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© 2005
Society for General Microbiology
Prevalence of antibodies to
Vaccinia virus
after smallpox vaccination in Italy
Mike M. Pütz
1
,
Isabella Alberini
2
,
Claire M. Midgley
1
,
Ilaria Manini
2
,
Emanuele Montomoli
2
and
Geoffrey L. Smith
1
1
Department of Virology, Faculty of Medicine, Imperial College London, St Mary's Campus, London W2 1PG, UK
2
Department of Physiopathology, Experimental Medicine and Public Health, University of Siena, Via A. Moro, 53100 Siena, Italy
Correspondence
Geoffrey L. Smith
glsmith{at}imperial.ac.uk
 |
ABSTRACT
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Decades after smallpox was eradicated and vaccination discontinued,
the level of residual immunity in today's population is largely
unknown. This study describes an epidemiological assessment
in Italians of antibodies against the intracellular mature virus
(IMV) and extracellular envelope virus (EEV) forms of
Vaccinia
virus
. Serum samples (
n
=642) were taken in 1993 and 2003 from
people between 11 and 102 years old. Most citizens >27 years
old were positive for antibodies to IMV and EEV. These antibodies
were long-lasting and similar titres were present in citizens
between 30 and 100 years old. Serum samples from 1993 and
2003 displayed very similar EEV- and IMV-specific antibody titres.
By using these data and demographic considerations, it was predicted
that, in 2003, 46 % of the Italian population were positive
for both IMV and EEV, 42 % were negative for both and 12 % were
positive for one antigen.
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MAIN TEXT
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Variola virus
, the causative agent of smallpox, was eradicated
in 1977 after widespread vaccination with
Vaccinia virus
(VACV)
(Fenner
et al
., 1988
). In Italy and many other European countries,
smallpox vaccination used predominantly VACV strain Lister/Elstree.
Vaccination was compulsory in Italy until 1976 (Tagarelli
et
al
., 2004
) although, after 1974, public-health services were
less stringent in their vaccination policy. Mass smallpox vaccination
was abandoned in most European countries in the early 1970s
and production of the vaccine was discontinued in the early
1980s.
Understanding of the immune responses induced after vaccination
with VACV is incomplete and concern about the deliberate release
of
Variola virus
(Smith & McFadden, 2002
) has prompted investigation
of how much immunity remains in populations today. It was generally
accepted that vaccination would protect most vaccinees for 5–10 years
(Fenner
et al
., 1988
), although the World Health Organization
(WHO) recommended revaccination every 3 years for those
in areas where smallpox was endemic. Recent studies have shown
that humoral (Crotty
et al
., 2003
; Frey
et al
., 2003
; Gallwitz
et al
., 2003
; Hammarlund
et al
., 2003
; Hatakeyama
et al
., 2005
;
Viner & Isaacs, 2005
) and cellular (Hammarlund
et al
., 2003
;
Amara
et al
., 2004
; Combadiere
et al
., 2004
; Kennedy
et al
.,
2004
) forms of immunity are long-lived after VACV immunization,
but it is unknown whether this remaining immunity will protect
against smallpox. Although analysis of historical data suggests
that protection after vaccination might last for several decades
(Hanna & Baxby, 2002
; Eichner, 2003a
), the last smallpox
fatality, in Birmingham, UK, in 1978, occurred despite the patient
having been vaccinated twice previously, once as a child and
once 12 years before contracting the disease (Shooter,
1980
).
VACV produces two morphologically and antigenically distinct
infectious forms of virus, called intracellular mature virus
(IMV) and extracellular envelope virus (EEV) (Smith
et al
.,
2002
). Most infectious virus particles remain in the cell as
IMV until cell lysis; this form is very stable and so is likely
to be responsible for host-to-host spread. EEV is wrapped by
a second lipid envelope containing several virus proteins. It
is released before cell lysis and is better-adapted for spread
within the host because it is relatively resistant to destruction
by complement (Vanderplasschen
et al
., 1998
) and neutralization
by antibodies (Abs) (Vanderplasschen
et al
., 1997
; Law &
Smith, 2001
). Studies in animal models showed that anti-EEV
Abs are more important than anti-IMV Abs for protection against
poxvirus challenge
in vivo
(Appleyard
et al
., 1971
; Boulter
& Appleyard, 1973
; Fogg
et al
., 2004
; Law
et al
., 2005
).
These findings emphasize the importance of measuring responses
to EEV as well as, or instead of, those against IMV when analysing
Abs induced by VACV vaccination.
Several virus-encoded glycoproteins are present on the EEV surface
(Smith
et al
., 2002
) and two of these, B5R and A33R, are important
targets for protective immune responses in animal models (Galmiche
et al
., 1999
; Hooper
et al
., 2003
; Fogg
et al
., 2004
; Pulford
et al
., 2004
). B5R is the major target of EEV-neutralizing Abs
induced after VACV immunization in rabbits (Law & Smith,
2001
; Law
et al
., 2005
) and in humans (Bell
et al
., 2004
; Law
et al
., 2005
) and, recently, mAbs that neutralize EEV by binding
to B5R were described (Aldaz-Carroll
et al
., 2005
). In addition,
the EEV-neutralizing activity of sera correlated with their
protective efficacy against intranasal VACV challenge in mice
(Galmiche
et al
., 1999
; Law
et al
., 2005
).
An epidemiological study of EEV-specific Abs decades after smallpox
vaccination has not been undertaken. In this study, we have
addressed this in the Italian population and measured the EEV
and IMV Ab titres by using ELISAs specific for recombinant B5R
protein and VACV-infected cell lysate, respectively (Law
et
al
., 2005
). ELISA Abs against VACV have been shown to correlate
with the presence of IMV-neutralizing Abs (Hammarlund
et al
.,
2003
; Hatakeyama
et al
., 2005
), whereas the Ab response to purified
B5R 42 kDa glycoprotein, produced in CHO cells (Law
et
al
., 2005
), correlates very well with EEV-neutralizing activity
(M. M. Pütz, C. M. Midgley, M. Law & G. L. Smith, unpublished
data) in human serum after VACV immunization. Anonymous serum
samples from routine laboratory testing in 1993 (
n
=119) (‘1993
group’) and between 2001 and 2003 (
n
=523) (‘2003
group’) were collected at the Central Laboratory in the
General Hospital of Siena, Italy, and were stored at –20
°C. Samples from subjects known to have an immunosuppressive
or acute infectious disease and from subjects who had undergone
a recent blood transfusion were excluded. Subjects ranged from
11 to 102 years of age at the time of sample collection
and their vaccination status was unknown.
To address what proportion of the Italian population contained
Abs to EEV and IMV and to address whether the titres of these
Abs varied with age, we used the ‘2003 group’ of
serum samples. Ninety-six-well plates were coated overnight
with 100 ng purified B5R or BSA (negative control) per
well, or UV-inactivated VACV-infected cell lysate corresponding
to 10
5
p.f.u. per well. Linear-regression plots were determined
for each serum sample and end-point titres were defined as dilutions
corresponding to twice the mean OD values obtained with BSA.
A control serum from an individual vaccinated twice (anti-B5R
titre, 1 : 544; anti-VACV titre, 1 : 2024) was used to normalize
results between plates and assays and the 60 serum samples from
subjects aged 11–20 years were used as a negative-control
group. Cut-off titres defining seropositivity/seronegativity
were calculated for B5R (1 : 75) and for VACV (1 : 364) as three
times the geometric mean titre (GMT) obtained in this group;
these values generated 100 % specificity.
In the ‘2003 group’, serum samples from the 11–20-year-old
group were all negative for Abs against B5R and VACV cell lysate,
but Abs to both antigens were detected in most older subjects
>25 years after vaccination with VACV was discontinued
in Italy (Table 1
, Fig. 1
). These findings show that
EEV-specific Abs persist long after smallpox vaccination and
are in accordance with the longevity of Abs against IMV described
previously (el-Ad
et al
., 1990
; Frey
et al
., 2003
; Gallwitz
et al
., 2003
; Hammarlund
et al
., 2003
). In the ‘2003 group’,
278 samples (53 %) were seropositive for B5R and 344 (66 %)
were positive for VACV (Table 1
). When seropositivity levels
obtained for B5R and VACV in the various age groups were compared
by using a Wilcoxon signed-rank test (
SPSS
12.0; SPSS Inc.),
a significantly higher seropositivity rate was observed for
VACV (
P
=0·0078). The majority of subjects negative for
both antigens were <30 years of age. In the group of
21–30-year-olds, only 15 (25 %) or 16 (27 %) subjects
were either B5R- or VACV-seropositive, respectively, and 15
(25 %) were seropositive for both antigens. The youngest subject
to test positive for both antigens was 28 years old (Fig. 1a,
b
) and was probably vaccinated at the very end of the smallpox-vaccination
campaign in Italy, 1976–1978.
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Table 1. Proportion of serum samples positive for B5R, VACV or both antigens by ELISA
The number and percentage (shown in parentheses) of positive and negative serum samples from 2003 and 1993 are shown. The contribution of each age group to Italian demography in 2003 is indicated and, from this, the percentage prevalence of seropositivity or seronegativity in the overall Italian population is estimated.
ND
, Not determined.
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Fig. 1. (a, b) Ab titres (reciprocal of dilution) against B5R (a) or VACV (b) detected in Italian people of different ages in 2003. (c) Geometric mean Ab titres and 95 % CI against B5R (filled bars) and VACV (empty bars) obtained in different age groups of the Italian population in 2003. (d) Comparison of B5R- and VACV-specific Ab titres obtained for all analysed samples (
n
=642). Cut-off titres defining seropositivity are indicated for B5R (dotted line) and VACV (dashed line).
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The percentage of subjects positive both for B5R and VACV was
in the range 49–64 %, except for the group of 41–50-year-olds
(82 %). An equally high percentage of ‘double positives'
was also observed in the serum samples of the 31–40-year-olds,
which were collected in 1993 and which are from the same decade
of birth (Table 1
, decade of birth 1953–1962). Surprisingly,
the different age groups (>30 years) showed similar
Ab levels (Fig. 1a, b
) and GMTs (Fig. 1c
) against
VACV and the same was true for B5R. Linear covariation analysis
using a two-tailed Spearman correlation test demonstrated no
correlation between the age of subjects and their B5R-specific
(
r
=–0·037,
P
=0·46) or VACV-specific (
r
=0·082,
P
=0·10) titres. To address this further, GMTs obtained
in the various 10-year cohorts (>30 years) were compared
by using a non-parametric, unpaired, two-tailed Mann–Whitney
U
test and a Bonferroni adjustment of the significance level
was applied for multiple comparisons. No significant differences
were observed when these age groups were compared with each
other (21 tests,
P
>0·0024), except for the group of
subjects aged 41–50 years, who displayed a higher
anti-B5R GMT than the subjects aged 61–70 years (
P
<0·001).
Similarly, the Ab GMTs in the serum samples collected in 1993
in age groups 31–40, 41–50 and 51–60 years
were not significantly different (Fig. 2
) (three tests,
P
>0·017).
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Fig. 2. Geometric mean antibody titres and 95 % CI against B5R (a) and VACV (b) obtained in different age groups (decades of birth) in 1993 (filled bars) and 2003 (empty bars).
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All these data suggested that the Ab titres were long-lived.
To investigate this further, additional serum samples that had
been collected in 1993 were tested and compared with the GMTs
of the ‘2003’ samples (Fig. 2
). The GMTs from
cohorts of the same decade of birth had very similar B5R- and
VACV-specific titres in 1993 and, 10 years later, in 2003
(
P
>0·05). The only significant difference was that,
surprisingly, the VACV-specific titre for people born between
1953 and 1962 was higher in 2003 than 1993 (
P
<0·05).
This might suggest that the size of the cohort analysed from
1993 was too small to prevent a bias being introduced through
sampling.
A comparison of the B5R- and VACV-specific ELISA titres (Fig. 1d
)
showed a reasonable correlation (two-tailed Spearman correlation
test,
r
=0·760,
P
<0·001,
n
=642), in that individuals
with higher titres for B5R also had higher titres for VACV.
Overall, the B5R-specific ELISA generated fewer positives than
the VACV-specific ELISA (Table 1
). This is probably because
the anti-VACV ELISA detects Abs to many different VACV antigens
and these are predominantly IMV or non-structural, because the
VACV-infected cell lysate used contains very little EEV-specific
antigenicity (Law
et al
., 2005
). In contrast, the EEV titre
is measured by a single antigen, which was produced in a mammalian-cell
expression system (Law
et al
., 2005
). Vaccinia immune globulin
(VIG) from vaccinated humans reacts predominantly with three
immunodominant antigens: H3L, an IMV envelope protein, and D13L
and A10L, two viral core proteins (Davies
et al
., 2005
). Our
observations suggest that IMV antigens also account for most
of the reactivity measured by VACV-specific ELISA (unpublished
data). Findings by Davies
et al
. (2005)
that VACV immunization
of humans induced no Abs against B5R in human VIG contrast with
our data (Law
et al
., 2005
) and might be due to use of an inappropriate
B5R protein that was unglycosylated and/or misfolded due to
its expression in
Escherichia coli
.
When taking into account the respective proportions of the different
age groups in the Italian population, it is predicted that the
267 samples from the ‘2003 group’ that contained
Abs against both B5R and VACV correspond to 46 % of the Italian
population (Table 1
). Similarly, the 168 ‘double-negative’
samples correspond to 42 % of the total population. The remaining
12 % were positive for one antigen only. The GMTs and the amount
of seropositive subjects observed for both B5R and VACV were
very similar in age groups over 30 years old. The group
aged 41–50 years displayed the highest percentage
of ‘double positives' in 2003; this may be due to a high
proportion of people born between 1953–1962 receiving
follow-up vaccinations during their compulsory schooling in
the course of the intensified immunization programme launched
by the WHO in 1967. Secondary immune responses after vaccination
occur more rapidly (McCarthy
et al
., 1958
; Frey
et al
., 2003
;
Greenberg
et al
., 2005
) and induce higher levels of remaining
Abs (Frey
et al
., 2003
; Hammarlund
et al
., 2003
; Greenberg
et
al
., 2005
; Viner & Isaacs, 2005
) than primary vaccination.
Further boosting (more than two vaccinations) had little effect
on long-term Ab levels (Hammarlund
et al
., 2003
; Viner &
Isaacs, 2005
).
Accurate knowledge of the residual immunity in a population
is important when evaluating the potential of
Variola virus
to spread in the human population if it were introduced (Gani
& Leach, 2001
) or policy options for controlling a potential
outbreak (Eichner, 2003b
; Ferguson
et al
., 2003
). In another
study, 1 year after revaccination with the Lister vaccine, we
observed levels (95 % confidence intervals) for B5R- and VACV-specific
Abs of 142–578 and 2084–5003, respectively (M. M.
Pütz, C. M. Midgley, M. Law & G. L. Smith, unpublished
data). If these titres are compared with the titres detected
in samples from the Italian population in 2003 and those samples
that are within these ranges (or higher) are counted, only 91
of the Italian samples, corresponding to 15 % of the Italian
population, are within the ranges for both antigens. However,
no conclusions can been drawn about the protective immunity
from the presence or absence of Abs against B5R and/or VACV,
because the exact contribution of neutralizing Abs in the mechanism
of protection is unknown. In the absence of any vaccination
records, it is impossible to determine what proportion of previously
vaccinated subjects lost their Ab immunity over time. A recent
report suggested that the capacity to neutralize EEV had diminished
by 20 years after vaccination (Viner & Isaacs, 2005
).
Except for some military personnel, health-care workers and
laboratory staff who have received vaccination recently, people
<27 years of age (29 % of the population) have never
been vaccinated and would be susceptible to smallpox.
In summary, this study describes the epidemiological prevalence
of EEV- and IMV-specific Abs in the Italian population. Regardless
of the fact that Abs induced against both infectious forms of
VACV are long-lived, a substantial proportion of the population
has never been vaccinated or has only very low Ab levels. High
levels of protection might only be achieved through revaccination
and, therefore, there is a need for a new and safer vaccine
against smallpox.
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ACKNOWLEDGEMENTS
|
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M. M. P. and C. M. M. are supported by a grant from the Department
of Health, UK. G. L. S. is a Wellcome Trust Principal Research
Fellow. The sample collection was funded from the University
of Siena project ‘Research Quote 2000’. We thank
Elena Kulinskaya (Statistical Advisory Service, Imperial College
London, UK) for advice on the statistical analysis.
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Received 15 June 2005;
accepted 20 July 2005.
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