Download that the increased numbers of NKG2C+ cells likely reflect the

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