ways to induce a potent immune response to the H5N1 strain... but our ability to translate these findings into commercial products is a long way off.Using genetically engineered common-cold viruses, two separate American laboratories have successfully vaccinated mice against various strains of H5N1 bird flu. Both teams used adenoviruses that were genetically modified so that they are unable to replicate and so that they incorporate the gene that expresses hemagglutinin, a surface protein of H5N1. In effect, these are adenovirus-flu hybrids. Injected into mice, various versions of the vaccines generated a potent immune response that consisted of both antibodies and activated white blood cells, and that protected the animals against a challenge by high doses of H5N1. Significantly, the vaccines were able to protect against viruses that did not match precisely the strains from which the hemagglutinin was derived. Conventional flu vaccines induce only antibodies, a limitation that requires new vaccines to be developed constantly to keep up with the mutating, evolving virus. The dual response in these new, experimental vaccines is important because it increases the likelihood that they will be at least partially effective against newly arising variants of H5N1, including a future pandemic strain readily transmissible between humans.Another recent development offers a possible method to enhance the immunogenicity of many different vaccines. Researchers at the University of British Columbia used genetic engineering techniques to incorporate into various viral vaccines two proteins that help cells of the immune system to process foreign antigens. They found that these proteins act as a potent booster, inducing the immunized recipient to produce greater numbers of immunologically active cells against foreign antigens also contained in the vaccines. In their animal model, in which a challenge of a potentially lethal dose of virus was administered after vaccination, one of their engineered vaccines "provided protection against a lethal challenge . . . at doses 100-fold lower" than controls that did not have the modification. Although these experiments involved viruses other than influenza, the technique is potentially applicable as well to flu and to adenovirus-flu hybrids.Scientists are also working on ways to boost the immunogenicity of vaccines by adding chemical ingredients known as adjuvants, which make it possible to use lower doses of the vaccine antigens themselves. Adjuvants are not specific to particular antigens but act in various ways to activate one or more components of the immune system. They may help to display vaccine antigens to appropriate antigen-presenting-cell (APC) types; to target particular intracellular APC compartments for optimal antigen presentation; or to induce appropriate APC maturation steps that increase the stimulation of T-lymphocytes, activate antibody production, and induce immune memory. France's Sanofi-Pasteur and Australia's CSI have begun trials of candidate pandemic vaccines that use adjuvants made of alum, an aluminum salt, the only adjuvant approved for use in humans in the United States, but California-based Chiron Corporation might have a more promising candidate. In clinical trials of an adjuvant called MF59, which has been incorporated into a candidate vaccine being tested for protection against avian flu strain H5N1, vaccine containing adjuvant was significantly better than vaccine alone at eliciting antibodies to H5N1. An important potential advantage of this adjuvant-containing vaccine is the discovery that it may offer protection against H5N1 even if the virus' cell-surface proteins change, or "drift," in a way that makes them slightly different immunologically. That suggests a viable, if not optimal, strategy to prepare for the pandemic: Stockpile vaccine against the current avian flu H5N1 strain, with adjuvant added to boost the immune response. Although it wouldn't be a perfect match to the pandemic strain, it might be useful as a first "priming" dose that could afford some protection until vaccine against the actual pandemic flu strain is available.However, MF59, used in European vaccines since 1997, has never been approved for use in a vaccine sold in the United States—at least partly because R&D on vaccines has become so unprofitable and unattractive that there has been little incentive to perfect a technology to boost their efficiency or to perform the expensive clinical testing necessary to license what regulators would regard as a new vaccine technology. Also, the addition to existing vaccines of an adjuvant—even one with a long history—would make a previously-approved vaccine a "new drug," requiring exhaustive testing (especially given that the products would be administered to very large numbers of healthy people).Various research groups are studying alternatives routes of administration of vaccines—intradermally, instead of via the usual intramuscular route, for example—in order to be able to use smaller dosages and/or to elicit larger immune responses. One study found that the dose of flu vaccine administered intradermally could be reduced to 40 percent of the usual intramuscular dose without compromising the immune response. Opting for a conservative strategy, British health authorities have ordered sufficient conventionally-produced vaccine against the actual pandemic strain to treat every person with the needed two doses. The limitation of this approach is that because production cannot begin until the pandemic begins and the virus is in hand, there will be a substantial lag—probably nine months at a minimum—until the vaccine is available. Why so long? The product must be shown to be reproducibly manufactured in batch after batch to high levels of purity and potency, and clinical trials performed and their results analyzed. Thus, although this approach is the most definitive in the long run, it would leave the population vulnerable to the first wave of the pandemic.In sum, the good news is that once we know the DNA sequence of the virus we can now "reverse engineer" flu virus and get a candidate vaccine into animal trials rapidly; various chemicals can be used to enhance the immune response; and we have good early prototype "subunit" vaccines that use only a single gene from the flu virus, can be grown in cultured cells instead of chicken eggs, induce both antibody-based and cellular immunity, and show a high degree of effectiveness at protecting mice against challenge with a variety of H5N1 strains.However, there are prodigious obstacles to translating these developments into a clinical setting, let alone into a commercial human vaccine.First, adenovirus infections are extremely common in children and adults, and if recipients previously have been infected with the particular adenovirus used in the vaccine (there are dozens of different strains that infect humans), they may be "immune" to the vaccine. In other words, they'll ward it off before it can carry out the "controlled infection" necessary to elicit immunity to the engineered adenovirus-flu hybrid.Second, some adenoviruses are thought to have the potential to induce malignancies.Third, the adenovirus-flu hybrid vaccines rely on the flu gene that expresses the viral surface protein, hemagglutinin, which is notorious for the antigenic "drift" or "shift" that enables the flu virus to elude vaccines. Thus, even with the advantage of being able to elicit cellular (T lymphocyte-mediated) immunity as well as antibodies, it's unclear how effective a vaccine against the current largely bird-specific H5N1 would be against an emergent pandemic strain.Fourth, mice are not little humans, and it's difficult to extrapolate with confidence the results of mouse experiments to humans. (Our ability to predict efficacy in humans would have been greater, had the investigators used transgenic mice engineered to have a human immune system.)Fifth, a published analysis of thousands of bird-flu samples taken from across southern China illustrates the difficulty of mounting an effective and proactive vaccine strategy against a possible pandemic strain (or even the bird-specific strains) of H5N1 avian flu. The authors concluded that the region, a reservoir of the virus for nearly a decade, has spawned divergent strains that have been spread as far as Russia and Turkey by migratory birds. That diversity makes choosing a vaccine strain(s) problematical. "The antigenic diversity of viruses currently circulating in Southeast Asia and southern China challenges the wisdom of reliance on a single human-vaccine candidate virus for pandemic preparedness," the authors wrote.Sixth, getting a vaccine production facility (which is very different in design from one that produces conventional, small-molecule drugs) up and running to the satisfaction of regulators currently requires 5-6 years and a huge financial investment, and we will need vast amounts of flu vaccine.Seventh, in the absence of a pandemic or of government-guaranteed vaccine purchases, that investment might be for naught.Finally, regulatory obstacles—especially where new technology is involved—are daunting. The notoriously risk-averse FDA has been especially tough on vaccines, continually raising the bar for approval. The agency required huge clinical trials—more than 72,000 children—of a recently-approved vaccine against rotavirus (a common, sometimes fatal gastrointestinal infection in children) in order to be able to detect even very rare side effects before approval. In fairness, one does need to be concerned about a new vaccine that is intended for large numbers of healthy people; even a rare but serious side effect in a drug administered to hundreds of millions of persons could have significant impacts. (Thirty years ago, the federal government attempted to administer "swine flu" vaccine to the 151 million Americans age 18 and over, but the program was halted after a small number of individuals suffered generalized paralysis following vaccine administration.)The challenge for regulators is to find an appropriate balance of pre- and post-marketing clinical trials that demonstrate that a vaccine can reduce the incidence of actual community-acquired infections or that use "surrogate" endpoints such as laboratory measures of antibody-mediated and cellular immunity as a measure of efficacy. In recent years, U.S. regulators too frequently have been overly conservative in their requirement, and also have rejected evidence of safety and efficacy from European and Canadian vaccine approvals and prematurely withdrawn life-saving products from the market because of mere perceptions of risk.In summary, government and private sector funding of high-quality research projects are bearing fruit. And the duplication of effort between laboratories is by no means undesirable: Competition in science, as in commerce, spurs innovation and efficiency. But the recent research advances leave us far from real-world solutions. Government both giveth and taketh away, and in recent years, the latter has dominated public policy. We need incentives for industry to develop the products that we need, and the FDA's gatekeeper function for new medicines should not be permitted to delay clinical progress unduly. The agency needs to develop and implement a plan for active collaboration on and rapid review of candidate vaccines. As has not been the case since World War II's Manhattan Project to develop the atomic bomb, we need a robust government-university-private-sector partnership (with cooperation on issues much broader than just vaccine development) to counter a universal and dire threat.Which strategies should we adopt? My answer is a wide variety simultaneously, and as expeditiously as possible. Our approach should be similar to the Manhattan Project's pursuit of various R&D strategies in parallel; at least three methods to enrich uranium for the needed isotope U-235 were developed independently, for example. In the end, the program developed both a uranium-based bomb (dropped on Hiroshima) and one that used plutonium (Nagasaki). The Manhattan Project was arguably the most ambitious and successful R&D undertaking in history, and the threat of an avian flu pandemic argues for a similar approach: numerous parallel strategies pursued on many fronts.Vaccines are widely acknowledged to have high "social value," but compared to therapeutic drugs their "economic value" to pharmaceutical companies is low. Because governmental misjudgments have caused market failures in vaccine R&D, government actions must be an integral part of the solution to rewarding the creation, testing and production of vaccines.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />