Correspondence
Correction
Immunization against Lyme Disease
N Engl J Med 1998; 339:1637-1639November 26, 1998
- Article
To the Editor:
The studies by Steere et al.1 and Sigal et al.2 (July 23 issue) suggest that the vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A is well tolerated and efficacious and “provides an important new public health approach to the prevention of Lyme disease.”1 The role of this vaccine in public health efforts to prevent Lyme disease needs further consideration.
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.
3 ReferencesEdward B. Hayes, M.D.
David T. Dennis, M.D., M.P.H.
Centers for Disease Control and Prevention, Fort Collins, CO 805261
Steere AC ,Sikand VK ,Meurice F , et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl J Med 1998;339:209-215
Full Text | Web of Science | Medline2
Sigal LH ,Zahradnik JM ,Lavin P , et al. A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. N Engl J Med 1998;339:216-222
Full Text | Web of Science | Medline3
Lyme disease -- United States, 1996
Medline
To the Editor:
In the report by Steere et al., what were the clinical outcomes for the patients in the group with laboratory-confirmed asymptomatic B. burgdorferi infection? Did symptoms develop? Did the results of Western blotting for IgG indicate a possible progressive latent infection? This group did not have asymptomatic infection (no living organisms were demonstrated), it had asymptomatic seroconversion. Seroconversion could be caused by the transfer of dead or nonviable spirochetes to the host from the feeding tick. It is more likely that the results in this group reflect either the success of the body's immune defense against the invading organism or the occurrence of a latent infection, in which case, clinical symptoms may develop at a future time. If in fact these patients were infected, were they treated? If they had asymptomatic seroconversion, I see no reason to treat them.
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 06095To the Editor:
The conduct of the studies by Steere et al. and Sigal et al. raises serious ethical issues. Both Steere et al. and Sigal et al. recruited their subjects during an eight-week period and demonstrated the efficacy of the two injections of vaccine given in the first year (estimated efficacy, 49 percent [P=0.009] and 68 percent [P<0.001], respectively). Therefore, at the time of the third injection, 12 months after the first, both groups should have had evidence of the vaccine's effectiveness. Nevertheless, they chose to give the subjects in the placebo group a placebo injection at 12 months and to monitor them without additional intervention for an additional 12 months. Had the subjects in the placebo group been given vaccine injections at months 12 and 13, many of the 94 cases of Lyme disease reported during the second year of follow-up in this group could have been prevented.
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.
2 ReferencesJames R. Anderson, Ph.D.
University of Nebraska Medical Center, Omaha, NE 691981
Freedman B . Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141-145
Full Text | Web of Science | Medline2
Food and Drug Administration
Medline
Author/Editor Response
The authors reply:
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 02111Dennis L. Parenti, M.D.
David S. Krause, M.D.
SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426Author/Editor Response
We agree with many of the points made by Drs. Hayes and Dennis. The cost effectiveness of a vaccine cannot be estimated until the efficacy and side effects of the vaccine have been established. The Food and Drug Administration would not allow studies of the efficacy of the vaccine in children until the completion of the studies in adults; these studies will be performed. Responsible and prudent educational programs and materials1 stress the importance of personal precautions in avoiding Lyme disease. As suggested by Meltzer et al. at the recent International Conference on Emerging Infectious Diseases,2 only targeted use of vaccination can be recommended; its use in persons with minimal risk of infection would not be beneficial to society, just as routine antibiotic prophylaxis against tick bites has no demonstrable utility.3,4 Since Ixodes scapularis ticks carry other pathogens, the use of this vaccine should not lead to a decrease in personal precautions. To achieve maximal public health benefit, the vaccine should be part of broader strategies to prevent Lyme disease and other tick-borne diseases.
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.
5 ReferencesLeonard H. Sigal, M.D.
University of Medicine and Dentistry of New Jersey–, Robert Wood Johnson Medical School, New Brunswick, NJ 08903John Zahradnik, M.D.
Pasteur Mérieux Connaught, Swiftwater, PA 18370Arthur Weinstein, M.D.
George Washington University Medical Center, Washington, DC 200071
Sigal LH , ed. National Clinical Conference on Lyme Disease. Am J Med 1995;98:Suppl 4A:1S-91S
CrossRef | Web of Science2
Meltzer MI, Dennis DT, Orloski KA. The cost and benefits of vaccinating against Lyme disease: a decision analysis. Presented at the International Conference on Emerging Infectious Diseases, Atlanta, March 8–11, 1998.
3
Magid D ,Schwartz B ,Craft J ,Schwartz JS . Prevention of Lyme disease after tick bites -- a cost-effectiveness analysis. N Engl J Med 1992;327:534-541
Full Text | Web of Science | Medline4
Gerber MA ,Shapiro ED ,Burke GS ,Parcells VJ ,Bell GL . Lyme disease in children in southeastern Connecticut. N Engl J Med 1996;335:1270-1274
Full Text | Web of Science | Medline5
Keller D ,Koster FT ,Marks DH ,Hosbach P ,Erdile LF ,Mays JP . Safety and immunogenicity of a recombinant outer surface protein A Lyme vaccine. JAMA 1994;271:1764-1768
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Dean T Nardelli, Erik L Munson, Steven M Callister, Ronald F Schell. (2009) Human Lyme disease vaccines: past and future concerns. Future Microbiology 4:4, 457-469
CrossRef2
G??ran G??nther, Mats Haglund. (2005) Tick-Borne Encephalopathies. CNS Drugs 19:12, 1009-1032
CrossRef3
Janine Evans. (1999) Lyme disease. Current Opinion in Rheumatology 11:4, 281-288
CrossRef
