More MS news articles for February 2001

The Risk of Vaccination -- The Importance of "Negative" Studies

The New England Journal of Medicine -- February 1, 2001 -- Vol. 344, No. 5

Falsehood flies and the truth comes limping after; so that when men come to be undeceived it is too late: the jest is over and the tale has had its effect.

-- Jonathan Swift (1)

Despite their success in the control and elimination of serious infectious diseases around the globe, vaccines are increasingly the focus of controversy rather than compliments. Concern about adverse effects -- real and otherwise -- has accompanied vaccines since the first uses of smallpox vaccine. (2) Yet skepticism about vaccines has flourished in our postmodern society, with its distrust of science, its increased attention to risk, and its citizens' advocacy for health. (3,4)

Perceptions of risk are amplified when the risk results from a deliberate human act rather than a random natural event, when the adverse consequence is debilitating, and when the associated benefit is unclear. (5,6) It is therefore not surprising that a vaccine that prevents hepatitis B infection is viewed in a different way from vaccines that prevent diseases with immediate, catastrophic manifestations, such as poliomyelitis or meningococcal disease. Yet for the public, as represented in the media, on the Internet, in the courtroom, and in the hearing rooms of Congress and state legislatures, the chief issues of concern do not always reflect the scientific evidence. Hypotheses can become "facts" long before the critical data are in.

The causes of some diseases remain unknown. When a substantial proportion of a population receives a vaccine, it is inevitable that some disease-related events will occur after its administration. If the cause of the disease is unknown, it is understandable that recipients of the vaccine and even some physicians may assume that sequence is consequence. It is easy for them to focus on the temporal association and conclude that the vaccination caused the disease or its increased activity.

This has been the problem with assessments of the role of immunizations in the pathogenesis of multiple sclerosis. (7,8,9) Because multiple sclerosis has an immunologic component whose precise mechanisms are unknown, it has been hypothesized that a stimulus of the immune system (such as a vaccine) might trigger a paradoxical response that results in an autoimmune disease. The vaccine hypothesis becomes more interesting when popular theories of immunology, such as molecular mimicry, are incorporated into the discussion of biologic plausibility, even if such theories are applied inappropriately. (10) In addition, the evidence for such a hypothesis may appear to be strengthened by anecdotes and published case reports that have the persuasive power of immediacy. Without doubt, some adverse events are caused by immunization; an example is vaccine-associated paralytic poliomyelitis after administration of the oral poliovirus vaccine. But, for many adverse events, particularly those that are rare or delayed beyond the immediate postimmunization period, only well-designed, well-conducted epidemiologic studies can determine which events are genuinely causally related.

A long-awaited "negative" study by Ascherio et al. in this issue of the Journal (11) provides solid evidence that there was no relation between the receipt of hepatitis B vaccine and the development of multiple sclerosis in a large population of women studied for many years. The study's robust design controlled for insidious effects of recall bias by means of rigorous confirmation of the dates of immunization as well as of the diagnosis of multiple sclerosis. Similarly, the study by Confavreux et al., also in this issue of the Journal, (12) demonstrates that the administration of vaccines against hepatitis B, influenza, and tetanus did not exacerbate the clinical course of multiple sclerosis in patients in whom the disease had already been diagnosed. The results of these studies should provide reassurance to recipients of these vaccines, to patients with multiple sclerosis, and to their physicians.

Traditionally, questions regarding the safety of vaccines came from members of the scientific community and were addressed by laboratory scientists, regulators, and epidemiologists during the course of vaccine development, clinical trials, and post-licensure surveillance. In recent years, however, stimulated by anecdotes and provocative stories highlighting the temporal sequence of events, concern has arisen about possible causal relations between immunizations and such disorders as sudden infant death syndrome, diabetes, and autism. It is the nature of science to challenge the status quo. Although some scientific controversies (for example, those surrounding cold fusion or cellular telephones and brain tumors (13)) can be settled with minimal effect on the public, contentions related to the safety of vaccines may have immediate consequences for public health when a wary public declines to be immunized. (14)

We should acknowledge the force of the consumer movement and the increasing influence on the scientific agenda of the questions and perceptions of the public and its spokespersons. (15) At what point do those questions gain sufficient standing to require the scientific community to undertake investigations? Resources, in terms of both dollars and expertise, are not unlimited, and setting priorities is difficult. Which of the public's questions ought to be investigated? How quickly? Which vaccine-related institutions should assume responsibility for conducting the studies? How are the results best disseminated to all who want and need them?

The public's understanding of immunizations is limited. A recent survey showed that 25 percent of parents believed that their child's immune system could actually be weakened by too many immunizations. Nearly the same proportion of parents thought that their children were already getting more vaccines than was good for them. (16) We need to make a concerted effort to educate everyone about what vaccines do and do not do and about the fact that temporal sequence does not demonstrate causality. The voice of science is important, but we cannot expect that scientific facts alone will be persuasive, especially since proving the absence of harm is the ultimate goal of studies of vaccine safety. If improved education is not successful, the fruits of our investments in immunization -- both now and in the future -- are likely to be viewed with skepticism, and necessary vaccines may remain on the shelf.


1. Swift J. The Examiner, Number 15 (November 9, 1710). In: Ellis FH, ed. Swift vs. Mainwaring: the examiner and the medley. Oxford, England: Clarendon Press, 1985:19-26.

2. Baxby D. Edward Jenner's inquiry: a bicentenary analysis. Vaccine 1999;17:301-7.

3. Gray JA. Postmodern medicine. Lancet 1999;354:1550-3.

4. Koch K. Vaccine controversies: are today's vaccines safe enough? CQ Researcher. August 25, 2000;10(28):641-72.

5. Covello VT. Risk comparison and risk communication: issues and problems in comparing health and environmental risks. In: Kasperson RE, Stallen PJM, eds. Communication risks to the public. Dordrecht, the Netherlands: Kluwer Academic, 1991:79-124.

6. Ball LK, Evans G, Bostrom A. Risky business: challenges in vaccine risk communication. Pediatrics 1998;101:453-8.

7. Sibley WA, Foley JM. Infection and immunization in multiple sclerosis. Ann New York Acad Sci 1965;122:457-68.

8. Halsey NA, Duclos P, Van Damme P, Margolis H. Hepatitis B vaccine and central nervous system demyelinating diseases. Pediatr Infect Dis J 1999;18:23-4.

9. Marshall E. A shadow falls on hepatitis B vaccination effort. Science 1998;281:630-1.

10. Stratton KR, Howe CJ, Johnston RB Jr. Adverse events associated with childhood vaccines: evidence bearing on causality. Washington, D.C.: National Academy Press, 1994:220.

11. Ascherio A, Zhang SM, Hernan MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001;344:327-32.

12. Confavreux C, Suissa S, Saddier P, Bourdes V, Vukusic S. Vaccinations and the risk of relapse in multiple sclerosis. N Engl J Med 2001;344:319-26.

13. Inskip PD, Tarone RE, Hatch EE, et al. Cellular-telephone use and brain tumors. N Engl J Med 2001;344:79-86.

14. Gangarosa EJ, Galazka AM, Wolfe CR, et al. Impact of anti-vaccine movements on pertussis control: the untold story. Lancet 1998;351:356-61.

15. Poland GA, Jacobson RM. Vaccine safety: injecting a dose of common sense. Mayo Clin Proc 2000;75:135-9.

16. Gellin BG, Maibach EW, Marcuse EK. Do parents understand immunizations? A national telephone survey. Pediatrics 2000;106:1097-102.

Bruce G. Gellin, M.D., M.P.H.
William Schaffner, M.D.
Vanderbilt University School of Medicine
Nashville, TN 37232

Copyright © 2001 by the Massachusetts Medical Society. All rights reserved.