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INTRODUCTION A major goal of the US Department of Defense (DOD) Transformational Medical Technologies Initiative (TMTI) is to develop countermeasures that will protect military personnel against bioweapons, including specific infectious-disease agents and toxins. An explicit TMTI objective is to respond quickly to such threats by producing an appropriate amount of an effective countermeasure—currently defined as enough material to treat or vaccinate 3 million personnel—within 12 months of identification of a specific threat. DOD officials call for TMTI programs to be up and running by 2014. Whether countermeasure development and production capacity will be situated directly in DOD, solely in the private sector, or jointly in DOD and the private sector remains to be determined. Achieving the goal may depend in large part on the availability of “manufacturing platforms” that are flexible and robust—capable of producing required quantities of finished products and capable of being redirected to make other products that address a particular threat. The requirements are all the more challenging because DOD has specified that countermeasures produced under the TMTI be reviewed and licensed by the Food and Drug Administration (FDA) before being deployed. Thus, an additional goal in identifying appropriate manufacturing platforms is to ensure that they can produce countermeasures that fulfill FDA criteria of safety and efficacy. It will also be necessary to identify the FDA review process that is best suited to such countermeasures, many of which would not be eligible for conventional clinical trials even if circumstances did not require accelerated review. The condensed timetable that is intrinsic to the TMTI program will probably require that countermeasures being produced under its aegis be put on a regulatory fast track. Because many of the pathogens that are likely to be used as bioweapons are highly lethal, the FDA “animal rule” comes into play in evaluating the efficacy of novel countermeasures because their efficacy cannot be evaluated in clinical trials. However, such candidate countermeasures may still be subject to safety testing in clinical settings. The TMTI’s condensed timetable is likely to drive countermeasure developers to pursue regulatory review at the same time as product-development efforts that include scaling up production. With respect to the likely review of TMTI countermeasures, it is instructive to look at how FDA officials annually evaluate changes in the trivalent influenza vaccine, which is reformulated to optimize activity against currently circulating variants of the influenza virus. The vaccine is reformulated each year, but consistency in the manufacturing platform and the cumulative experience in producing and using the vaccine over several decades make it possible to review and approve each set of reformulated products rapidly—typically within 30 days. However, as discussed later in this summary, there may be limitations on the precedent set by the influenza example. 1 1 Another potential precedent, the European Union’s so-called mockup vaccine dossiers for pandemic influenza vaccines, was noted during review. A regulatory authority essentially “preapproves” a pandemic vaccine on the basis of information provided on a surrogate influenza strain. 1

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The TMTI is focusing on several classes of countermeasures. Low-molecular- weight drugs 2 make up one class, but biologics were the topic of this workshop. In particular, the workshop focused on therapeutic proteins in the form of monoclonal antibodies (MAbs) and on vaccines, whose principal role is to prevent infectious diseases. Both classes are capable of blocking the action of toxins that may be associated with infectious agents. MAbs were selected for discussion because of industry experience in manufacturing them with a platform approach. Although MAb production is by no means simple, industry representatives say that procedures for making such proteins and then scaling up their production are relatively routine and reliable. Vaccines were selected for discussion because their development is less straightforward. There is less uniformity because of the wide array of vaccine types, including live attenuated or killed viruses, killed bacterial cells, purified polysaccharides and proteins, glycoproteins, conjugate molecules, and vaccines that consist of DNA molecules that encode specific proteins. TMTI Case For Versatile Production Platforms Brian Reinhardt, TMTI discovery deputy, and Darrell Galloway, director of the Defense Threat Reduction Agency Chemical and Biological Technologies Directorate, described a key goal of the TMTI program as fostering development and production of broad-spectrum countermeasures against genetically modified and other novel biological threats. In the face of a threat, it will be critical to have available adequate amounts of appropriate countermeasures for protecting or treating US troops. To develop particular countermeasures, Galloway stated, it is essential first to identify the threat agents that might be or are being deployed. During the preliminary threat-identification phase, the TMTI envisions taking advantage of analytic platforms in several DOD programs, particularly the DNA-sequencing and bioinformatics capabilities in the US Army Medical Research Institute for Infectious Diseases at Fort Detrick in Frederick, Maryland. Some threat agents may consist of familiar biologic pathogens; others might be novel or “unknown”—consisting, for example, of components derived from two or more microbiologic pathogens or of components that are genetically engineered for novelty. Galloway explained that the next stage of the countermeasure-development process, drug discovery, depends in part on identifying appropriate molecular targets in the threat agents and on finding appropriate chemical entities that can neutralize or inactivate them. This process will entail both analytic and empirical steps, including computer modeling, to determine which countermeasures are likely to be suitable for the particular threat agent at hand. The TMTI expects that the countermeasures themselves will be produced to meet FDA good-manufacturing-practice standards and that enough will be produced at appropriate dosages to treat or to vaccinate several million US troops. (In some cases, that figure was presented as 3 million doses; in others, TMTI representatives mentioned producing quantities that could be used to treat 300,000 US troops. Dosing requirements 2 Small molecules that can be synthesized chemically. 2

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are uncertain because in some cases people might be treated with multiple doses of a vaccine or therapeutic product. Furthermore, the use of adjuvants with vaccines can allow lower doses.) Those figures are tentative and subject to refinement, according to Galloway. In part, they are from figures developed through a separate program in the DOD Defense Advanced Research Projects Agency (DARPA), which specifies a timeline of 12 weeks for producing enough of a specific countermeasure to treat 3 million people. That DARPA program is exploring characteristics of rapid countermeasure production and has been focusing on plants, fungi, and bacteria as means for producing countermeasures. Discussion Of TMTI Efforts In discussion, Galloway said that one TMTI scenario is a single countermeasure- production facility with the capacity to produce appropriate quantities of 5 to 10 molecular entities per year; they could include MAbs, vaccines, and low-molecular-weight therapeutics. Such a facility could cost a few hundred million dollars to build and substantial amounts to maintain; therefore, the TMTI is analyzing alternatives before committing to that scenario. He also described the countermeasure capabilities in the TMTI as including some 40 separate projects, some of which operate with great rapidity. One goal is to integrate the separate projects to enable them to operate more efficiently in the overall countermeasure- discovery process. Galloway said that DOD expects some products to be produced and then stored and anticipates that some of these products will have shelf-lives of many years. There was some debate among workshop participants about whether products needed to be stable for many years and whether, instead of storing products for many years, robust production technologies could be used to meet supply demands on short notice, perhaps by holding appropriate precursors in storage so that they are ready for rapid end-product manufacture. Some participants suggested that the latter approach provides an advantage—instead of relying on stored products, the TMTI program could specify short-term production of an alternative, possibly upgraded countermeasure, allowing for adjustments that take into account recent technical or scientific advances—and likened the adjustments to what happens each year when the seasonal influenza vaccine is produced. However, Harry Greenberg, senior associate dean for research at Stanford University, said that the analogy does not fit the situation that the TMTI faces in that experience with the influenza vaccines covers at least 40 years of regular use in human populations, whereas the substitution of a new countermeasure for one that is only slightly older could not have built up a comparable clinical record. Other participants, such as Edward Arcuri, chief operating officer for VaxInnate 3 , said that FDA officials are likely to scrutinize novel products derived from novel technologies more closely than products or processes that are considered proven and with which they have established “comfort levels”. Similarly, David Robinson, vice president for bioprocess research and development at Merck, said that there are slightly different issues to deal with in developing countermeasures against familiar pathogens as opposed to countermeasures that will need to 3 Edward Arcuri is now at Novartis Vaccines and Diagnostics, Inc. 3

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be both safe and effective against biothreat “unknowns”. Furthermore, even in dealing with surrogate markers for familiar pathogens, it is important to understand their pathology. Stephen W. Drew, of Drew Solutions and Science Partners LLC, pointed to several issues that should be noted for further consideration: how to choose countermeasure discovery and production platform, how to integrate such platforms, how to assemble a cadre of people to use and maintain the platforms, and how to keep the people up to date so they are prepared when called on to adapt the platforms to new demands. PLATFOMS FOR LARGE-SCALE MONOCLONAL ANTIBODY PRODUCTION Brian Kelley, senior director of bioprocess development at Genentech, and Dane Zabriskie, vice president of process development at Amgen, described similar processes for producing MAbs on an industrial scale for human health applications. Kelley said that large-scale MAb production processes are consistent and reliable, so they are more likely than an altogether novel approach to be used for producing therapeutic materials to meet the timetable specified by DOD under the TMTI. Except for minor differences in detail, Zabriskie generally agreed with Kelley about the feasibility of using MAb production platforms. However, both raised questions about the efficacy of MAbs as countermeasures against pathogens used in bioweapons. The details of their presentations and the discussion that followed are described in the next few pages. Presentation by Brian Kelley Genentech produces five FDA-licensed recombinant MAbs in four US facilities and a fifth being built in Singapore. Operations in all five facilities are based on large- scale mammalian cell culture, as are those of other large-scale MAb manufacturers, according to Kelley. In all, FDA has licensed more than 30 MAbs for clinical applications. It is important to note that except for one product, marketed as Synagis (a MedImmune product to protect infants against respiratory syncytial virus), currently licensed MAbs are not used for treating infectious diseases. Instead, most licensed MAbs are aimed at mainly chronic diseases. Kelley framed the TMTI challenge partly as requiring manufacturing capacity to produce one million doses of antibody in less than 1 year or, in other terms, to produce on a 1,000-kg scale. Adapting the process quickly to cease making one type of MAb and start making another remains challenging, but the scale of MAb production is no longer considered a limiting factor. Indeed, during the last five years, improvements in productivity, including modification of mammalian cells to yield high-titer MAbs and then refinement of later-stage processes to purify them with greater efficiency, were so successful that the overall commercial capacity for producing MAbs exceeds current demand. The Genentech approach to producing MAbs depends on several key elements, including the use of well-defined Chinese hamster ovary (CHO) cells; defined and consistent growth media and other materials, such as formulation buffers; standardized 4

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analytic technologies; a consistent purification process; and cumulative experience in refining and working with the production platform. Typically, once a particular recombinant MAb can be produced stably in a newly re-engineered CHO cell line, seed cells are introduced into a bioreactor for a 12- to 14-day batch-production cycle during which the product titer rises to about 2 g/L. Production can then be scaled up. For example, a facility equipped with six 15-kL bioreactors could produce about 4 tons of MAb products per year, according to Kelley. One key technical drawback with respect to meeting TMTI timetables is that it typically takes four months to transfect, adapt, and select a modified CHO-producer cell for each new MAb entering production. Moreover, it may take a month to build up the cell-production stock for full-scale use. More time may be needed on the front end to identify at the molecular level appropriate criteria for the particular MAb being produced. However, if the MAb is based on antibodies obtained from a human who survived exposure to a specific threat agent, it might be possible to speed up this early phase. There are other technical issues to consider, including whether IgG1 effector functions are sought, in which case the MAb will not perform properly unless it is appropriately glycosylated (modified by the addition of carbohydrates), and whether a particular MAb, because of its genetic sequence, will be “humanized” and also optimized for affinity. Such refinements can add several months to the early phase of development during which cells are being optimized for production. In general, according to Kelley, the overall time to develop and produce a MAb is 14 months if no time to optimize the cell lines or other components of the process are included. During this period, a producer would also need to be working with FDA officials for the purpose of evaluating and licensing the final product, and also for certifying the production process insofar as is necessary. Kelley stated, in part because of such regulatory issues, it seems preferable to keep to the current, fully vetted approach to producing MAbs instead of switching to an alternative process. He noted that one potential way to shorten the current production timeframe—applicable only to threat agents already identified—is to develop a series of CHO-producer lines that could be stored for production use when needed. In the event of an emergency in which DOD requires a particular countermeasure for treating US troops, it could be difficult to build and bring on line a new manufacturing facility to meet TMTI requirements, according to Kelley. He argued that it seems better to have a production facility that is poised for what he and others call a warm start, that is, ready to begin producing specified MAbs as soon as appropriate seed cells are provided. Such a facility might be a dedicated DOD facility that is already up and running. Alternatively, TMTI, through its commercial partners, might draw on the excess production capacity that is now in place in the private sector. In a fast-start or emergency production scenario, it might be possible to use disposable bioreactors, which are now being designed in the 2,000-L range, according to Kelley. Another potential drawback with respect to meeting TMTI goals, according to Kelley, is that, for these early developmental steps en route to producing MAb countermeasure products, specific vectors, media, and tailored host cells tend to be covered by patents and thus raise intellectual-property (IP) issues. However, he believes that forging partnership and licensure agreements could overcome many or all IP-related obstacles. A nontechnical issue to address is that a fully outfitted large-scale production 5

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facility typically can cost as much as $800 million to build—a figure that is considerably higher than those mentioned by the TMTI. Kelley summed up his presentation by concluding that product finish-and-fill issues and stability and safety questions pose fewer challenges than does the central question of determining the efficacy of MAbs that are produced as countermeasures against bioweapons. Assuming that phase 1 clinical-safety studies are required to satisfy FDA regulatory review, it could prove challenging to complete them within the specified product-delivery time; subjecting an MAb that targets an infectious agent to regulatory review by FDA as a test case would be a valuable exercise for determining how to approach that hurdle in the event of a genuine emergency. Kelley suggested that the public–private partnership forged during World War II to produce penicillin might be a useful model for the TMTI to consider. Presentation by Dane Zabriskie Amgen has four major manufacturing facilities, each equipped to produce MAbs on a 15-kL scale, and the company product pipeline includes more than 60 candidates, many of them MAbs, according to Zabriskie. The average time from gene construction to receipt of an investigational new drug (IND) approval for a MAb is 12–18 months. Zabriskie pointed out that several features of Amgen’s approach to selecting and producing MAbs are distinct from Genentech’s and might help to accelerate production. For example, Amgen uses a “XenoMouse” in which the murine genes involved in antibody synthesis have been replaced with their human counterparts, so the antibodies produced are fully human rather than murine. Moreover, the company uses high-throughput robotic procedures to identify MAb-producing cells that will work with high efficiencies in later bioreactor steps. Although the largest known bioreactor for growth of mammalian cell lines is thought to be the 25-kL vessel at Genentech, Zabriskie predicts that efficiency gains at the cell level and at other stages of MAb production between now and 2014 could mean that smaller bioreactors will be sufficient to meet TMTI-specified production goals. The overall yield of 10 MAbs that Amgen had in development as of 2005 varied from 40% to 80%; it was about 70% for most of them. When the process is scaled up to use 15-kL bioreactors, recovery is as high as 80%, for a yield of 4 g/L. Production efficiencies are improving; the cost of finished MAbs continues to drop and is expected to fall below $1,000/g soon, and with the cost of building a production facility with four 15-kL bioreactors and other equipment needed for finish-and-fill of final products about $1.8 billion—higher than some estimates. Several steps in the production of clinically useful MAbs are considered routine by those working in this field, but technical challenges are expected to arise for each new product, according to Zabriskie. That expectation reflects the intrinsic heterogeneity and complexity of such molecules. For instance, the behavior of MAb proteins on cation- exchange columns, although often tractable, can prove unpredictable, reflecting heterogeneity in the surface charges of some of the proteins. Other sources of heterogeneity—including additions of sugars, oxidation, and deamidation of various amino 6

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acid side chains—change physical properties and could affect safety and efficacy. Product sponsors may be required to address such issues. FDA officials routinely consider some 30 attributes of MAbs in their regulatory evaluations and for continuing quality-control purposes to characterize product lots for consistency after licensing. Zabriskie noted that stakeholders are working with FDA to establish acceptable critical quality attributes (CQAs) for raw materials and for process characteristics that could help sponsors and regulatory officials when they are using risk- management tools. FDA defines CQAs as factors that could affect the safety or efficacy of a biologic product; translating this broad definition into specific examples is a major challenge now facing the industry. For MAbs in particular, companies are determining whether minor changes meet the CQA threshold or are incidental to product safety and efficacy. The 12- to 18-month timeline cited by Zabriskie starts with gene construction and ends with IND approval. In contrast, the overall development time from initial discovery to approval and manufacture of a therapeutic product ranges from 10 to 15 years, according to Zabriskie. The first seven years focus on in vitro and in vivo preclinical development and formulation of a product, including initial safety assessments. The next eight-year phase depends in large part on clinical development and evaluation and is very much “clinically driven.” If TMTI products will not be subjected to traditional clinical-efficacy trials, the required safety and pharmacokinetic clinical trials could be completed in 7–12 months, according to Zabriskie. Nevertheless, determining the appropriate molecular targets for effective use of MAbs as countermeasures against particular biothreat agents is a time- consuming step—one that could take up to six years to complete, according to Zabriskie. Zabriskie offered several recommendations:  Work closely with FDA to determine whether a clinical-safety platform could be established that would apply broadly to countermeasures being developed.  Focus attention on the drug-discovery process to make it faster and better able to predict the efficacy of novel countermeasures in humans.  Accelerate the development of MAb cell lines to take less than the usual 6–12 months.  Validate process platforms.  Determine how to accept CQAs for MAbs as a class instead of case by case.  Reframe the regulatory process for MAbs for DOD-related products to take into account the special circumstances surrounding biodefense situations. Zabriskie framed the overall analysis of MAb readiness for the TMTI as a series of 10 critical readiness issues. He was optimistic about whether the platforms can produce most of the antibodies of interest; about the ability of platforms to lower costs of development, scale up and operation, and construction; and about the existence of a “common logic” in the industry. He was skeptical about whether CQAs can alone define safety and efficacy, saying that identification of a new regulatory approach for biodefense MAbs is most important. His outlook on the idea of producing supplies in 7–12 months is somewhere in the middle: have an early product serve as a surrogate for others and gain earlier FDA approval by using platforms. 7

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Discussion The workshop participants discussed whether it was reasonable to expect MAb production to supply TMTI-estimated needs, how to increase efficiency and reduce the timeline for producing necessary product, and industry versus government manufacturing facilities and the impact of issues beyond mere production capability. Suitability of Platforms and Supply Needed MAb production platforms appear suitable for supplying TMTI-estimated needed quantities of MAbs, according to Phil Gomez, of PRTM. Nonetheless, he recommended that the capacity issue be refined in terms of estimated doses that will be required to treat affected US forces. For instance, despite references to producing 1 million doses, enough to supply 1 g/soldier, it might be more realistic to speak in terms of milligrams per dose of some products. Participants noted that overall efficiencies might rise if effective doses were lower than the original assumption. Mark Schenerman, vice president of analytic biochemistry at MedImmune, said that that will affect planning for production facilities and manufacturing capacity and that product requirements might be reduced further if a product is packaged and stored in disposable units. However, he also noted that refining dose requirements would depend on what soldiers were exposed to. Reducing Timeline After discussing overall capability, workshop participants reviewed options for reducing timelines during the early phase of manufacturing. One approach would be to set up pools of cloned cells (a mixed population of cells, all producing the same antibody) at the early phase in which CHO cells are transfected with DNA that specifies which MAbs the cells are to make. Establishing pools of such cells might allow for selection of particular producer cells of higher efficiencies, and that choice might speed the overall production process. Jonathan Coffman, of Wyeth BioPharma, suggested that such a scenario may result in the manufacturing of 100,000 doses within about 100 days of the initial CHO-cell transfection. One idea raised was the use of “transient” transfectant cells to speed early steps toward production. A drawback to that approach is that such cells tend to be unstable; this is why they are used at Genentech for research and development but not for production, according to Kelley. Zabriskie suggested a situation in which several MAbs against several potential pathogen targets could be made simultaneously and assessed in combination during the early phase of development, whereas selection for the most appropriate MAb in the mix would be delayed until much later in product development. In another option to cut time, Kelley said that MAb-producing cells that target known pathogens could be produced and banked for later use in the case of an emergency in which one or more of the specific pathogens were being deployed against US troops. Most of the discussion centered around using mammalian cells to produce MAbs, but the group also discussed whether production timelines could be condensed by 8

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producing MAb molecules from Escherichia coli cells—a process that can speed production compared with the use of mammalian cells. Amgen has developed a “peptibody” product platform that combines a ligand-binding domain with the Fc domain of an antibody. The antibody-like products are produced in E. coli, according to Zabriskie. However, Kelley said that overall time savings through use of bacterial cells or similar alternative production sources are unpredictable, particularly because current purification procedures were developed on the basis of making MAbs in mammalian cells. In addition, bacterially produced MAbs would lack effector functions. In connection with the previous discussion of nonmammalian-cell platforms for producing MAbs, Greenberg said that FDA has dealt with about 30 MAb products that were produced from mammalian cells. The cumulative experience makes this platform attractive regardless of alternative approaches that depend on bacterial or other cells and that might speed some phases of the production process. Placing the discussion of mammalian cell efficiencies in perspective, Kelley estimated that time savings from implementing even several of the refinements would be around 10–20%, not 50%, for overall production of MAbs. Manufacturing Production Capacity Moving beyond the discussion of whether MAb platforms in general are capable of meeting the TMTI’s needs, participants discussed manufacturing facilities. Several discussed the pros and cons of the government’s building its own countermeasure- production facility, which might be used by industry when it is not needed for TMTI production purposes, as opposed to leasing space in privately owned facilities. Participants discussed the merits of having a specialized MAb-production facility poised for action—what some called the warm-start option. In particular, Coffman pointed out that it would be helpful to have a team of skilled producers on hand who could keep in practice, perhaps by making about five MAb products per year. Gomez said that building a small, more flexible facility might be a way to give DOD experience in making a variety of countermeasure products. Michael Ascher, of the University of California, Davis, and other participants asked whether industry could reserve MAb-production capacity for the TMTI to use in emergencies—for example, by maintaining extra capacity that would be kept “in tune” or up to date through intermittent use. Kelley and Zabriskie said that companies already have excess production capacity that could be drawn on as needed in a national emergency. To prepare for such emergencies, a participant suggested that the federal government should consider forming partnerships with companies and begin producing MAbs that target known pathogens as part of a preparedness exercise. Such partnerships and production runs could also be used to train personnel, providing them with the skills needed to conduct such large-scale, specialized production operations. 9

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Regulatory Issues The group discussed what Peter A. Patriarca, of Biologics Consulting Group, Inc., described as generally more time-consuming than production: consideration of safety and efficacy. Because postproduction regulatory issues might slow the approval process for countermeasures that the TMTI is seeking, several participants suggested that DOD consider investing in research that addresses the CQA issues outlined by Zabriskie above. Participants also noted that the FDA sponsors workshops that include exercises in which product sponsors submit mock IND filings to the agency as a way of gaining experience that can be used in shepherding real products through regulatory reviews. Specific safety and efficacy issues discussed are highlighted here. Safety Participants described regulatory consideration of MAb safety. Specifically, Zabriskie noted that the regulatory agencies focus on rare adverse events and on safety issues of theoretical concern in addition to the conventional ones, and Coffman pointed out that in his experience MAbs directed against human antigens fail safety and toxicity tests in about one-fourth of the cases. MAbs directed against nonhuman, nonanimal targets are less likely to have toxic side effects, although some tissue cross-reactivity can occur. Coffman suggested that DOD set up toxicology testing facilities to test any product quickly. Tissue cross-reactivity studies could also focus on antigens often seen in autoimmune disorders. A few specific types of possible risks posed by MAbs 4 were mentioned, but overall the discussions focused on how to make the consideration of risk efficient and appropriate. Galloway noted that the DOD mandate for the TMTI calls for providing medical countermeasures for use by the “war-fighting community”, not the general public. Such circumscribed use could influence decision-making about the safety of such products. Griffin Trotter, of Saint Louis University Center for Health Care Ethics, said that risk profiles of products should reflect whether soldiers need the countermeasures for an actual attack or need them for the possibility of a future attack. Leslie Benet, of the University of California, San Francisco, and other participants said that political pressure should be applied to FDA to ensure that development of MAb countermeasures has “no- fault” status. Other participants suggested that DOD make its case to FDA by presenting an analysis that emphasizes the value and benefit of such products over the risks that they pose. Robinson said that establishing a standard risk-benefit ratio for countermeasures would be helpful, but whether products for DOD could be held to different standards than those produced for the general population is a tricky issue, in part because of liability questions but also because of the possibility that negative publicity of any kind could damage corporate reputations. Zabriskie said it would be helpful if FDA would serve as a forum for exchanging otherwise proprietary information about experiences with MAbs and vaccines, and thus for developing a better and shared understanding of “best practices” within these industry subspecialties. Fred Murphy, of the University of Texas Medical Branch at Galveston, 4 MAbs directed against human targets, potential cross-reactions if soldiers receive both prophylactic vaccines and post-exposure therapy. 10

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suggested that DOD, the National Institutes of Health, and the Centers for Disease Control and Prevention could also be involved in providing such a forum. Efficacy Although safety is important, the major issue concerning MAbs is efficacy, according to Zabriskie. Indeed, Ascher said that MAbs, when tested, have failed as potential countermeasures against several pathogens that might be used in bioweapons. MAbs were selected as a main subject of this workshop not because of their potential efficacy but because their production in a platform process is relatively well worked out. When the value of using MAbs as countermeasures against exotic, unknown, or synthetic pathogens was questioned, Galloway noted that TMTI and other agencies of the federal government are looking at many platforms and products to produce effective countermeasures. Denise Faustman, of Harvard Medical School, and James A. Marks, of the University of California, San Francisco, raised the possibility of using polyclonal instead of monoclonal antibodies for counteracting pathogens. However, that approach could complicate regulatory reviews, particularly if a bank of several dozen MAb-producing cell lines were used to make the polyclonal-antibody mixture, according to Kelley. PLATFORMS FOR VACCINE PRODUCTION Presentation By David Robinson Merck has been producing vaccines for more than 100 years. There are many varieties of vaccines, and they now include attenuated or inactivated viruses and bacteria; subunits made of polysaccharides, recombinant subunits from protein conjugates, and virus- like particles; and antigen-encoding vaccines consisting of plasmid DNA or modified adenoviruses that depend on cells in hosts to generate appropriate immunogens. Other companies are developing a baculovirus-based platform for making vaccines. Merck recently built a pilot plant that incorporates several vaccine-production platforms, including a newer yeast-cell–based production system that is used when necessary for making glycoprotein immunogens. Within that facility, two platform systems can be run simultaneously in separate suites, and it is also possible to switch relatively quickly from one operation to another in the same space. No platform process can cover the whole array of vaccines, according to Robinson, but DNA vaccines can be made from a single platform, and they can be used for producing a wide array of immunogens. Merck has not proved the clinical efficacy of any DNA-based vaccine product, but other producers are reporting success with DNA-based vaccines, including one that protects horses against West Nile virus and another that can protect salmon against a viral disease. Similarly, the array of adenovirus-based vaccines is amenable to platform production, and genetically modified adenoviruses can elicit both cell-based and humoral immune responses in human hosts, according to Robinson. He explained that one problem 11

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with an adenovirus-based approach to making vaccines is that many humans are already exposed to serotype 5 of the adenovirus that is used for vaccines, so they are probably immune to the carrier virus and thus less susceptible to the sought-after vaccine responses. Again, as is the case with DNA-based vaccines, the clinical efficacy of adenovirus-based vaccines remains elusive. Indeed, Robinson stated that in a recent clinical study, recipients who had pre-existing immune responses to the adenovirus serotype 5 backbone of an experimental adenovirus-based vaccine intended to protect against HIV had higher infection rates than did recipients in the control group—a finding that remains unexplained. Robinson described the Merck human papilloma virus (HPV) vaccine (marketed as Gardasil) as consisting of four recombinant yeast-produced conjugate proteins that were derived from, and now protect recipients against, the main serotypes of HPV that are responsible for causing genital warts and cervical cancer. The vaccine is administered with an alum adjuvant. Each of the four proteins is made in the same way, but one is much less stable than the other three. Dealing with that instability proved challenging during vaccine development, and the challenge was met by developing a complex disassembly and reassembly scheme involving chemical reducing agents. In addressing TMTI requirements with this system, vaccine developers can expect to face similar stability challenges during the initial seven month product-development phase, according to Robinson. Merck is now in phase 2 clinical testing of a similar conjugate vaccine that is designed to protect against the bacterial pathogen Staphylococcus aureus; the same production platform was adapted to deal with immunogens derived from this bacterial pathogen. Robinson stated that Merck is concerned with CQAs as they apply to its variety of vaccines, and its standard approach is to look directly at characteristic signs of safety and efficacy in vaccines that are under development. Bioassays for determining CQAs for specific vaccine products remain proprietary. One key element on which release of a batch of product rests is a favorable result of cell-culture assays that shows that a vaccine continues to affect relevant cells, according to Robinson. Ligand-binding tests are also used, but they have to be validated through comparisons with clinical performance and shown to distinguish between good and bad lots of vaccine. Robinson summarized his presentation by indicating that vaccine technologies are generally amenable to platform production, but the variety of approaches to making vaccines dictates a number of production platforms. Determining which vaccine type will be best suited for protecting against a particular threat agent is not straightforward. In addition, demonstrating the efficacy of some of the versatile vaccine platforms, such as the DNA- based and adenovirus-based platforms, is apt to prove challenging. Vaccine developers are immersed in determining efficacy, but Robinson stated that they also need to be developing appropriate bioassays that will later be used as surrogate markers of clinical efficacy. Discussion Participants discussed platform technologies, manufacturing, and regulatory and efficacy issues. 12

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Various Platforms Arcuri and Drew agreed with Robinson that a single platform for vaccine production is not possible; Drew estimated that about six distinct vaccine-production platforms are necessary. A number of participants expressed optimism about the DNA-based platform. One stated that the reproducibility of production of DNA-based vaccines and vaccines based on recombinant proteins was comparable with the reproducibility of MAb production. Robinson said that development of DNA-based vaccines tends to be much faster; that is, it is faster in producing an experimental product that encodes a new antigen and in readying the product for a clinical trial. Such products can be made quickly, whereas other types of vaccines cannot be made within the 7–12 months that the TMTI has specified. Gomez pointed to development of a particular experimental vaccine for H5N1 influenza that was ready for clinical evaluation in about 6 months. Robinson pointed out that regardless of production platform, predicting timelines for overall vaccine development is challenging, if not impossible. He summarized several Merck experiences in which development of particular vaccines, such as the rotavirus and varicella virus vaccines, each took about 20 years, and development of the HPV vaccine took about 10 years. As for which platform (DNA-based or other) might be used to produce a countermeasure against a particular agent, Robinson said that although vaccine-production processes are generally understood, choosing a particular approach for developing a vaccine for a novel agent can be challenging. In general, platform-based production lowers costs, but some production options may still prove expensive. Manufacturing Facilities Participants addressed production capacity for vaccines. In contrast with the capacity to produce antibodies, the industry does not have excess capacity for producing vaccines, according to Arcuri and Robinson, particularly vaccines that consist of live attenuated viruses. Robinson thought that it would be helpful for the government to foster the development of surge capacity, possibly by guaranteeing markets for such products. Contract manufacturers could help in meeting vaccine-production needs, but building production capacity among producers of specialized vaccines seemed preferable to at least one participant. The construction of multipurpose vaccine facilities is feasible; Merck has a pilot vaccine facility that is capable of running different platforms, and its versatility encompasses several production platforms, including adenovirus, E. coli, yeast, and CHO cells. Shifting from one cell type to another can take place within days, and personnel running the Merck facility are trained to work with the variety of platforms available there. In response to questions about the current vision of a government-owned countermeasure-production facility, Jerome Donlon said that it would probably be built to produce both vaccines and MAbs on well-understood platforms but also include additional production components that are under development. Kelley pointed out that a 13

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operations capable of producing 100-kg batches of MAbs would have little overlap with vaccine-production operations if the two platforms were set up in a single facility, and Coffman suggested that it would be more practical to design separate facilities for the two platforms because housing them together could lead to less efficient production of MAbs. Regulatory Issues At least one participant thought that platform reliability is likely to be a plus for vaccines in dealing with FDA reviews. This participant noted that gaining regulatory acceptance of novel approaches, such as one that depends on baculovirus for production, would prolong initial reviews of vaccines that were intended to serve as TMTI countermeasures. For example, the first reviews of DNA-based vaccines drew heightened scrutiny from FDA. Participants discussed the evaluation of whether a vaccine provides protective immunity. Robinson said that animal models are useful in some cases, particularly when a bioassay is sought for use in releasing vaccine lots; in the absence of an animal model of a particular disease, however, developing such bioassays can be difficult. Participants discussed ways other than animal-model bioassays to evaluate vaccine effectiveness. Robinson thought that obtaining neutralizing antibodies (for use as a surrogate measure of immunity or in animal bioassays) would be especially challenging in the case of an unknown or newly emerging biothreat agent. Participants asked whether there are general rules for determining what protective immunity will depend on. Robinson responded that it seems that only in relatively rare cases—such as those involving the updated influenza, pneumococcal, and HPV vaccines—might there be consistency in predicting how vaccines will behave. Research and empirical analysis typically are needed when one is selecting appropriate antibodies, including antibodies that will be used as reagents in bioassays, according to Robinson. Greenberg described the influenza-vaccine experience. Decades of experience in adjusting the influenza vaccine each season provide some confidence that raising antibodies to a newly circulating hemagglutinin determinant of that virus will protect against influenza infections. However, making such changes in reformulating the seasonal influenza vaccine is far from perfect, and this might account for some of the variation in the vaccine’s performance from year to year. Consideration of what could be learned from the influenza-vaccine experience led to questions about the role and value of vaccine adjuvants in recent efforts to expand coverage of the influenza vaccine. Greenberg said that adjuvants typically increase the quantitative, not the qualitative, immune response to a vaccine. However, by intensifying overall responses to a particular vaccine, an adjuvant might broaden coverage by raising host responses to ordinarily minor epitopes that might otherwise have remained undetected by the humoral components of the host immune system. Richard Jaffe, Senior Medical Advisor at the Office of the Deputy Assistant to the Secretary of Defense for Chemical and Biological Defense and Chemical Demilitarization Programs, said that something similar happens at the cellular level: a minor component of a pathogen may trigger an immune response in T cells. 14

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The discussion shifted to the use of vaccines against intracellular bacterial pathogens and the pathogens that cause hemorrhagic fever; these pathogens are the subjects of TMTI efforts. Several participants stated that the development of vaccines to protect against intracellular pathogens remains particularly challenging, if not intractable. Galloway pointed out that the TMTI is not committed to developing conventional vaccines and is seeking novel ways to induce protective host responses. SUMMARY OF KEY POINTS Patriarca reviewed what was discussed at the workshop, namely the prospects of producing adequate supplies of safe and effective MAbs and vaccines to meet TMTI needs to provide US military forces with countermeasures against biothreats. Patriarca thought that, in general, it appears feasible to produce enough MAbs or vaccines within the TMTI-designated timeframe. However, he described several additional key points of the workshop: 5  Manufacturing of MAbs appears relatively straightforward, but it is not the most time-consuming step in the development of countermeasures, in his view. Participants urged further discussion of discovery-related issues for critical products.  Vaccine-manufacturing platforms are considerably more complicated than those for MAbs; there are at least a half-dozen such platforms for making vaccines, and only some are well characterized. However, Jennie Hunter- Cevera 6 , of the University of Maryland Biotechnology Institute, noted that discovering molecular targets, which is essential in developing MAbs, is not always needed for vaccine development.  Demonstrating safety and efficacy of both vaccine-based and MAb-based countermeasures will be challenging even with the use of surrogate end points. As emphasized by Schenerman, it will be important to devise a risk–benefit algorithm to satisfy FDA criteria for evaluating the safety and efficacy of biothreat countermeasures for US troops in the face of an emergency. 5 The summary statements made by Peter Patriarca reflect his views and are not meant to imply a consensus of the workshop participants. 6 Jennie Hunter-Cevera is now at RTI International. 15