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that the increased numbers of NKG2C+ cells likely reflect the challenge exerted by the virus on the innate immune system and that the frequency of reactivation episodes might be relevant in this context. In line with this hypothesis, the observations in HIV-1–positive patients suggested that immune control of the virus might be less efficient, if not defective, in healthy HCMV-positive individuals with higher numbers of NKG2C+ cells. In that case, the analysis of NKG2C+ cells might become a useful parameter for monitoring the host-pathogen relationship in different clinical settings. Monica Gumá and Miguel López-Botet Molecular Immunopathology Unit, Department of Experimental and Health Sciences— Universitat Pompeu Fabra, Barcelona, Spain References 1. Mela CM, Goodier MR. The contribution of cytomegalovirus to changes in NK cell receptor expression in HIV-1–infected individuals [letter]. J Infect Dis 2006; 195:158–9 (in this issue). 2. Gumá M, Cabrera C, Erkizia I, et al. Human cytomegalovirus infection is associated with increased proportions of NK cells that express the CD94/NKG2C receptor in aviremic HIV-1– positive patients. J Infect Dis 2006; 194:38–41. 3. Guma M, Angulo A, Vilches C, Gomez-Lozano N, Malats N, López-Botet M. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 2004; 104:3664–71. 4. Guma M, Budt M, Saez A, et al. Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood 2006; 107:3624–31. Potential conflicts of interest: none reported Reprints or correspondence: Miguel López-Botet, Molecular Immunopathology Unit, Dept. of Experimental and Health Sciences—Universitat Pompeu Fabra, C/ Dr Aiguader, 80, 08003 Barcelona, Spain ([email protected]). The Journal of Infectious Diseases 2007;195:159–60 2006 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2007/19501-0020$15.00 Predicting Residual Immunity against Smallpox To the Editor—Kim et al. [1] reported that an intradermal skin test using inactivated vaccinia virus would be useful for the evaluation of vaccine-induced immunity against smallpox. They wrote that the skin test is “a simple, rapidly interpretable, and reliable method for prediction of residual immunity to smallpox” (p. 383) and compared the test with those using a neutralizing antibody or a cellmediated immune reaction. Although it is certainly true that knowing the immunity status of the present population is important, we have serious concerns about the authors’ methods and discussion. Unfortunately, the experimental design is technically flawed. The authors assessed the diagnostic performance of the skin test in predicting the characteristic skin reactions to vaccinia virus [1]. That is, they suggested that sizes of induration and erythema after the intradermal skin test explained the outcome variable (i.e., the presence of the “skin reaction”; p. 379) better than other laboratory immune reactions. Even without the authors’ experiments, it is clear that one type of skin sign at the site of vaccination almost perfectly predicts another type of skin reaction to the same vaccination (i.e., laboratory immune reactions must be far less efficient at predicting the characteristic skin reaction). The most telling phrase, which was not discussed by the authors in detail, is “the correlate between the major reaction to vaccination and actual protection against smallpox.” Although the authors argued that the skin test might imply residual immunity (i.e., partial protection) against smallpox, there is no firm evidence suggesting that this is the case; thus, any direct implications regarding smallpox are speculative. From our epidemiological and historical viewpoints, Kim et al. have made the same mistake made by previous smallpox specialists. Shortly after the discovery of the cowpox vaccine by Jenner in the late 18th century, Dr. Luigi Sacco, an Italian physician, inoculated himself and others several times with cowpox and suggested the usefulness of revaccination in assessing the effectiveness of prior vaccination [2]. In his experiment, the absence of immunity after primary vaccination was con- 160 • JID 2007:195 (1 January) • CORRESPONDENCE firmed by observing a major reaction to revaccination (i.e., Jennerian vesicles at the vaccination site), as in the study by Kim et al. Because this method of evaluating immunity appeared to be convenient, a number of similar trials were conducted during the late 19th and early 20th century, mainly in the United Kingdom and Germany [3, 4]. However, because the absence of major reactions appeared to not be predictive of actual protection against smallpox, and because a negative reaction to revaccination after several months or years has often been mistaken as evidence of immunity, the Expert Committee on Smallpox of the World Health Organization recommended that this method should not be used for the assessment of vaccine-induced immunity against smallpox [5]. Moreover, in evaluating the reaction to revaccination, it is technically difficult to give definite opinions as to the expected major reaction (i.e., vaccine “take” after revaccination) [6]. Thus, the history of smallpox control has taught us that the presence or absence of a major reaction to revaccination is not at all useful in evaluating vaccine-induced immunity (especially when the revaccination occurs long after primary vaccination). We agree that it would be extremely useful if we could measure the immune status of the present population at an individual level. We are far from convinced, however, that a skin test is truly the appropriate approach for this problem. In the absence of smallpox, methods to assess residual protection must rely on either laboratory-based immunological reactions [7] or epidemiological estimates based on previous outbreaks [8–10]. Rather than an inconclusive skin test, epidemiological estimates of the duration of immunity at a population level would be more useful for roughly predicting partial protection of the present population [9, 10]. On the basis of our estimates, the duration of vaccine-induced immunity against smallpox (i.e., protection against the disease) might be almost completely lost ∼30 years after primary vaccination; thus, it is reasonable to assume that the present population will not be protected unless recently vaccinated [9]. On the other hand, we found a longlasting partial protection against severe and fatal smallpox, which may be life-long for a substantial fraction of the population [8–10]. Thus, in the event of a bioterrorist attack, epidemiological estimates suggest that persons involved in emergency tasks before emergency vaccination practices are reestablished should ideally have been recently, or at least previously, vaccinated. In addition to this population-based conclusion, the actual roles played by each immune reaction should be carefully explored to predict the immune status of previously vaccinated individuals. ondary vaccination failure. Infection 2006; 34: 241–6. Financial support: Banyu Life Science Foundation International (support to H.N.); DG Sanco (project MODELREL to M.E.); European Union (project INFTRANS to M.E.); German Ministry of Health and Social Security (support to M.E.). Potential conflicts of interest: none reported. Reprints or correspondence: Dr. Hiroshi Nishiura, Dept. of Medical Biometry, University of Tübingen, Westbahnhofstr. 55, Tübingen, D-72070, Germany ([email protected]). The Journal of Infectious Diseases 2007;195:160–1 2006 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2007/19501-0021$15.00 Reply to Nishiura and Eichner To the Editor—We appreciate the thoughtful comments of Nishiura and Eichner [1] about our article [2]. They suggested that skin lesions after smallpox vaccination are not useful in the evaluation of vaccineinduced immunity. However, smallpox vaccination has been used as an immunization procedure and as a test of existing immunity since Jenner’s time [3]. Since the early 1900s, the descriptive terms “vaccinia” (or “primary reaction,” seen in those who have completely lost effective immunity), “vaccinoid” (or “accelerated reaction,” seen in those who retain only partial immunity), and “immune reaction” have come into more general use [4, 5]. Later, the use of the term “immune reaction” was discontinued, and “immediate reaction” was used to describe the peak of the reaction within 3 days after vaccination [6]. As Nishiura and Eichner’s Hiroshi Nishiura1,2 and Martin Eichner1 1 Department of Medical Biometry, University of Tübingen, Tübingen, Germany; 2Research Center for Tropical Infectious Diseases, Nagasaki University Institute of Tropical Medicine, Nagasaki, Japan References 1. Kim S-H, Bang J-W, Park K-H, et al. Prediction of residual immunity to smallpox, by means of an intradermal skin test with inactivated vaccinia virus. J Infect Dis 2006; 194: 377–84. 2. Sacco L. Trattato di vaccinazione con osservazioni sul giavardo e vajuolo pecorino. Milano: Tipografia Mussi, 1809. 3. Acland TD. Vaccinia in man: a clinical study. London: Macmillan, 1897. 4. von Pirquet CP. Klinische Studien über Vakzination und vakzinale Allergie. Münch Med Wochenschr 1906; 53:1457–8. 5. World Health Organization. WHO Expert Committee on Smallpox: first report. WHO Tech Rep Ser 1964; 283:1–37. Available at: http: //whqlibdoc.who.int/trs/WHO_TRS_283.pdf. Accessed 28 July 2006. 6. Rao AR. Smallpox. Bombay: The Kothari Book Dept, 1972:168–9. 7. Hammarlund E, Lewis MW, Hansen SG, et al. Duration of antiviral immunity after smallpox vaccination. Nat Med 2003; 9:1131–7. 8. Eichner M. Analysis of historical data suggests long-lasting protective effects of smallpox vaccination. Am J Epidemiol 2003; 158:717–23. 9. Nishiura H, Schwehm M, Eichner M. Still protected against smallpox? Estimation of the duration of vaccine-induced immunity against smallpox. Epidemiology 2006; 17:576–81. 10. Nishiura H, Eichner M. Estimation of the duration of vaccine-induced residual protection against severe and fatal smallpox based on sec- Figure 1. Dot plot of the correlation between peak vaccinia viral shedding (log10 plaque-forming units/mL) and size of induration (A) and erythema (B) in a skin test. There was a significant correlation between peak viral shedding and the size of induration (P ! .001 ) and erythema (P ! .001). The dotted line is the line of best fit. CORRESPONDENCE • JID 2007:195 (1 January) • 161