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Many vaccines benefit public health by providing widespread immunity against potentially severe or fatal, and often untreatable, diseases. Vaccine-induced herd immunity against contagious diseases reduces the risk among unvaccinated persons. Lyme disease is a noncontagious, treatable, and nonfatal disease. Because humans are dead-end hosts of B. burgdorferi, vaccinating some humans will not decrease the risk of acquiring Lyme disease for others. Although the incidence of Lyme disease is highest in children,3 the safety and efficacy of the vaccine in children have not been established. The need for and timing of booster doses are also unknown. Furthermore, whether vaccination is more cost effective than early diagnosis and treatment of Lyme disease has not been established. Finally, should vaccination against Lyme disease result in a complacent decrease in personal efforts to avoid tick bites, then vaccinated persons in areas in which the disease is endemic may be at increased risk for other tick-borne diseases, such as ehrlichiosis, babesiosis, Rocky Mountain spotted fever, and tularemia.
In the United States, Lyme disease is primarily transmitted in certain counties in northeastern, north central, and Pacific states.3 Vaccination of persons with frequent or prolonged exposure to tick habitats in areas where the disease is endemic is likely to be an important preventive strategy. For those who have only brief or intermittent exposure to tick habitats in such areas, the public health benefits of vaccination, as compared with those of early recognition and treatment of Lyme disease, are not clear. For persons who live in areas in which the disease is not endemic and for those who travel to areas in which the disease is endemic but who are not exposed to tick habitats, vaccination would not seem to be beneficial.
Edward B. Hayes, M.D.
David T. Dennis, M.D., M.P.H.
Centers for Disease Control and Prevention
Fort Collins, CO 80526
References
From a cost standpoint, it seems very expensive to treat 11,000 patients with three doses of a vaccine (at a total cost of probably well over $1 million) to prevent 70 cases of erythema migrans, which could be treated with oral antibiotics at a cost of $15 per patient. The importance of a Lyme disease vaccine is not its ability to prevent erythema migrans or asymptomatic seroconversion but its ability to prevent the later (and more difficult to treat) complications of Lyme disease. This difference may become clear if the later complications of Lyme disease develop in the patients with asymptomatic seroconversion.
Steven Luger, M.D.
Kaiser Permanente
Windsor, CT 06095
It is particularly troubling that both studies had data and safety monitoring committees, but neither committee apparently insisted on any interim analyses of the outcome. Clinical trials are only ethical when there is no compelling reason to suggest that one intervention is to be preferred over another.1 Most randomized trials now require interim analyses to allow early termination should there be compelling evidence of differences in outcome between treatment groups. Such information should then be made available to subjects.2 The ethical duty to act is not conditional on the seriousness of the outcome being studied. Definitive information on the effectiveness of these vaccines should have been available to the researchers before the scheduled 12-month visit, and subjects who were randomly assigned to the placebo group should have been informed of the vaccine's effectiveness at the time of the 12-month visit and offered the opportunity to receive vaccine injections at months 12 and 13.
James R. Anderson, Ph.D.
University of Nebraska Medical Center
Omaha, NE 69198
References
To the Editor: We reported that vaccination with outer-surface protein A with adjuvant was safe and effective in preventing most cases of definite Lyme disease or asymptomatic B. burgdorferi infection. As pointed out by Drs. Hayes and Dennis, there are still unanswered questions. One concerns the efficacy and safety of the vaccine in children. A large clinical trial is currently in progress to evaluate the safety of the vaccine in children. Additional studies are under way to assess the need for booster injections. Official recommendations from the Advisory Committee for Immunization Practices regarding vaccine use should be available after the vaccine is licensed.
We agree with Dr. Luger that an important reason for vaccination is to prevent the later and more serious complications of Lyme disease. The vaccine was highly effective in preventing asymptomatic seroconversion, which in some cases might have been followed by late manifestations of the disorder. In our study, it was not possible to determine the frequency of late disease after asymptomatic seroconversion, since most patients with asymptomatic seroconversion, after discussion with their physician, were treated with antibiotic therapy. However, Lyme arthritis subsequently developed in one such patient who decided against antibiotic treatment. This finding shows that Lyme arthritis after asymptomatic seroconversion may be the presenting manifestation of the illness. Thus, at least in some cases, asymptomatic seroconversion does indicate infection.
It is always difficult to decide how long a double-blind, placebo-controlled trial should be continued before the code is broken. The design of our study was conceived after a meeting of the Vaccine Advisory Committee of the Food and Drug Administration in 1994. At that meeting, two years of follow-up data were requested to assess the safety of the vaccine, which required a comparison of the vaccine and placebo groups. In addition, the members of the data and safety monitoring board thought that a clearer picture of the vaccine's efficacy could be obtained with the use of three injections of vaccine over a two-year period, rather than two injections over a one-year period. The study investigators, the members of the data and safety monitoring board, and the study sponsor decided that this design was justified, without interim analysis, since all study participants were followed carefully and antibiotic treatment was recommended for all subjects in whom evidence of B. burgdorferi infection developed.
Allen C. Steere, M.D.
New England Medical Center
Boston, MA 02111
Dennis L. Parenti, M.D.
David S. Krause, M.D.
SmithKline Beecham Pharmaceuticals
Collegeville, PA 19426
Dr. Anderson contends that it was unethical for the data and safety monitoring committee to have allowed the study to proceed into the second year. Since there was prior evidence that three injections of the vaccine were needed to achieve optimal levels of specific antibodies,5 there was reason to believe that a third (or booster) injection at month 12 was needed to provide the increased efficacy noted in results obtained in the second year (months 13 to 24). Although the calculated efficacy of the vaccine was 68 percent after two doses, the lower bound of the 95 percent confidence interval was only 36 percent. The importance of continuing the double-blind study into the second year can be seen in the results: the overall efficacy was 77 percent, with a lower bound of the 95 percent confidence interval of 58 percent. Therefore, ending the study after 12 months or shortly thereafter would have precluded us from learning the very data needed to determine the cost effectiveness of the vaccine, as discussed by Hayes and Dennis. Thus, we disagree with Dr. Anderson: there was no ethical issue raised by continuing the study to its completion.
The last entry in the left-most column of Table 2 of our article should have read, "Two or three injections per protocol," not "Three injections, per protocol." Also, on page 218, line 7 from the top of the left-hand column should have read, "both years among subjects who received two or three injections," not "both years among subjects who received three injections." Finally, the last seven authors were omitted from the title page of our article. The complete list of authors is as follows: L.H. Sigal, M.D., J.M. Zahradnik, M.D., P. Lavin, Ph.D., S.J. Patella, M.S.N., N.P.-C., G. Bryant, M.D., R. Haselby, D.O., E. Hilton, M.D., M. Kunkel, M.D., D. Adler-Klein, M.D., T. Doherty, M.D., J. Evans, M.D., S.E. Malawista, M.D., P. Molloy, M.D., A. Seidner, M.D., J. Sabetta, M.D., H.J. Simon, M.D., M.S. Klempner, M.D., J. Mays, Ph.D., and D. Marks, M.D.
Leonard H. Sigal, M.D.
University of Medicine and Dentistry of New Jersey–
Robert Wood Johnson Medical School
New Brunswick, NJ 08903
John Zahradnik, M.D.
Pasteur Mérieux Connaught
Swiftwater, PA 18370
Arthur Weinstein, M.D.
George Washington University Medical Center
Washington, DC 20007
References
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