Testimony

Statement by
Gerald W. Parker, DVM, PhD, MS, 
Principal Deputy Assistant Secretary
Office of the Assistant Secretary for Preparedness and Response
U.S. Department of Health and Human Services

on
Pandemic Influenza Preparedness: Update on the Development & Acquisition of Medical Countermeasures 

before
Committee on Appropriations
Subcommittee on Labor, Health and Human Services, Education and Related Agencies
United States Senate

Wednesday, January 24, 2007

Mr. Chairman and Members of the Subcommittee, I am honored to be here today to describe for you how the Department of Health and Human Services is working to improve preparedness for a potential human influenza pandemic, specifically by pursuing a strategic and comprehensive approach to the development and acquisition of medical countermeasures including vaccines, antivirals, diagnostics, and through building domestic manufacturing infrastructure for influenza vaccines. We are working cooperatively to leverage resources throughout the Department and with industry to meet the program goals. We recently formalized linkages within HHS through the establishment of the Public Health Emergency Medical Countermeasures Enterprise, led by the leaders of the Office of the Assistant Secretary for Preparedness and Response, the Centers for Disease Control and Prevention, the National Institutes of Health, and the Food and Drug Administration. Thank you for the invitation to testify on this topic which Secretary Mike Leavitt has made a top priority.

On November 1, 2005, the President requested $7.1 billion in emergency funding for the National Strategy for Pandemic Influenza, of which $6.7 billion was designated for HHS. Congress appropriated $3.8 billion in December 2005 as the first installment of the President's request to begin these priority activities, and of this amount, $3.3 billion was provided to HHS. The second appropriation in June 2006 provided HHS with $2.3 billion. We appreciate the action of Congress on these appropriations, as it takes us an essential step forward in becoming the first generation in history to be prepared for a possible pandemic.

The potential for a human influenza pandemic is a current public health concern with an immense potential impact. We know that the influenza virus has the potential to cause a pandemic but we don't know when a pandemic will occur. We don't know how severe a pandemic might be and we don't know which influenza virus will be the one that develops the ability to spark a pandemic. However, we do know that the H5N1 strain of avian flu has spread to more than 50 countries and has led to the deaths of hundreds of millions of birds, and that more than 260 human cases of avian influenza (so called "bird flu") have occurred in 10 countries. More than half of those persons infected have died. This has heightened global concern about the possibility of a human flu pandemic. To date, H5N1 avian influenza has remained primarily an animal disease, but should the virus mutate further and acquire the ability for sustained transmission among humans, a severe influenza pandemic could result that may have grave consequences for global public health. And while a mild pandemic would be primarily a public health problem, the consequences of a severe pandemic on the global economy and on the functioning of society could be enormous.

National and HHS-Specific Pandemic Influenza Plans
On November 1, 2005, the President announced the National Strategy for Pandemic Influenza, with the three pillars of Preparedness and Communications, Surveillance and Detection, and Response and Containment.

The day after the release of the President's National Strategy for Pandemic Influenza, Secretary Leavitt announced the HHS Pandemic Influenza Plan - a blueprint for all HHS pandemic influenza preparedness and response planning - and released Parts 1 and 2. Part 1, the HHS Strategic Plan, outlines federal plans and preparation for public health and medical support in the event of a pandemic. It identifies the key roles of HHS and its agencies in a pandemic and provides planning assumptions for federal, state and local governments and public health operations plans. Part 2, Public Health Guidance for State and Local Partners, provides detailed guidance to state and local health departments in 11 key areas.

In May 2006, the National Strategy for Pandemic Influenza Implementation Plan was released. It translated the National Strategy for Pandemic Influenza into more than 300 actions, timelines, and metrics for Federal departments and agencies and set clear expectations for State and local governments and other non-Federal entities. One of the Federal priority actions was to "Accelerate the Development of Medical Countermeasures" and included these efforts:

• Establish stockpiles of vaccine and antiviral medications
• Advance technology and production capacity for influenza vaccine
• Develop rapid diagnostics

Cascading from the National Strategy and National Implementation Plan, one of the key components of the HHS plan called for increasing capacity to produce pandemic influenza antivirals and vaccines, and increasing stockpiles of these countermeasures. Specific strategic goals for pandemic medical countermeasures are displayed in Table 1.

Table 1. HHS Pandemic Medical Countermeasure Goals

The Pandemic Influenza Medical Countermeasure Program now includes 25 contracts obligating over $3 billion. Table 2 illustrates the multi-pronged approach and diversified portfolio of programs that have been established to help us achieve the Implementation Plan's medical countermeasure goals.

Table 2. HHS Pandemic Influenza Medical Countermeasure Programs.

I would now like to take this opportunity to provide details about the substantive progress toward meeting our public health emergency preparedness goals in each of these medical countermeasure programs.

VACCINES
Vaccines are the optimal way to control the spread and associated morbidity and mortality of seasonal epidemics or pandemics. Broadly speaking, our approach to developing vaccines for a pandemic may be divided into two categories: those that are developed against strains of animal influenza viruses that have caused isolated infections in human, which may be regarded as "pre-pandemic" vaccines; and those that are developed against strains that have evolved the capacity for sustained and efficient human-to-human transmission ("pandemic" vaccines). Because emergence in human populations necessarily reflects genetic changes within the pandemic virus, pre-pandemic vaccines may be a good or poor match for - and offer greater or lesser protection against - the pandemic strain that ultimately emerges. Thus, the HHS strategy is to simultaneously stockpile a limited amount of pre-pandemic vaccine, build vaccine manufacturing capacity so that we can quickly produce pandemic vaccine should a pandemic occur, and explore approaches utilizing adjuvants to enhance the likelihood that a vaccine administered prior to a pandemic will provide useful protection during a pandemic. Further, this approach will strengthen and integrate both the seasonal and pandemic influenza preparedness needs.

Vaccines - Advanced Development
The Office of the Assistant Secretary for Preparedness and Response (ASPR) supports vaccine advanced development and is currently managing a program that includes 4 projects with 10 contracts and obligations over $1.3 billion (Table 3). These projects support new influenza vaccine technologies and are precursors to enhancing vaccine manufacturing capacity.

Table 3. HHS Advanced Development Vaccine Projects.

Cell-based Projects
As part of the President's plan to prepare for a pandemic, HHS awarded in May 2006 more than $1 billion to accelerate development and production of new technologies for influenza vaccines within the U.S. These five contracts and an additional contract awarded in 2005 provided support for the advanced development of cell-based production technologies for seasonal and pre-pandemic H5N1 influenza vaccines. Additionally, these contracts facilitated the modernization and strengthening of the nation's influenza vaccine production by creating an alternative to producing influenza vaccines in eggs. Notably, these contracts required commitments by each manufacturer to establish U.S.-based manufacturing facilities with a vaccine production capacity of at least 150 million doses within six months of a pandemic.

Accelerating the development of this vaccine technology and enhancing domestic production capacity are critical enhancements of our public health emergency preparedness efforts. Cell-based vaccine manufacturing -- a technology that is used for the manufacturing of many other modern vaccines -- holds the potential of a reliable, flexible, and scalable method of producing influenza vaccines.

Using a cell culture approach to produce influenza vaccines offers a number of benefits. Currently licensed influenza vaccines are produced in embryonated hens' eggs in a technique that has changed little in the past 50 years. With increasing demand for seasonal influenza vaccine and with the looming threat of a pandemic, a system that allows surge capacity in an emergency is needed. Vaccine manufacturers utilizing cell-culture technology may be able to bypass the steps needed to adapt the virus strains to grow in eggs, which may save weeks in vaccine production during a pandemic. Since cell-culture technology is used to produce other licensed biologicals, emergency usage of such facilities for pandemic vaccine production is more feasible than with egg-based vaccine manufacturing, which requires highly specialized equipment for egg handling. Further, manufacture of influenza vaccines produced by cell culture also will provide security against risks associated with egg-based production, such as the potential for egg supplies to be unavailable as a result of various poultry-based diseases. Finally, the new cell-based influenza vaccines will provide an option for people who are allergic to eggs and therefore unable to receive the currently licensed vaccines.

Currently, six manufacturers are in Phase 1 clinical studies in the U.S. to determine the safety and immunogenicity of these cell-based products; however, several of these seasonal influenza vaccine products have already been evaluated clinically in Europe and have been shown to be well-tolerated, immunogenic, and efficacious. H5N1 vaccine products under development in these contracts include inactivated split and whole virion vaccine candidates formulated with adjuvants and live, attenuated virus vaccine candidates. In pursuit of Pandemic Vaccine Goal 2, the impact of these contracts on domestic surge capacity is forecasted to begin by 2009, and will grow through 2013.

Antigen-Sparing Projects
Earlier this month, HHS announced the award of contracts totaling $132.5 million to three vaccine manufacturers for the advanced development of H5N1 influenza vaccines using an immune system booster called an adjuvant, which is a substance that may be added to a vaccine to increase the body's immune response to the vaccine's active ingredient, called an antigen. In the event of an influenza pandemic, a vaccine that uses adjuvant could optimize utilization of the vaccine stockpile and could provide a way to extend a limited vaccine supply to more people. Another key feature of these adjuvants is that early studies indicate that they may confer cross protection properties upon influenza vaccines to afford efficacy against "antigenic drift" variants - that is, an H5N1 vaccine made against the circulating strain in 2006 may offer cross protection against new H5N1 virus strains emerging in future years.

The contracts provide support for advanced development of antigen-sparing pandemic vaccine with adjuvants through U.S. clinical trials towards U.S-licensure. Further, these contracts facilitate the establishment of manufacturing capabilities for these adjuvants and development of delivery devices, including adjuvant containing patches which could similarly extend a limited vaccine supply.

Under the contracts, each company will build up to a capacity to produce, within six months after the onset of an influenza pandemic, either 150 million doses of an adjuvant-based pandemic influenza vaccine or enough adjuvant to be stockpiled for 150 million doses of a pandemic influenza vaccine. In addition to supporting the development of each company's antigen-sparing vaccine candidate, the contracts also require each company to provide its proprietary adjuvant for U.S. Government-sponsored, independent evaluation with influenza vaccines from other manufacturers.

Initial clinical studies conducted by NIH on antigen-alone H5N1 vaccine candidates in humans have shown that two 90-microgram doses of the vaccine are required to stimulate a level of immune response that researchers anticipate would provide protection for an individual against the H5N1 strains that have been spreading among birds in Asia. However, the addition of adjuvant to these candidate vaccines has been shown, in initial European clinical studies, to reduce by 10-to-20-fold the amount of antigen per dose needed to achieve effective individual protection. Phase 1 and 2 clinical studies for safety, immunogenicity, and cross protection are planned in 2007 for the H5N1 vaccine products with the each of the three new adjuvants. If these results are confirmed in larger clinical studies, then these adjuvants may make reaching the goal of U.S. and global pandemic vaccine preparedness faster and more feasible, and help to achieve Pandemic Vaccine Goals 1 and 2.

Egg-based Supply
To be able to manufacture flu vaccines in the event of a pandemic flu outbreak or future vaccine shortages, HHS awarded a contract in November 2004 for $43 million to develop and implement an egg supply plan for transition to a secure, year-round egg supply, stockpile other vaccine manufacturing supplies, such as vials, caps, and stoppers, and to develop and manufacture pandemic vaccine candidates for clinical investigation. In April 2005 a secure year-round egg supply for domestic influenza vaccine manufacturing was realized, and two pandemic vaccine candidates - H5N1 clade 2 and H7N7 - have been produced for NIH clinical investigations under this contract.

Vaccines - Acquisitions
ASPR currently has a vaccine acquisition program that includes four projects with six contracts and obligations over $500 million to procure pre-pandemic vaccine (Table 4).

Table 4. HHS H5N1 vaccine acquisition projects.

Manufacturing these pre-pandemic vaccines not only provides the industry experience in producing novel influenza vaccine candidates at a commercial scale, but also provides a foundation for pre-pandemic vaccine stockpiles. In the early stages of a severe pandemic, and before a well-matched vaccine is available, pre-pandemic vaccines may be used in selected populations to mitigate disease, support essential operations, and maintain social and economic systems.

Currently, 1.3 million doses of H5N1 Clade 1 vaccine (90 ug/dose) have been filled in vials. More than 6 million doses (90ug/dose) of H5N1 Clade 1 vaccine remain in bulk form and await instructions for formulation into final vaccine vials. Additionally, approximately 5 million doses of H5N1 Clade 2 vaccine are currently under production.

Vaccines - Infrastructure Building
In order to achieve pandemic preparedness, the influenza vaccine surge capacity needs to be expanded. Expansion of commercial scale egg- or cell-based production could be accomplished by renovation of existing domestic manufacturing facilities already licensed for approved biologicals. Furthermore, pandemic vaccine surge capacity required extension of the time dedicated to its production, as H5N1 vaccine stockpile manufacturing was limited to the 3 months each year when influenza manufacturers are not producing seasonal flu vaccine. Therefore, in July 2006, HHS issued a solicitation for proposals to retrofit or remodel these existing domestic manufacturing facilities and establish warm-base capabilities for the emergency production of pandemic vaccine. HHS plans to award these contracts in February 2007 (Table 5). These contracts will not only increase domestic pandemic influenza vaccine capacity, but will also allow year-round production of pre-pandemic stockpiles.

To further capitalize on the promise of cell-based influenza vaccines, HHS plans to issue an RFP later this year to assist in the establishment of new U.S.-based vaccine manufacturing facilities for the production of cell-based seasonal and pandemic influenza vaccines (Table 5), helping us achieve Pandemic Vaccine Goal 1.

Table 5. HHS influenza vaccine manufacturing infrastructure building projects.

ANTIVIRAL DRUGS
Antivirals are principally used to treat influenza infections. Under certain circumstances, antivirals may also reduce transmission of the influenza virus or even prevent infection. Two antiviral drugs were effective against the H5N1 virus in laboratory testing. In the event of a pandemic, antiviral drugs may be a key line of defense before a well-matched pandemic vaccine is available.

HHS funding was therefore allocated to acquire antiviral drugs. Currently two drugs, oseltamivir (Tamiflu®) and zanamivir (Relenza®) may provide clinical benefit against most H5N1 virus strains currently circulating in Asia; however, several cases of drug-resistant H5N1 viruses in humans have been identified. Accordingly HHS is stimulating the development of new and more promising influenza antivirals and establishing antiviral drug stockpiles to achieve antiviral goals #1 and #2.

ANTIVIRAL DRUGS: ADVANCED DEVELOPMENT
ASPR has an antiviral advanced development program that earlier this month awarded a $102 million contract for the development of a new influenza antiviral - Peramivir, which is a member of the neuraminidase inhibitor class of influenza antiviral drugs (Table 6). The drug resistant profile for Peramivir is dissimilar to those of the licensed antiviral drugs. While the other antiviral drugs in this class are either taken orally (oseltamivir/Tamiflu®) or by an inhaler (zanamivir/Relenza®), peramivir is being studied as a drug that can be administered parenterally, that is through intravenous or intramuscular injection.

Table 6. HHS influenza antiviral drug advanced development project.

Funding in this contract over the next 4 years will support manufacturing of clinical investigational and consistency lots; Phase 2 and 3 clinical studies to evaluate safety and efficacy in support of product approval in the U.S.; manufacturing process validation; and other product approval requirements.

ANTIVIRAL DRUGS: FEDERAL AND STATE ACQUISITIONS
Another key goal in the HHS Pandemic Influenza Plan is to ensure the availability of antiviral treatment courses for 25 percent of the population, or 75 million individuals. By FY 2008, the Federal government will complete the 20 million course antiviral stockpile purchase to maintain the function of the health care system and protect first responders, and stockpile an additional 24 million treatment courses for treatment of pandemic influenza, for a total of 44 million treatment courses. In addition, the Federal government plans to stockpile 6 million treatment courses to attempt to contain no more than two local outbreaks at the outset of a pandemic in the U.S. To date, HHS has ordered more than 36 million courses of influenza antivirals for which 26 million courses have been delivered to the Strategic National Stockpile for pro rata distribution to States during a pandemic (Table 7). A small portion of the Federal stockpile has been deployed to eastern Asia to help contain a potential outbreak.

Table 7. HHS influenza antiviral drug stockpile projects.

Additionally, the Implementation Plan calls for States to purchase 31 million antiviral treatment courses, for which the Federal government subsidizes at 25 percent of the cost ($170 M total).