Testimony

January 29, 2004

Good afternoon. I am Dr. Phillip Baker, the Lyme Disease Program Officer and the Vector Borne/Zoonotic Bacterial Diseases Program Officer, with the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, U.S. Department of Health and Human Services.

Introduction

NIAID has a long-standing commitment to Lyme borreliosis research (Lyme disease) that began more than 20 years ago when the cause of the disease was not yet known. In 1981, NIAID-funded researchers identified Borrelia burgdorferi as the causative agent of Lyme disease, and since then, basic and clinical research efforts have been expanded in scope to address a variety of issues related to this illness. These activities include both intramural and extramural research on animal models, microbial physiology, molecular and cellular mechanisms of pathogenesis, mechanisms of protective immunity, vectors and disease transmission, efficacy of different modes of antibiotic therapy, and the development of more sensitive and reliable diagnostic tests for both early (acute) and late (chronic) Lyme disease.

Other NIH institutes and centers (ICs) that conduct Lyme disease research are the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Mental Health (NIMH), the National Institute of Neurological Disorders and Stroke (NINDS), the Fogarty International Center (FIC), and the National Center for Research Resources (NCRR).

Diagnostic Procedures

Approximately 20 percent of NIAID's extramural Lyme disease portfolio is devoted to the development of novel and more sensitive diagnostic procedures; the NIAID also regularly re-evaluates the effectiveness of currently-used diagnostic methods. In collaboration with the CDC, the Institute plays a major role in the development of new approaches for diagnosing Lyme borreliosis in the presence of co-infecting agents, as well as in individuals who have been immunized. In addition, there is a strong need to develop a procedure that will enable one to distinguish those who are actively infected with B. burgdorferi from those who either have recovered from a previous infection or have been immunized with the LYMErixTM vaccine. Since the genome of B. burgdorferi has now been completely sequenced, greater advances are anticipated as this information is used both to improve diagnosis and provide new insights on the pathogenesis of the disease through the application of micro-array technology and proteomics.

Co-Infection

Co-infection looms as a major potential problem, mainly because the Ixodes ticks that transmit B. burgdorferi often carry and simultaneously transmit other emerging pathogens such as Ehrlichia species, the causative agent of human granulocytic ehrlichiosis (HGE), and Babesia microti, which causes babesiosis. In Europe and Asia, Ixodes ticks also are known to transmit tick-borne encephalitis viruses; fortunately, this tick-borne viral infection has not yet been reported in the U.S., although co-infections with Powasan virus and deer tick virus have been reported. Co-infection by some or all of these other infectious agents may interfere with the clinical diagnosis of Lyme borreliosis and/or adversely influence host defense mechanisms, thereby altering landmark characteristics of the disease and the severity of infection. For example, studies conducted by NIAID extramural researchers have shown that co-infection with HGE increases the severity of Lyme borreliosis. The issue of co-infection and its potential implications also is being examined in all of NIAID's clinical studies on Lyme disease.

Antibiotic Therapy

A clinical study on the efficacy of antibiotic therapy for the treatment of chronic Lyme disease was completed in late 2000. It was funded through a contract awarded to the New England Medical Center (NEMC) in Boston and involved randomized, double-blind, placebo-controlled multi-center studies to examine the safety and efficacy of ceftriaxone and doxycycline for the treatment of patients with either seropositive or seronegative chronic Lyme disease. The clinical protocols for these studies, which have been posted on the NIAID Web site at http://www.niaid.nih.gov/dmid/lyme/#2a, were developed through collaboration and extensive discussions with Lyme disease research experts, as well as with an NIAID Lyme disease advisory panel composed of patients with Lyme disease, members of patient advocacy groups, practicing physicians who treat patients with Lyme disease, and basic research scientists with expertise in either infectious diseases or Lyme disease. This Panel provided input on the implementation of the protocols selected for use in this study, as well as on intramural clinical studies.

In late 2000, the Data and Safety Monitoring Board (DSMB) for the NEMC clinical trials reviewed a planned interim analysis of the data. After its review, the DSMB unanimously recommended that NIAID terminate the treatment component of these studies. The preliminary data analysis showed that, after 90 days of continuous antibiotic therapy, there were no significant differences in the percentage of patients who felt that their symptoms had improved, worsened, or stayed the same between the antibiotic treatment and placebo groups in either trial.

In addition, the DSMB further recommended that the investigators continue to follow the study patients to monitor their longer-term safety and to obtain additional information that might have value in determining the underlying basis of chronic Lyme disease and in suggesting more effective therapeutic approaches. These extensive follow-up studies are still in progress; no new therapeutic studies will be contemplated until these have been completed and the results analyzed. The results of the NEMC clinical trials were published in the New England Journal of Medicine (NEJM 345: 85-93, 2001).

Both the intramural and extramural studies mentioned above involved data collection as well as the maintenance of specimen repositories. Such specimens have been made available to other investigators working on Lyme disease and thus have contributed significantly to the development of improved and/or novel diagnostic procedures. Animal models also have provided considerable information on the transmission and pathogenesis of Lyme borreliosis, as well as on the mechanisms involved in the development of protective immunity. The NIAID, in collaboration with NINDS, has broadened these efforts to include comprehensive studies on non-human primate animal models for experimental research on the neuropathology associated with chronic Lyme borreliosis. These studies will expand knowledge of those factors that contribute to the pathology associated with persistent infection of the central nervous system by B. burgdorferi, and ultimately will enable researchers to devise more effective clinical approaches for the treatment of chronic Lyme borreliosis in humans. They also will supplement and enhance the results of current clinical studies on the efficacy of antibiotic therapies for the treatment of chronic Lyme disease, and provide precedents for use in the design of future clinical studies.

Vaccine Production

Two pharmaceutical companies have devoted considerable efforts towards the development of a vaccine for Lyme disease. Double-blind, randomized, placebo-controlled clinical trials involving more than 10,000 volunteers from regions in the U.S. where Lyme disease is highly endemic, have been completed for each of two B. burgdorferi recombinant outer-surface lipoprotein A (OspA) vaccines manufactured by GlaxoSmithKline (formerly SmithKline Beecham [SKB]) and Pasteur Merieux Connaught (PMC). These vaccines were found to be 49 to 68 percent effective in preventing Lyme disease after two injections, and 68 to 92 percent effective in preventing Lyme disease after three injections. The duration of the protective immunity generated in response to the SKB vaccine [LYMErixTM], which was licensed by the FDA in December of 1998, is not known.

Although LYMErixTM has been licensed for use in individuals from 15 to 70 years of age, the results of a recently-completed study involving about 250 children from 5 to 15 years of age indicate that LYMErixTM is well tolerated and highly immunogenic in children as well. A larger pediatric study involving more than 3,000 children from 4 to 14 years of age, showed that just two doses rather than the three usually given to adults, were enough to provide protection; only minor side effects were observed. The FDA is reviewing these findings to determine if LYMErixTM should be approved for use in children four years of age and older. The NIAID was not directly involved in the design and implementation of these particular vaccine trials. However, patents for cloning the genes used for the expression of recombinant OspA, as well as knowledge of the role of antibody(ies) against OspA in the development of protective immunity, were derived from basic research grants funded by the NIAID.

In April 2002, GlaxoSmithKline announced that, even with the incidence of Lyme disease on the increase, sales for the LYMErixTM declined from about 1.5 million doses in 1999 to a projected 10,000 doses in 2002. Although studies conducted by the FDA did not reveal that any reported adverse events were vaccine-associated (Vaccine 20: 1603, 2002), GlaxoSmithKline discontinued manufacturing the vaccine for economic reasons.

The NIAID also is funding pre-clinical studies on the development and testing of other candidate vaccines (e.g., decorin-binding protein A or DbpA) for Lyme disease. MedImmune, Inc. (a NIAID Small Business Innovation Research grantee) and Aventis Pharmaceuticals Inc., reported that a combination vaccine composed of the DbpA and OspA is more effective than either one being given alone in preventing the development of borreliosis in experimental animals. On the basis of these encouraging findings, both companies have entered into an agreement to develop a new, more effective, second-generation vaccine to prevent Lyme disease in humans.

Conclusion

As demonstrated above, NIAID has a comprehensive Lyme disease research portfolio with the goal of advancing the understanding of the disease and developing ways to improve its diagnosis, treatment, and prevention. These efforts highlight several specific avenues of investigation: 1) improving the ability to diagnose Lyme disease in the presence of co-infecting agents; 2) evaluating the efficacy of antibiotic treatment for Lyme disease; 3) researching candidate replacement vaccines for the discontinued LYMErixTM vaccine.

The NIAID is fully committed to continuing to explore these and other, yet-undiscovered areas of research, in the hope that future research findings will provide important clues to better understanding this painful disease.

Lyme disease research will continue to be a priority for the NIAID for the foreseeable future.

Last Revised: February 3, 2004

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