Testimony

Statement by
Anthony S. Fauci, M.D.
Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services
on
NIH's Role in Implementing A Smallpox Vaccination Program
before the
Senate Committee on Health, Education, Labor, and Pensions

January 30, 2003

Mr. Chairman and Members of the Committee, thank you for inviting me here today to discuss the implementation of the President's smallpox vaccination plan, which is intended to protect the American people against the threat of a smallpox attack. Because of the long-standing expertise of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) in biomedical research on emerging and reemerging infectious diseases, including smallpox and other potential bioterror agents, the Institute has been designated by President Bush to play a leading role in the nation's fight against bioterrorism. As Director of the NIAID, I am committed to bringing all of our research expertise to bear on the full implementation of this important effort.

SMALLPOX VACCINE IMPLEMENTION PLAN

On December 13, 2002, the President announced a plan to prepare and protect the American people against the threat of a possible smallpox attack by hostile groups or governments. Under the plan, the Department of Health and Human Services (DHHS), through the Centers for Disease Control and Prevention (CDC), will work with state and local governments to form volunteer "Smallpox Response Teams" who can provide critical services to their fellow Americans in the event of a smallpox attack. To ensure that these teams can mobilize and perform effectively in an emergency, it is recommended that health care workers and other critical personnel volunteer to receive the smallpox vaccine. The President also announced that the Department of Defense will vaccinate certain military and civilian personnel who are or may be deployed in high threat areas. Some U.S. personnel assigned to certain overseas embassies also will be offered vaccination. It should be noted that the Federal government is not recommending vaccination for the general public at this time.

SMALLPOX THE DISEASE

Smallpox is a serious, contagious, and sometimes fatal disease. The symptoms of smallpox infection appear approximately 12 to 14 days (range: 7 to 17 days) following exposure. Initial symptoms include high fever, fatigue, and head and back aches. A characteristic rash, most prominent on the face, arms, and legs, follows in 2-3 days. The rash starts with flat red lesions (a "maculopapular" rash) all beginning at the same time. These lesions become pus-filled and begin to crust, forming scabs that separate and fall off after about 3-4 weeks. Individuals are generally infectious to others from the time period immediately prior to the eruption of the maculopapular rash until the time of the shedding of scabs, but are most infectious during the first 7 to 10 days of rash. The mortality of smallpox infection is approximately 30 percent, although mortality is likely to be much higher in those with compromised immunity, such as individuals with HIV infection and those receiving cancer therapies or drugs to prevent the rejection of transplanted organs. Smallpox patients who recover frequently have disfiguring scars over large areas of their body, especially their face; some are left blind. There is no licensed treatment for smallpox disease, and the only known prevention is vaccination.

A massive vaccination program led by the World Health Organization (WHO) eradicated all known smallpox disease from the world in the late 1970's, a resounding success story for vaccination and public health. The last case of smallpox in the U.S.A. was in 1949, and use of the vaccine in this country was discontinued in 1972. In 1980, WHO recommended that all countries stop vaccinating for smallpox. At the present time, small quantities of smallpox virus are stored in two secure facilities in the United States and Russia explicitly for research purposes, but it is believed that unrecognized stores of smallpox virus exist elsewhere in the world.

Prior to its eradication, smallpox was considered one of the most devastating infectious diseases known to mankind. Today, with the real possibility that smallpox may be used as an agent of bioterrorism, it may be once again poised to threaten public health worldwide.

SMALLPOX THE VACCINE

The "Smallpox Response Teams" and "first responders" identified in the President's Smallpox Vaccination Plan will receive FDA-licensed Dryvax smallpox vaccine in the undiluted form. This vaccine was made by Wyeth Laboratories and approximately 15 million doses have been in storage since 1982, when the company stopped making the vaccine. Historically, Dryvax smallpox vaccine has proven to be 95% effective in preventing smallpox infection. In unvaccinated people exposed to smallpox, the vaccine can lessen the severity of, or even prevent, illness if given within 3 days after exposure.

The vaccine is freeze-dried, live vaccinia virus, a poxvirus related to smallpox virus it is not a dead virus like many other vaccines. The vaccine is delivered in an unusual way, using a technique called scarification whereby the material is pricked into the skin using a two-pronged needle. Successful vaccination is measured by the development of a clear-cut pustule 6-8 days after vaccination. This is known as a "take." The blister dries up and a scab begins to form, and by the third week the scab falls off, leaving a scar. The immunization site remains contagious for vaccinia until the scab dries up completely and falls off. For that reason, the vaccination site must be cared for carefully to prevent the virus from spreading. Approximately one week after vaccination, many people experience fever, malaise, myalgia, soreness at the vaccination site, and swelling of the lymph nodes in the area of the vaccine, particularly under the arms.

In order to determine whether the existing supply of Dryvax vaccine (15 million doses) retained its potency and could even be diluted to expand the stock, a series of clinical trials were performed. In this regard, NIAID conducted a study on adults who had not been previously vaccinated to determine whether Dryvax could be diluted effectively to make more doses of this smallpox vaccine available. This clinical trial showed that the existing U.S. supply of smallpox vaccine was still very potent in its undiluted form and could be diluted five-fold and retain its potency, effectively expanding the number of doses of smallpox vaccine in the United States to 75 million. A report describing these findings appeared in the April 25, 2002, issue of The New England Journal of Medicine. The Dryvax vaccine also is being studied by NIAID in previously vaccinated populations to determine whether any residual immunity exists from earlier vaccinations.

In addition to Dryvax, NIAID is sponsoring clinical trials of another vaccine against smallpox developed by Aventis Pasteur. Eighty million doses of Aventis Pasteur's smallpox vaccine, a different formulation of the vaccinia smallpox vaccine, have been in storage for 40 years. NIAID-supported studies performed through its Vaccine Treatment and Evaluation Units will determine the safety and preliminary efficacy of various concentrations of Aventis Pasteur's smallpox vaccine in adults. To further ensure adequate supplies of smallpox vaccine, DHHS has contracted with Acambis, Inc. to produce a cell culture based smallpox vaccine for licensure.

SMALLPOX VACCINE RESEARCH CHALLENGES AND OPPORTUNITIES

While the Dryvax smallpox vaccine is currently the most effective weapon against a possible smallpox attack, it still poses risks, even in healthy populations. Fortunately, most individuals experience only mild symptoms. However, serious reactions to smallpox vaccination are well documented in studies dating back to the 1960s when smallpox vaccination was routine in the United States. Those data indicate that, for every 1 million people vaccinated, there are 14 to 52 life-threatening adverse events such as post-vaccinial encephalitis with 1 to 2 deaths. In addition, there are 49 to 935 serious, but not life-threatening events. Moreover, because smallpox vaccination ceased in the U.S. more than 25 years ago, there is limited experience with this vaccine in the era of HIV infection, organ transplantation, and immunosuppressive therapy.

The protection of all populations, including immunocompromised individuals, pregnant women, and children is the next critical important step in addressing the smallpox threat. NIAID is carefully examining alternatives to Dryvax including modified vaccinia Ankara (MVA), which may be a viable "second generation" smallpox vaccine for individuals at high risk of complications from the current Dryvax smallpox vaccine.

Several of the complications of smallpox vaccination can be treated with Vaccinia Immune Globulin (VIG), which is derived from the plasma of volunteers who previously have received a smallpox vaccination. DHHS currently has more than enough VIG to cover the adverse events that are projected to be associated with vaccinating the smallpox response teams and first responders under the President's smallpox vaccination plan. Furthermore, the CDC has contracted for additional supplies of VIG to ensure an adequate stockpile of this product by this summer to cover the severe adverse events that might be expected for over 300 million vaccinees.

Assessments of MVA vaccine candidates in multiple animal models, including immunosuppressed animals, are providing important data on the safety and efficacy of the vaccine. In addition, historical data from people who received an MVA vaccine in Germany in the 1970's adds to the body of scientific data. Importantly, the clinical trials conducted in Germany at the time included children, who are known to be at risk for adverse events associated with the conventional vaccinia-based vaccine. MVA vaccine also has been tested recently as an experimental vaccine vector for the delivery of other vaccine candidates, including HIV and cancer vaccines. These studies suggest that the vaccine may be safe in immunocompromised individuals.

In late 2002, the NIAID issued a Request for Proposals (RFPs) intended to provide resources for the initial development of MVA vaccine candidates. NIAID intends to issue a second RFP during the summer of 2003, entitled "Production and Acquisition of MVA Vaccine." The objective of the second RFP will be to manufacture, formulate, fill and finish, and test, in accordance with current Good Manufacturing Processes (cGMP) regulations, up to 30 million doses of MVA vaccine to constitute the U.S. government's stockpile for emergency use under Investigational New Drug (IND) status and to provide a licensure plan to include the conduct of expanded human safety studies required for licensure and the conduct of pivotal animal protection studies. A third contract solicitation for the acquisition of a licensed product is being planned for 2005, under the auspices of the CDC.

In addition, the NIAID Vaccine Research Center on the NIH campus in Bethesda, MD, is conducting a clinical trial to determine the safety of MVA and to compare the immunogenicity of MVA and Dryvax. This study is being conducted in healthy volunteers who have not been previously immunized with vaccinia; a future trial with vaccinia-experienced subjects is being planned. NIAID also is looking ahead to develop "third" generation smallpox vaccines, including recombinant protein vaccines.

NIAID is also evaluating drugs for use against smallpox virus. NIAID-supported scientists have developed a form of the antiviral drug cidofovir that can be administered orally. Injectable cidofovir already has been approved by the Food and Drug Administration (FDA) for treating CMV retinitis in individuals with HIV/AIDS and has shown activity against smallpox and related viruses in laboratory and animal studies. Preliminary data from these experiments suggest that cidofovir may be helpful in controlling the progression of serious vaccinia-related complications. To illuminate this issue, NIAID worked last year with colleagues at the CDC, the FDA and the Department of Defense (DoD) to develop an Investigational New Drug application to evaluate cidofovir in the treatment of smallpox. NIAID continues to explore the development of additional therapeutic interventions against smallpox and other potential bioterror agents.

BIODEFENSE RESEARCH

Smallpox is only one of a number of potential bioterror threats to our nation. In 2002, NIAID convened two Blue Ribbon Panels to provide objective scientific advice on NIAID's biodefense research activities involving smallpox as well as other potential agents of bioterror. As a result of these deliberations, the Institute has developed two research agendas: one focuses on the CDC's Category A agents, which include smallpox, while the second focuses on NIAID's Category B and C Priority Pathogens. Guided by the recommendations outlined in these agendas, NIAID developed a total of 52 biodefense initiatives to stimulate research in Fiscal Years 2002 and 2003; 36 are new initiatives and 16 are significant expansions. During this same time period, NIAID has seen a 30 percent increase in the number of grant applications; the vast majority of these are in response to our biodefense initiatives.

In Fiscal Year 2002, several NIAID initiatives encouraged industry partnerships and focused on the development of new diagnostics, vaccines and therapeutics for CDC Category A agents. These types of research initiatives have been well received. As a result, NIAID has expanded and reissued many of these collaborative efforts in Fiscal Year 2003, and plans to do the same in Fiscal Year 2004. In addition, the new initiatives will be broadened to address NIAID's Category B and C Priority Pathogens.

A number of significant advances in understanding, treating and preventing potential agents of bioterror have already been realized. For example, NIAID-supported scientists determined how anthrax toxin gains entry into a cell and demonstrated how the toxin can be effectively blocked from entering the cell, suggesting that the development of specific anthrax toxin-blocking compounds could be a viable approach to treating anthrax disease. Furthermore, intramural researchers at NIAID's Vaccine Research Center are working on the development and pre-clinical testing of an Ebola vaccine, while others have discovered a single gene mutation in the plague bacterium, Yersinia pestis, which may have been responsible for the emergence of the "Black Death" in the 14th century.

NIAID also has expanded genomic sequencing of potential agents of bioterrorism, including anthrax and plague, and has recently awarded contracts to two companies designed to spur development of a new anthrax vaccine. Similarly, the Institute has new initiatives planned to encourage development of vaccines against plague and therapeutic strategies against Botulinum toxin.

In Fiscal Year 2003, NIAID will establish a nationwide network of Regional Centers of Excellence for Biodefense and Emerging Infectious Disease Research and pursue an initiative to design, build, and renovate a system of Regional and National Biocontainment Laboratories to serve as national resources for biodefense research and product development. These facilities will include a small number of Biosafety Level-4 (BSL-4) laboratories, the level of containment necessary to study highly pathogenic organisms.

CONCLUSION

The threat of resurgent smallpox is real and its potential is devastating; however, the President's Plan moves us in the right direction to address this threat head-on. We will continue to work closely with the Administration, including our colleagues within HHS, to fully implement the President's smallpox vaccine action plan. In addition, NIAID will continue to bolster our biodefense research efforts, which span basic, clinical and product development research, and infrastructure development. With a strong research base and talented investigators throughout the country, we fully expect that NIAID's research programs will provide the elements essential to enhance significantly our nation's defenses against the threat of bioterrorism.

Thank you for the opportunity to testify. I will be happy to answer any questions.

Last Revised: January 31, 2003