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Vaccine 22 (2004) 3707–3712

Tetanus and diphtheria antibodies and response to


a booster dose in Brazilian HIV-1-infected women
Tatiana C.S. Bonetti, Regina C.M. Succi, Lily Y. Weckx,
L. Tavares-Lopes, M. Isabel de Moraes-Pinto∗
Department of Pediatrics, Division of Pediatric Infectious Diseases, Federal University of São Paulo, São Paulo, Brazil
Received 4 July 2003; accepted 9 March 2004

Available online 9 April 2004

Abstract
Tetanus and diphtheria (Td) antibodies were studied in HIV-1-infected women during puerperium. HIV group (n = 61) was compared
with Control group (n = 101). Twenty-one women from HIV and 13 from Control group who had antibody levels lower than 0.1 IU/mL
received a booster with Td vaccine. Antibodies were assessed by double antigen ELISA. Mean tetanus and diphtheria antibody levels from
HIV group were lower than those from Control group. Multiple linear regression analysis showed that tetanus and diphtheria antibody
levels were decreased by HIV-1-infection, and that was independent of the reduction due to the time interval between last booster and
antibody assessment. After a booster dose, both groups had an increase in mean tetanus and diphtheria antibody levels, but in Control
group the levels were higher than in HIV group.
© 2004 Elsevier Ltd. All rights reserved.
Keywords: Tetanus; Diphtheria; HIV infection

1. Introduction regular boosters such as tetanus and diphtheria, antibody de-


cay tends to be faster in HIV-infected subjects [6].
Tetanus and diphtheria (Td) are life-threatening diseases Previous studies have already assessed tetanus and diph-
that can be prevented through immunization. After routine theria antibodies in HIV-infected individuals [7–12]. How-
vaccination, booster doses are necessary to maintain anti- ever, small numbers of patients were tested and, except for
body levels [1]. In areas where diphtheria is still endemic, one, they have not foccused on women of childbearing age.
natural boosters can occur and that will contribute to in- Considering the potential risk of low antibody levels for
crease diphtheria antibodies [2]. both women and their offspring in developing countries, we
Tetanus toxoid administration is especially relevant in have evaluated tetanus and diphtheria antibodies in that pop-
women of childbearing age to prevent neonatal tetanus, so ulation, and have compared them with healthy uninfected
that during pregnancy, the time interval between boosters controls.
should be shortened to 5 years [3]. As for diphtheria, a clear
example of the risk of enlarging pool of susceptible persons
was the diphtheria outbreak in countries belonging to the 2. Material and methods
ex-URSS in the nineties [4].
In HIV-seropositive individuals who were infected after 2.1. Study population
primary immunization, antibody levels against vaccine pre-
ventable diseases tend to be similar to those found in general The present study was conducted from January 1998–
population [5]. However, especially for antigens that need 2002 at the Federal University of São Paulo, in São Paulo,
Brazil. This work was submitted to Ethics Committee of the
∗ ◦ Federal University of São Paulo, Brazil and written consent
Corresponding author. Present address: Rua Pedro de Toledo, n

781-9 Andar, Vila Clementino, São Paulo, SP, Brazil.
was obtained from all patients.
Tel.: +55-11-55746471; fax: +55-11-55746471. Participants were women in the puerperium who were
E-mail address: m.isabelmp@uol.com.br (M.I. de Moraes-Pinto). divided in two groups: HIV group, with HIV-1-infected

0264-410X/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2004.03.023
3708 T.C.S. Bonetti et al. / Vaccine 22 (2004) 3707–3712

women whose children were regulary followed up at For diphtheria antibodies, the same method was applied
the Pediatric AIDS Clinic; Control group, with healthy with some modifications: 0.05 ␮g/mL of diphtheria toxoid
HIV-seronegative women who had given birth at the Ma- (Butantan Institute, Brazil), diphtheria reference serum (in
ternity Hospital of the Federal University of São Paulo. house standard calibrated against “diphtheria antitoxin hu-
HIV-1-infection was defined using the CDC criteria [13]. man serum 91/534”—NIBSC reagent) and biotin-labeled
Women from HIV group who had recent available CD4+ T diphtheria toxoid were used as substitutes for the correspon-
cells counts were divided into three groups: CD4+ T lym- dent tetanus reagents.
phocyte count ≥500, <500 and ≥200 and <200 cells/␮L. Tetanus and diphtheria antibodies were expressed in In-
For each participant a form was completed with informa- ternational Units per millilitre (IU/mL) using the curve com-
tion about age, previous immunization, antenatal care and parison method to transform optical density in concentration
most recent CD4+ T lymphocyte count. Women who re- units.
ferred at least one dose of tetanus and diphtheria vaccine in
the last 10 years before this study were selected for antibody 2.5. Protective antibody levels
analysis.
Patients were classified according to internationally
2.2. Blood sample collection accepted criteria of protective antibody levels [15–19].
Tetanus and diphtheria antibody concentrations lower than
Venous blood samples were collected from all participants 0.01 IU/mL were considered without protection; levels be-
at study entry. For individuals who received a booster dose tween 0.01 and 0.09 IU/mL, basic immunity; and levels
of Td, blood was also drawn at two other occasions: up to greater than 0.1 IU/mL, full protection.
90 days before vaccination and 25–90 days after.
Samples were centrifuged at 800 × g for 10 min. Serum
was separated and stored at −70 ◦ C until tested. 2.6. Statistical analysis

2.3. Immunization For statistical analysis, sera without detectable antibodies


were arbitrarily assigned the value of 0.005 IU/mL. Geomet-
Thirteen women in Control group and 21 in HIV ric means of tetanus and diphtheria antibodies were calcu-
group with tetanus and/or diphtheria antibodies lower than lated from raw data.
0.1 IU/mL received a booster dose with Td vaccine (Butan- Due to non-normal distribution of values, they were sub-
tan Institute, Brazil). This vaccine contained 10 Lf/dose of mitted to logarithmic transformation before analysis.
tetanus toxoid and 2 Lf/dose of diphtheria toxoid. Mean antibody levels were compared using Student’s
t-test and ANOVA, with differences among groups assessed
2.4. Measurement of antibodies by Tukey comparison. Fisher exact and chi-square tests
were used to compare proportions of individuals in each
Tetanus and diphtheria antibodies were measured by dou- group in relation to age, origin, antenatal care and time
ble antigen ELISA as described by Kristiansen et al. [14]. interval between last booster and antibody assessment.
For tetanus antibodies, 0.08 ␮g/mL of tetanus toxoid (Butan- Multiple linear regression analysis was used to investi-
tan Institute, Brazil) diluted in 0.1 M carbonate-bicarbonate gate the interference of each studied variable in tetanus and
buffer, pH 9.6, were used to coat 96-well microtiter plates diphtheria antibody levels.
(Dynex, USA) overnight at 4 ◦ C.
Two-fold serial dilutions of serum samples and of
tetanus reference serum (in house standard calibrated 3. Results
against “tetanus antitoxin human immunoglobulin NIBSC
reagent 1976 (76/589)”) in dilution buffer (0.01M PBS, 3.1. Characteristics of study population
pH 7.2, 1% Triton X-100) with 1% bovine serum albu-
min (BSA) were added to the plate and incubated for 1 h All participants were women in puerperium. The Con-
at 37 ◦ C. In the next step, biotin-labeled tetanus toxoid in trol group consisted of 101 women and the HIV group,
dilution buffer was added to the plate and incubated for 61 women. The mean age in Control group was 27 years
1 h at 37 ◦ C. Streptavidin-alkaline phosphatase conjugate (range, 16–43 years) and in HIV group was 30 years (range,
(Zymed, USA) in dilution buffer was incubated for 1 h 19–44) (Student’s t-test, P = 0.002). The two groups did
at 37 ◦ C. p-Nitrophenyl-phosphate (Sigma, USA) in 1 M not differ in terms of antenatal care during the pregnancy
diethanolamine, 0.005 M magnesium chloride buffer, pH (Control group: 97.5%; HIV group: 96.7%; Fisher exact
9.8, was used as substrate and the absorbance was read test, P = 0.063), origin (women born in the State of São
at 450 nm in an immunoreader ELX-800 (Bio-Tek Instru- Paulo—Control group: 54.9%; HIV group: 55.0%; χ2 , P =
ments, USA). Between steps, the plate was washed five 0.995) and the time interval between last booster and anti-
times in dilution buffer. body assessment Control group: 1.5 years (range, 0.01–8.0);
T.C.S. Bonetti et al. / Vaccine 22 (2004) 3707–3712 3709

Table 1 Table 2
Epidemiologic characteristics of the study population Distribution of women from Control and HIV groups in categories of
immunity for tetanus and diphtheria
Group Control HIV P
Control group HIV group
Mean age, in years 27 (16–43) 30 (19–44) 0.002a
(range) Tetanusa (IU/mL)
Antenatal care during 97.5% 96.7% 0.063b <0.01 2% (2/101) 11% (7/61)
pregnancy ≥0.01 and <0.1 7% (7/101) 18% (11/61)
Women born in the 54.9% 55.0% 0.995c ≥ 0.1 91% (92/101) 71% (43/61)
State of São Paulo
Diphtheriab (IU/mL)
Mean time interval, in 1.5 (0.01–8.0) 0.7 (0.1–8.0) 0.617a
<0.01 1% (1/101) 3% (2/61)
yearsd (range)
≥0.01 and <0.1 5% (5/101) 21% (13/61)
a Student’s t-test. ≥0.1 94% (95/101) 76% (46/61)
b Fisher exact test.
c Chi-square test. a The proportion of women in Control group with tetanus antibody
d Time interval, in years, between last booster and antibody assessment. levels ≥0.1 IU/mL (91%) was higher than that of women in HIV group
(71%) (χ2 : P = 0.001). The proportion of women in Control group
with tetanus antibody levels <0.01 IU/mL (2%) was smaller than that of
HIV group: 0.7 years (range, 0.1–8.0; Student’s t-test, P = women in HIV group (11%) (Fisher exact test: P = 0.027).
b The proportion of women in Control group with diphtheria antibody
0.617). The epidemiologic characteristics of the individuals
levels ≥0.1 IU/mL (94%) was higher than that of women in HIV group
enrolled in the study are summarized in Table 1. (76%) (χ2 : P = 0.001). The proportion of women in Control group
with diphtheria antibody levels <0.01 IU/mL (1%) was similar to that of
3.2. Seroprevalence of tetanus and diphtheria antibodies women in HIV group (3%) (Fisher exact test: P = 0.557).

Mean tetanus antibody levels were significantly lower act test, P = 0.557). However, for tetanus, the propor-
in HIV group (0.22 IU/mL) than in Control group tion of women in Control group with antibodies lower than
(1.34 IU/mL), (Student’s t-test, P < 0.001) (Fig. 1A). The 0.01 IU/mL (2%) was smaller than that of women in HIV
same was observed for diphtheria antibodies, with mean group (11%) (Fisher exact test, P = 0.027).
levels in HIV group (0.41 IU/mL) significantly lower than
those from Control group (1.83 IU/mL) (Student’s t-test, 3.3. Tetanus and diphtheria antibodies according to
P < 0.001) (Fig. 1B). CD4+ T lymphocyte counts
The percentage of individuals with full protection against
tetanus in HIV group (71%) was lower than in Control group Mean tetanus antibody levels in HIV-1-infected individ-
(91%) (χ2 , P = 0.001). For diphtheria, the percentage of uals subdivided according to CD4+ T lymphocyte counts
individuals with antibody levels ≥0.1 IU/mL was also lower were significantly lower in two subgroups (CD4+ ≥500 and
in HIV group (76%) than in Control group (94%) (χ2 , P = <500 and ≥200) when compared with Control group (Tukey
0.001) (Table 2). No statistical difference was noticed be- comparison, P = 0.01 and 0.01, respectively) (Fig. 2A).
tween HIV and Control groups when women were divided For diphtheria antibodies, the same situation was observed:
using 0.01 IU/mL antibody levels for diphtheria (Fisher ex- HIV subgroups CD4+ ≥ 500 and CD4+ < 500 and ≥ 200

p < 0.001 p < 0.001


GM (IU/mL) 1.83 0.41
GM (IU/mL) 1.34 0.22
148.4
Diphtheria antibody levels (IU/mL)

148.4 n = 101 n = 61 n = 101 n = 61


Tetanus antibody levels(IU/mL)

12.2
12.2

1.0 1.0

0.08 0.08

0.007 0.007

Control HIV Control HIV


(A) group group (B) group group

Fig. 1. (A) Tetanus antibody levels in Control and HIV groups. (B) Diphtheria antibody levels in Control and HIV groups. Geometric mean (GM) antibody
levels and number of individuals in each group are shown over graphs for both tetanus and diphtheria. Statistical analysis employed Student’s t-test.
3710 T.C.S. Bonetti et al. / Vaccine 22 (2004) 3707–3712

p = 0.01 p = 0.03
p = 0.01 p = 0.01

GM (IU/mL) 1.34 0.17 0.24 0.41 GM (IU/mL) 1.83 0.48 0.35 1.06
Diphtheria antibody levels (IU/mL)
Tetanus antibody levels (IU/mL)

148.4 n = 101 n = 18 n = 16 n=9 n = 101 n = 18 n = 16 n=9


148.4

12.2 12.2

1.0 1.0

0.08 0.08

0.007 0.007

Control CD4 < 500 Control CD4 < 500 CD4 < 200
CD4 >= 500 CD4 < 200 CD4 >= 500
(A) group and >= 200 (B) group and >= 200
HIV HIV
group group

Fig. 2. Tetanus and diphtheria antibody levels in Control and HIV groups. HIV group was subdivided according to CD4+ T lymphocyte counts (cells/␮L).
Geometric mean (GM) antibody levels and number of individuals in each group are shown over graphs for both tetanus and diphtheria. Statistical analysis
employed ANOVA, with differences between groups assessed by Tukey comparison.

showed a statistical difference from Control group (Tukey Table 3


comparison, P = 0.01 and 0.03, respectively) (Fig. 2B). No Effects of independent variables (HIV infection, age, origin and time
interval between last booster and antibody assessment) on tetanus and
differences were found among HIV subgroups neither for
diphtheria antibody levels
tetanus nor for diphtheria antibodies.
Variables Coefficient S.D. P

3.4. Multiple linear regression analysis Tetanus


Constant 2.47 0.60 <0.001
Group −1.71 0.32 <0.001
Multiple regression analysis showed that HIV infection Age (years) −0.06 0.02 0.008
per se reduced tetanus antibody levels in 1.71 IU/mL (P < Origin −0.62 0.30 0.040
0.001); for diphtheria, the reduction was in 1.47 IU/mL (P = Time interval (years) −0.22 0.08 0.004
0.011). On the other hand, independently of HIV status, an- Diphtheria
tibody levels proved to be inversely correlated with the time Constant 0.58 0.25 0.02
since last immunization, decreasing them by 0.22 IU/mL for Group −1.47 0.30 0.011
tetanus (P = 0.004) and by 0.21 IU/mL for diphtheria (P = Origin 0.73 0.28 0.011
Time interval (years) −0.21 0.07 0.005
0.005) for each year. Mean tetanus antibodies were also de-
creased by 0.06 IU/mL for each year of age (P = 0.008). Note: Estimates are derived from multiple linear regression analysis of
natural log on tetanus antibody levels and diphtheria antibody levels.
To be born in a Brazilian State other than the State of São
Tetanus regression equation: ln tetanus antibody levels = 2.47–1.71 group,
Paulo decreased tetanus antibody levels by 0.62 IU/mL (P = −0.06 age, −0.62 origin, −0.22 time interval. Diphtheria regression
0.040), and increased diphtheria antibodies by 0.73 IU/mL equation: ln diphtheria antibody levels = 0.58–1.47 group, +0.73 origin,
(P = 0.011) (Table 3). −0.21 time interval.

3.5. Tetanus and diphtheria antibodies after one Td dose mean diphtheria antibody levels after booster (0.55 IU/mL)
than Control group (2.94 IU/mL), with P value close to
We compared the response to one Td vaccine dose in 21 significance level (Student’s t-test, P = 0.069) (Fig. 3).
women from HIV and 13 women from Control group. Be- Due to the small number of women who were assessed
fore booster, women from both groups had tetanus and/or for the response to a booster Td dose, we were not able to
diphtheria antibodies lower than 0.1 IU/mL. Mean antibody subdivide the HIV group according to CD4+ T lymphocyte
levels did not differ either: 0.04 and 0.04 IU/mL for tetanus levels.
(Student’s t-test, P = 0.43) and 0.02 and 0.04 IU/mL for
diphtheria (Student’s t-test, P = 0.085) in HIV and Control
groups, respectively. 4. Discussion
After a booster dose, both groups had an increase in
mean tetanus and diphtheria antibody levels. Mean tetanus In this study, we have tested tetanus and diphtheria anti-
post-booster antibody levels were significantly lower in HIV bodies in Brazilian HIV-1-infected women of childbearing
group (2.94 IU/mL) than in Control group (7.87 IU/mL) age. We chose this population because, apart from assessing
(Student’s t-test, P = 0.025). HIV group had also lower specific immunity to these diseases in the women, we would
T.C.S. Bonetti et al. / Vaccine 22 (2004) 3707–3712 3711

P = 0.025 P = 0.069

P =0.0001 P = 0.0003 P = 0.0001 P = 0.0004

GM (IU/mL) 0.04 7.87 0.04 2.94 GM(IU/mL) 0.04 2.94 0.02 0.55

148.4
Diphtheria antibody levels (IU/mL)

148.4
Tetanus antibody levels (IU/mL)

20.1 20.1

2.72 2.72

0.37 0.37

0.05 0.05

0.007 0.007

0.001 0.001
pre-boosterp ost-boosterp re-booster post-booster pre-booster post-booster pre-booster post-booster

Control group HIV group Control group HIV group


(A) n =9 n = 15 (B) n = 10 n = 11

Fig. 3. Tetanus and diphtheria antibody levels in Control and HIV groups before and after one Td dose. Geometric mean (GM) antibody levels and
number of individuals in each group are shown over graphs for both tetanus and diphtheria. Statistical analysis employed paired Student’s t-test to
assess differences between pre- and post-booster antibody levels within each group; Student’s t-test was used to assess differences between post-booster
antibody levels in Control and HIV groups for both tetanus and diphtheria.

be indirectly evaluating their capacity to transmit tetanus into immunologic categories for HIV infection. However, no
passive immunity to their offspring in the event of a future difference among HIV subgroups was observed. Although
pregnancy. this finding may indicate a qualitative derangement in early
Women from HIV and Control groups had similar epi- phases of HIV disease, it may also reflect a small sample
demiologic characteristics, except for age (Table 1). As size in different subgroups.
tetanus and diphtheria antibodies tend to decrease with Kroon et al. [10] did not find statistically lower diph-
time [16,20], we were aware that difference in age between theria antibodies in HIV-infected individuals, and found
groups might introduce a bias in the study. However, results lower tetanus antibodies only in those with CD4+ T cells
from multiple regression analysis proved that other variables lower than 100 cells/␮L when compared with Control
were independently associated with antibody levels. HIV-negative subjects.
Both tetanus and diphtheria antibodies were lower in We have then performed multiple regression analyses to
HIV group when compared with Control group (tetanus, assess the effect of each separate variable on tetanus and
1.34 IU/mL versus 0.22 IU/mL; diphtheria, 1.83 IU/mL ver- diphtheria antibodies. We have shown that HIV infection
sus 0.41 IU/mL) (Fig. 1A and B). Previous studies have was associated with a strong reduction in both tetanus and
not found differences in tetanus [11] or diphtheria antibod- diphtheria mean antibodies and that was independent of the
ies [10] when HIV and healthy controls were compared. effect of time interval between last booster and antibody as-
This lack of difference might be due to different laboratory sessment, which was also associated with lower antibodies.
techniques to assess antibodies with different degrees of ac- Interestingly, older age was associated with a mean decrease
curacy [11]. Also, some researchers had small sample sizes in tetanus but not diphtheria antibodies. Other authors have
[10], what might have interfered with their results. On the found that susceptibility to both diseases increased with age
other hand, as will be discussed later, studying a group of [18,21–24].
HIV-infected individuals with a less altered immune system Higher mean diphtheria antibodies were associated with
might lead to a reduced difference with healthy subjects. women who were born in Brazilian States other than the
The distribution of both groups in categories for tetanus State of São Paulo. While diphtheria is controlled in the
and diphtheria (Table 2) also showed a lower proportion of latter, cases of the disease still occur in other Brazilian re-
HIV-infected women fully immune to tetanus and diphtheria gions [25]. We then hypothesize that more frequent natural
(≥0.1 IU/mL). We have also observed a higher proportion boosters might have contributed to the association observed
of women from HIV group who were susceptible to tetanus through multiple regression analysis.
(<0.01 IU/mL). The large percentage of HIV-infected Lastly, we assessed the effect of a booster Td dose in
women in the intermediate immune category for both dis- women from both groups who had shown low tetanus and/or
eases probably reflects the effect of a faster antibody decay diphtheria antibodies (lower than 0.1 IU/mL). They were in-
and a lower response to booster doses in that population [6]. dividuals who really needed the intervention and pre-booster
We expected to find a progressive reduction in mean an- antibody assessment was similar in both groups. Our results
tibody levels when women from HIV group were divided have shown that women from HIV and Control groups are
3712 T.C.S. Bonetti et al. / Vaccine 22 (2004) 3707–3712

able to respond to the vaccination. However, the magnitude differentiation of B lymphocytes from asymptomatic human
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