U.S. Policy Regarding Pandemic-Influenza Vaccines
Chapter
2
Unlike a good deal of federally funded biomedical research, the work supported by the Department of Health and Human Services to develop new vaccines and new types of vaccine production is product-oriented. The objective of that applied work is to produce vaccines that are more effective and produced faster, more reliably, and in larger volumes than in the past. Rather than seeking to advance knowledge in the general hope that a cure or treatment might eventually emerge, HHS’s efforts are directed at taking vaccines through clinical trails to approval for use.
HHS is concentrating on three specific development areas: The first involves the constraints imposed by limited capacity for production, which could be overcome by the use of adjuvants, substances that can be added to a vaccine to boost its ability to produce an immune system response. If manufacturers can develop and use adjuvanted vaccines, they should be able to produce more doses of vaccine with current domestic capacity because each dose can contain a smaller amount of antigen, or active ingredient. The second area of research involves manufacturing influenza vaccines through cell-based technology, which now is in wide use for other kinds of vaccines. The third area focuses on long-term alternatives to current vaccines and their manufacturing processes. That work aims to develop next-generation vaccines, and it includes efforts to reduce the time necessary to produce large quantities of vaccine that would be needed in the event of an influenza pandemic.
Projects supported by HHS are in various stages of development. Some projects have not entered the clinical-trial phase; others in Phase III (the final stage of clinical trials) in the United States have been approved in Europe. HHS hopes to accelerate the typical drug approval process by funding clinical trials and testing to arrive more quickly at the licensing phase. Typically, clinical trials can last five to seven years (see Box 2-1). HHS is encouraging the development of vaccines based on H5N1 (the "bird flu" virus) and other currently circulating virus strains with pandemic potential so that manufacturers gain experience producing pandemic-like vaccines. Then, if a pandemic occurs, HHS hopes that within six months of onset, manufacturers will be in a position to deliver vaccines based on the correct virus strain.
Although this paper considers them separately, in practice it is difficult to distinguish the development of a vaccine from the development of its production facility. The regulatory process requires at least some of the vaccine used in Phase III clinical trials to be manufactured at full-scale production volumes in facilities that meet industry standards for manufacturing. The Food and Drug Administration must approve both the vaccine and the manufacturing facility.
The pandemic-influenza vaccine that is currently licensed in the United States at best offers poor to moderate protection against the H5N1 virus, even though a course contains 12 times the amount of antigen used to combat a single seasonal-influenza virus strain (Poland 2006). HHS therefore considers the H5N1 vaccine a good candidate for research in adjuvanted vaccines, which offer the promise of requiring smaller amounts of antigen per dose and provide some hope of protection against virus strains that are different from but related to the strain used to make the vaccine.
Successful development of adjuvanted vaccines could affect many aspects of HHS’s plan. If they are used with the older egg-based vaccines or with those produced by cell-based techniques, the success of adjuvanted vaccine could mean that a smaller stockpile could protect a larger number of people and that existing manufacturing capacity might be stretched to provide enough vaccine for a larger share of the population.
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Box 2-1.
Vaccine Development: Typical Time and Cost  On average, it takes a little over a decade for a drug to move from preclinical development to the marketplace, and it is an expensive undertaking. The cost for clinical trials alone—only a portion of the process—can exceed $100 million. The analysis presented here assumes that the schedules and costs of developing pharmaceutical drugs and vaccines are similar, although industry observers often focus on pharmaceutical drugs, which are chemically synthesized, rather than on biopharmaceuticals, which are derived from living sources. (Influenza vaccines, for example, come from viruses grown in hens’ eggs). The Web site of the Food and Drug Administration (FDA) explains the development process for vaccines.1 Development Timeline for a Vaccine
Before a vaccine enters human testing, the developer conducts laboratory (in vitro) and laboratory animal (in vivo) testing to determine whether the product will be safe enough for researchers to proceed to clinical trials. The developer must obtain the FDA’s approval to begin clinical trials through the submission of an investigational new drug, or IND, application. Clinical trials typically have three phases. Phase I focuses on the vaccine’s safety and generally involves fewer than 100 human subjects. The purpose of Phase II, which typically involves several hundred subjects, is to expand Phase I safety data and identify whether and at what dose the vaccine elicits a protective immune response. Phase III typically involves thousands of people and is used to document effectiveness and develop additional safety data (notably concerning the incidence and severity of side effects) required for licensing. Clinical trials generally last five to seven years. If all three phases of the clinical development are successful, the developer may submit a biologics license application, or BLA, to the FDA for review. If the FDA approves the application, the developer launches the new vaccine, a process that includes training its sales force and increasing production capabilities to meet the anticipated demand. Costs of Clinical Trials
Researchers at the Federal Trade Commission have analyzed the cost of clinical trials (Adams and Brantner, 2008). They report that drug trials can cost from $12 million annually at the 25th percentile to $26 million annually at the 75th percentile. That is, in 25 percent of the cases, the manufacturers spent $12 million or less; in 25 percent of the cases, they spent $26 million or more; and in 50 percent of the cases, they spent between $12 million and $26 million per year for a drug in clinical trials. The researchers also reported average spending per drug of $38 million per year (see the table to the right). The Cost of Clinical Trials for an Investigational New Drug, by Percentile
(Millions of dollars)
The researchers calculated that the total cost to take a drug through clinical trials ranges from $78 million at the 25th percentile to $166 million at the 75th percentile. They also reported that average spending (of $239 million) exceeded spending at the 75th percentile, which suggests that average spending is heavily influenced by a relatively small share of drugs that are very expensive to develop. (The Congressional Budget Office converted the published estimates, which were expressed in 1999 dollars, to 2007 values using the consumer price index for all urban consumers for medical expenditures. That index was used instead of the gross domestic product deflator or the producer price index because medical costs, including the costs of clinical trials, have risen much faster than the rate of inflation.) The cost of developing influenza vaccines is more likely to fall in the range between the 25th and 75th percentiles than it is to be comparable to average spending for drug development. Other types of clinical trials (those for some cancer drugs, for example) require expensive hospital stays for study participants or involve drugs that are expensive to manufacture. Clinical trials for influenza vaccines, by contrast, are relatively simple: In Phases I and II, subjects are given the flu shot; after a few weeks, laboratory tests determine the blood concentrations of antibodies to the virus, and subjects are assessed for side effects. In Phase III, subjects are given the injection and assessed later to determine whether they have become sick with influenza or have developed any health complications. Clinical trials account for something between one-fifth and one-third of the total costs of developing a drug. Other expenses include research and preclinical development; opportunity costs incurred by forgoing the return a developer might receive from a different investment; and the costs of drugs that do not proceed through the development and approval process. See CBO (2006b) for a review of pharmaceutical research and development costs. 1. See "Vaccine Product Approval Process," www.fda.gov/Cber/vaccine/vacappr.htm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The adjuvanted vaccines currently licensed for use in the United States—against diphtheria, tetanus, hepatitis A, and hepatitis B—are made with aluminum (Vogel and Hem 2004, p. 70). But aluminum adjuvants do not reduce the amount of antigen needed by enough to substantially increase the amount of vaccine that would be available during a pandemic. Some other influenza vaccines formulated with proprietary adjuvants—mainly emulsions containing special oils in water—have shown the ability to allow significant reductions in the amount of antigen required, however, and they might be sufficient to confront the challenge of an influenza pandemic. Even though some of those influenza vaccines formulated with proprietary adjuvants have been approved in Europe, the FDA’s approval is likely to require the manufacturers to supply additional data on the safety of adjuvanted vaccines. The FDA has not approved a human vaccine containing a new type of adjuvant in many years. Other types of adjuvants have thus far produced too many side effects to meet the FDA’s standards, and, in at least one case in Europe, an approved adjuvanted influenza vaccine had to be withdrawn because of its association with Bell’s palsy (Kenney and Edelman 2004, pp. 215–216).1 The FDA’s requirements for additional data are likely to increase the costs of development and delay approval.
HHS has awarded contracts, for a total of $133 million, to three companies (GlaxoSmithKline, Novartis Vaccines and Diagnostics, and Iomai Corporation) to support the development of H5N1 influenza vaccines with adjuvants (see Table 2-1). The contracts support work through Phase III clinical trials in the United States aimed at obtaining U.S. licensure for the products. Each company must provide its proprietary adjuvant for government-sponsored, independent evaluation with influenza vaccines from other manufacturers.
Egg-Based Pandemic-Influenza Vaccines, With and Without Adjuvants
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HHS Obligations
(Millions of dollars)
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Adjuvant
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Dose
(Micrograms)a
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Approval Statusb
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|
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|
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|
|
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|
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|
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Sanofi Pasteur
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0
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|
None
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90.0
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Approved in U.S.
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|
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Iomai
|
14
|
|
Proprietary
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45.0
|
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Phase II
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|
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GlaxoSmithKline
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0
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|
Aluminum
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15.0
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Approved in EU
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Novartis
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55
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|
Proprietary
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7.5
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|
Approved in EU
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|
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GlaxoSmithKline
|
63
|
|
Proprietary
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3.8
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|
Approved in EU
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|
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Sanofi Pasteur
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0
|
|
Proprietary
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1.9
|
|
Phase I
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|
|
|
|
|
|
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|
|
|
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Total
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133
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Source: Congressional Budget Office based on European Medicines Agency (2007a, b; 2008), HHS (2007a), Iomai (2008a, b), NIH (2008c), and Sanofi Pasteur (2007a, c).
Note: HHS = Department of Health and Human Services; EU = European Union.
a. All vaccines other than that produced by Iomai (which is administered as a combination of a patch and a single injection) are administered in two injected doses. A microgram is one one-millionth of a gram.
b. See Box 2-1 for a discussion of the various steps in the approval process.
Novartis is working on a proprietary adjuvanted H5N1 influenza vaccine that has demonstrated an acceptable immune response when administered in a course of two doses of 7.5 micrograms of antigen each, about one-twelfth the dose of the currently licensed H5N1 vaccine. In May 2007, the European Commission approved the vaccine for use in the event that a pandemic is officially declared by the World Health Organization or the European Union (European Medicines Agency 2007b). The manufacturer will produce a formulation that contains the influenza strain causing the pandemic. Novartis also sells a seasonal-influenza vaccine that contains the same adjuvant that is in its H5N1 vaccine. That formulation is licensed for use in most of Europe in people over the age of 64. Since its approval, about 30 million doses have been distributed (Novartis 2007, p. 39).
GSK also formulated a prepandemic H5N1 influenza vaccine with its proprietary adjuvant. (The vaccine, developed from a virus strain that has the potential to cause a pandemic, is called prepandemic because it would be produced before a pandemic begins. It is intended for use before or in the early stages of a pandemic.) The adjuvanted vaccine was documented to elicit an acceptable immune response when administered in two doses of 3.8 micrograms of antigen each, a 24-fold decrease in the amount of antigen required relative to the currently licensed pandemic vaccine (GSK 2007). In May 2008, the European Commission approved the vaccine (European Medicines Agency 2008). By the end of 2008, the company plans to submit the vaccine to the FDA for U.S. approval (Whalen 2008a).
GSK also has a pandemic-influenza vaccine formulated with an aluminum adjuvant.2 That adjuvanted vaccine, which was approved by the European Commission in March 2007, elicited an acceptable immune response when administered in two doses of 15 micrograms of antigen each, which is one-sixth the dosage of the currently licensed H5N1 vaccine (European Medicines Agency 2007a).
Iomai is developing a skin patch that contains an adjuvant for use in tandem with an injected vaccine formulation; the product is still in the early stages of clinical trials. According to the company, in a recently completed Phase I/II clinical trial, the combination vaccination elicited an acceptable immune response when administered in a single dose of 45 micrograms of antigen, a fourfold decrease in the amount of antigen required relative to the currently licensed pandemic vaccine (Iomai 2008b).3 Iomai announced in April 2008 that it is working with HHS on a budget for a new Phase II trial (Iomai 2008a).
Sanofi Pasteur currently is funding its own early clinical trials for a vaccine formulated with its proprietary adjuvant. The company stated that, in Phase I clinical trials, the compound elicited an acceptable immune response when administered in two doses of 1.9 micrograms of antigen each (Lewcock 2007c).
HHS has budgeted more funding for the development of adjuvanted vaccines even though only about $5 million of the $133 million obligated to date has been spent. Specific amounts have not been announced, but an agency press release stated that Iomai may receive an additional $114 million in funding upon successful completion of Phase I trials (HHS 2007).
Manufacturers could decide to develop two distinct vaccines: a seasonal vaccine without adjuvants and a pandemic-influenza vaccine with adjuvants. The benefit–risk calculus, and therefore the regulatory landscape, is likely to change in the event of a pandemic. Because of the lower risk associated with seasonal influenza, those vaccines are held to high standards: They must be absolutely safe; extremely well-tolerated; and elicit few, if any, side effects. By contrast, because the risk of illness and death from whatever virus causes a pandemic is much higher, a higher risk of side effects from a vaccine could be acceptable. Adjuvanted vaccines might also be used in the United States, as in Europe, for patient groups that do not respond well to the conventional vaccines against seasonal influenza (for example, elderly people).
HHS’s funding for the development of cell-based influenza vaccines is motivated by the potential drawbacks of egg-based production, particularly the need for large supplies of eggs (and the hens to produce them) and specialized manufacturing facilities. According to HHS, the domestic supply would be inadequate in the event of a pandemic, and the specialized manufacturing facilities are not easily duplicated. The egg supply also could be threatened by influenza viruses, including H5N1, that infect poultry flocks.
Cell-based vaccines use antigens from viruses grown in purified strains (or lines) of cells, for example, from the kidneys of dogs. Cell-based production technology is widely used to manufacture vaccines against polio, chicken pox, measles, mumps, and rubella. Policymakers at HHS believe that cell-based production could offer a more reliable and flexible method of producing influenza vaccines that can be scaled up to meet pandemic needs. Unlike eggs, which are perishable and must be ordered months in advance, cell lines can be kept frozen indefinitely, a benefit should it prove necessary to scale up a major manufacturing capability on short notice (HHS 2006c, p. 7).
Some industry analysts believe that HHS’s planning emphasis should not be on cell-based production because it does not substantially reduce production times (Matthews 2006). Rather, they believe HHS should focus on bringing next-generation vaccines to market. In addition, some of the cell lines that have the potential to produce large volumes of influenza vaccine also could cause tumors (Homeland Security Council 2006, footnote 16, p. 105).
To date, HHS has obligated $1.3 billion to promote the development of new influenza vaccines based on cell culture (see Table 2-2). The agency is contracting with several manufacturers in the hope of diversifying and expanding the supply of influenza vaccine for the United States. In the past, dependence on a few suppliers has contributed to shortages of seasonal vaccine when one or another has experienced disruptions in supply. In May 2006, HHS added to the $97 million contract signed earlier with Sanofi Pasteur when it awarded five contracts worth $1 billion in all. To reinforce the commitment, in November 2007 HHS extended its contract with DynPort Vaccine and Baxter International for another $201 million.
HHS’s Contract Awards and Development Status for Cell-Based Influenza Vaccines
|
|
|
|
Vaccine
|
||
|
|
|
Obligations
(Millions of dollars) |
Seasonal
|
Pandemic
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
DynPort Vaccine and Baxtera
|
242
|
|
Phase III
|
Phase I
|
|
|
GlaxoSmithKline
|
275
|
|
Preclinical Development
|
Preclinical Development
|
|
|
MedImmune
|
169
|
|
Phase I
|
Preclinical Development
|
|
|
Novartis Vaccines and Diagnostics
|
221
|
|
Phase III
|
Preclinical Development
|
|
|
Sanofi Pasteur
|
97
|
|
Phase II
|
Phase I
|
|
|
Solvay Pharmaceuticals
|
299
|
|
Phase I
|
Phase I
|
|
|
|
|
|
|
|
|
|
|
Total
|
1,302
|
|
|
|
|
|
|
|
|
|
|
Source: Congressional Budget Office based on Computer Sciences Corporation (2007), HHS (2005a, 2006b), NIH (2008b), Novartis (2007, p. 35), Program for Appropriate Technology in Health (2007, p. 13), Sanofi Pasteur (2007b), and WHO (2007c).
Notes: HHS = Department of Health and Human Services.
See Box 2-1 for a discussion of the various steps in the development and approval process.
a. DynPort Vaccine is the prime contractor; it manages the clinical trials. Baxter is developing the candidate vaccines; it will manufacture the vaccines and own all clinical data and licenses.
The manufacturers are at various points along the path toward approval for cell-based vaccines (see Table 2-2). Some have products that are still in preclinical development; others have cell-based vaccines moving through Phase III clinical trials. Novartis expects to submit an application for a U.S. license in 2008 for a seasonal-influenza vaccine, already approved in the European Union, and to make it available in Europe for the 2008–2009 influenza season (Lewcock 2007a). DynPort Vaccine is managing a Phase III clinical trial for a cell-based seasonal-influenza vaccine and a Phase I clinical trial for a cell-based pandemic-influenza vaccine, both developed and manufactured by Baxter (Computer Sciences Corporation 2007).
Rather than using an adjuvant to cut the amount of antigen needed per dose of vaccine, Baxter’s pandemic-influenza vaccine uses the whole virus. Whole-virus vaccines have been shown to be more effective than subunit vaccines that consist of just the purified proteins from the virus. However, because whole-virus vaccines also have been more prone to cause adverse reactions, all injectable seasonal-influenza vaccines licensed in the United States are subunit vaccines.
Baxter is developing another whole-virus, cell-based, pandemic-influenza vaccine that, according to the company, can be produced in three months instead of the typical six months (Ehrlich and others 2008; Wright 2008). Baxter’s production process for that vaccine is faster largely because it uses a "wild-type" virus (one that circulates in nature). Other companies first modify the H5N1 virus so it can be grown in eggs without killing the embryo; that modification and the associated safety testing take about two months. The disadvantages of using the wild-type virus include increased risks of infection among production workers and of the virus’s escaping the production facility. Thus, facilities for manufacturing wild-type vaccines must meet stricter safety standards than are required for seasonal-influenza-vaccine manufacturing. HHS’s contracts support the development of cell-based pandemic vaccines using modified H5N1, but not wild-type, viruses (see Table 2-2).
In general, the vaccines for which HHS is providing support are somewhere between Phase I and Phase II clinical trials (see Table 2-2). Phase II and Phase III studies take a little over two years each (see Box 2-1); submitting the product for the FDA’s review and launching it in the marketplace can add another year or two.4 So it is likely to be another six years before most of the companies that were awarded contracts from HHS can complete development of their cell-based influenza vaccines and bring them to market.
Results of a study by researchers at the Federal Trade Commission suggest that manufacturers’ expenditures for a single drug in clinical trials typically range between $12 million and $26 million per year, although clinical trials for some drugs can cost much more (see Box 2-1). Those estimates do not include the cost of failures or return on private investment. On that basis, for each successful vaccine, the additional costs incurred in the remaining four years for Phase II and Phase III clinical trials would add between $48 million and $104 million to what is already spent, with a median value of $84 million. On the basis of that calculation, the estimated remaining cost to develop 12 vaccines—one seasonal and one pandemic version of a cell-based vaccine for each of the six companies—is likely to range between $600 million and $1.2 billion.
The $1.3 billion obligated to date could be sufficient to ensure the development of cell-based vaccines. As of January 2008, the contracting companies had requested that HHS reimburse them for $160 million (roughly 12 percent of the total contracts). The contracts’ balance of $1.1 billion would cover the remaining costs of clinical trials, as long as those costs do not approach or exceed the high end of the estimated range.
The six months that it takes to produce egg-based or most cell-based vaccines could be too long to respond to an influenza pandemic: Past outbreaks have reached the United States within two to five months of emerging in Asia, and some experts believe that the increase in international travel could facilitate an even faster transmission from abroad. After the egg-based and cell-based techniques, the next generation of vaccine manufacturing, based on the use of recombinant-DNA technology, offers the prospect of increased efficacy, shorter production times, and perhaps broader protection against some or all influenza strains for years or even a lifetime (see Box 2-2), although the vaccines could be 10 years or more away from the market. HHS has yet to fund their development for use against influenza, in part because it has chosen to build on the decades of experience in using cell culture to produce other vaccines.
What Constitutes the Next Generation of Influenza Vaccines?
Vaccine manufacturers hope to make extensive use of recombinant DNA techniques to produce large amounts of vaccine more quickly than is possible with egg-based or cell-based production. Universal vaccines that protect against a range of strains—or perhaps all strains—could protect the population in advance of an influenza pandemic.
Recombinant vaccines are made by splicing antigen-producing genes into the DNA of another organism. The modified organisms then reproduce to provide bulk quantities of antigen (the active ingredient in the vaccine). Recombinant techniques are already in use to make vaccines against hepatitis B and human papillomavirus (CDC 2006, FDA 2006). The hepatitis B vaccine is made by splicing the genes that produce the antigen into plasmids—viruslike DNA molecules—inserting the modified plasmids into yeast cells, and then growing the recombinant yeast cells to produce more antigen. One manufacturer has a recombinant seasonal-influenza vaccine in Phase III clinical trials (NIH 2008a). However, most recombinant influenza vaccines have not yet advanced past early-stage clinical trials.
Even though many vaccines last years or a lifetime, people now must be vaccinated every year to maintain immunity against seasonal influenza. Current influenza vaccines target hemagglutinin, a protein on the surface of the virus, and the vaccines "train" the immune system to react to that protein. Because the hemagglutinin protein changes rapidly as influenza viruses mutate, however, the pattern the immune system tries to recognize is not the same from year to year. Scientists are investigating vaccines that target other proteins that do not change so rapidly and that are present in all strains of influenza. At least one company has reported promising results in Phase I clinical trials (Gray 2008).
However, HHS plans to award contracts worth $155 million for the development of next-generation vaccines (Robinson 2007). Even without contracts from HHS, several companies have been working on next-generation vaccines, sometimes with help from agencies within HHS, including the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC). One article in a medical journal in 2007 enumerated 29 next-generation influenza vaccines in development, concluding that the "pipeline for new influenza vaccines is robust" (Belshe 2007, pp. 746, 748). With one exception, however, next-generation vaccines have not advanced past early-stage clinical trials.
The funding of the development of cell-based vaccines and the expansion of egg-based capacity (discussed in Chapter 3) could solidify the hold of those technologies on the market for seasonal-influenza vaccine. Once plants open, it will be difficult for new entrants to compete, unless their costs are markedly below those of existing producers. Increases in capacity could saturate the market and drive down the price of seasonal vaccine, making the market less attractive to newcomers. New technology alone will not be sufficient to increase market share. The newer live influenza virus vaccine, for example, has not captured a significant portion of the market, even though it offers greater cross-protection against different virus strains. It also is administered as a nasal spray, rather than by injection, which can be a benefit to people who find shots unpleasant or painful.
To be sure, next-generation vaccines could replace egg- or cell-based formulations if they proved substantially better than current formulations. In some years, the seasonal vaccine does not confer good protection against seasonal influenza because the strains in the vaccine are different from the strains that happen to be circulating that year. The mismatch is the result of the long production timeline, which requires manufacturers and public health officials to choose the strains far in advance of the season. Some next-generation vaccines in development hold the promise of much-shortened production timelines, allowing for the decision about which strains to include in a given year’s vaccine to be made much closer to the flu season so as to reduce the probability of strain mismatches.
Even more desirable would be a vaccine that protects against all influenza strains. The hope is that someday it will be possible to be vaccinated just once for a lifetime of immunity against all strains of influenza.
If, in the end, the private sector does not find that next-generation vaccines are an attractive investment, then the federal government probably would need to supply well more than $155 million to bring the new formulations to market. The discussion of development costs in Box 2-1 illustrates the point: Getting one next-generation vaccine through clinical trials could cost well over $100 million, exclusive of the costs of capital or of the costs associated with the failure of a given vaccine to advance to the regulatory finish line of FDA approval. Because the principal characteristics of next-generation vaccines are still largely unknown, it is likely that there will be many failures, which will in turn drive up the costs of bringing those products to market. Moreover, because most next-generation vaccines are still in the earlier stages of development, additional research will be necessary before clinical trials can begin.
International Efforts at Funding the Development of Vaccines
The European Commission funds research on the development of influenza vaccines under its Sixth Framework Programme, which supports a multinational consortium of vaccine specialists who are trying to develop an H5N1 vaccine (Cordis 2007; European Commission 2007). The program announced a grant of $5.5 million.5 The schedule for the four-year effort calls for clinical trials to begin within two years. The effort is part of a longer program that has spent $102 million on all aspects of influenza research, not just vaccines, since 2001. Of that amount, $55 million has gone to research on vaccines, including some veterinary vaccines. Although CBO has not been able to ascertain the specific funding by individual countries’ ministries of health, a BBC News (2006) report stated that Germany is spending $313 million on vaccine development.
The adjuvant in question belonged to a different family of adjuvants than those discussed for use in a pandemic-influenza vaccine (Couch 2004; Mutsch and others 2004).
That vaccine is a whole-virus vaccine; seasonal-influenza vaccines licensed in the U.S. are subunit vaccines. Vaccines formulated from whole viruses can be more effective at lower doses, but they also generally cause more side effects (Fukuda and others 2004, pp. 346–347).
Phase I/II clinical trials combine the objectives of Phases I and II to examine both the safety of the vaccine and its ability to elicit a protective immune response.
Several research groups have examined drug development times, including Adams and Brantner (2006, 2008); DiMasi and Grabowski (2007); DiMasi, Hansen, and Grabowski (2003); and Struck (1996). However, some of that work tracked the development of drugs from as early as 1983, before the enactment in 1992 of the Prescription Drug User Fee Act (PDUFA), which has since been reauthorized several times, most recently in 2007. Many analysts, including Berndt and colleagues (2005) and Abrantes-Metz, Adams, and Metz (2006), concur that PDUFA and its reauthorizations have sped development.
Values shown are converted from euros at an exchange rate of 1.57 dollars to the euro, the average for May, June, and July 2008.
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