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*
Medical Research Council Laboratories, Banjul, The Gambia;
World Health Organization Center of Vaccinology and Neonatal Immunology, University of Geneva Medical School, Geneva, Switzerland;
London School of Hygiene and Tropical Medicine, London, United Kingdom;
Wellcome Trust Center for Molecular Mechanisms in Disease, University of Cambridge, Cambridge, United Kingdom; and
¶ Danish Epidemiology Science Center, Copenhagen, Denmark
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4 million infants yearly (1, 2). This
increased susceptibility to infections is related to an immaturity of
the immune system that also prevents the induction of protective immune
responses by vaccines (1, 2). Studies in mice indicate
that immune responses at birth are often biased toward the Th2 type and
defective in the Th1 type, the central defense mechanism against
intracellular pathogens (1, 3). Relatively little is known
about helper T cell responses in human newborns. Recent data showing
that human cord blood-derived dendritic cells have a profound defect in
the production of IL-12, a cytokine playing a central role in the
differentiation of Th1 lymphocytes, suggest that type 1 responses could
also be defective in human newborns (4). In contrast, we
observed that Mycobacterium bovis bacillus
Calmette-Guérin
(BCG)3 vaccination
induces a potent Th1-type immune response at birth in humans as in mice
(5, 6, 7). This could be related to the potent APC-activating
properties of BCG and/or to its persistence during the maturation of
the immune system (1). By inducing a potent Th1-type
response at birth, BCG could influence the immune response to unrelated
Ags. We have observed that BCG immunization during the first week of
life is associated with a reduced risk of atopy in children in
Guinea-Bissau (8). BCG is the world’s most widely used
vaccine and although its efficacy against adult disease is variable, it
protects against childhood tuberculosis (9). Therefore, an
influence of BCG on immune responses to unrelated Ags would have
important public health implications. The objective of this study was to evaluate whether the Th1-type immune response induced by BCG could influence the T cell and the Ab responses to unrelated vaccine Ags. Children were recruited at birth and were randomly allocated to one of three study groups: those receiving BCG at birth, at 2 mo, or at 4.5 mo of age. This design allowed us to analyze the effect of BCG when given (1) at the time of priming with hepatitis B vaccine (HBV) and oral polio vaccine (OPV) at birth or with diphtheria/pertussis/tetanus vaccine (DPT) at 2 mo of age or (2) at the time of booster immunization with HBV and OPV at 2 mo of age. Immune responses to vaccines were measured at 4.5 mo of age and, therefore, were not influenced by BCG in control infants who received BCG at 4.5 mo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study was a prospective and randomized trial approved by
The Gambia Government/Medical Research Council Ethics Committee.
Newborns were enrolled at birth at Royal Victoria Hospital (Banjul, The
Gambia) after maternal informed consent. The following were excluded
from the study: neonates born to mothers with systemic infection at the
time of delivery, newborns with congenital defects, newborns with birth
weight less than 2.5 kg, and twins. When a person with a suggestive
history of tuberculosis was found in the compound, the newborn was
vaccinated with BCG and was excluded from the study. Enrolled newborns
were randomly allocated in blocks of six to one of three groups: those
receiving BCG immediately (group 1), those receiving BCG at 2 mo of age
(group 2), or those receiving BCG at 4.5 mo of age (control infants;
Table I). All other vaccines
were given according to recommendation of the Gambian Expanded Program
for Immunization, including OPV at birth, and at 1, 2, and 3 mo; HBV at
birth, and at 2, and 4 mo; and DPT at 2, 3, and 4 mo (Table I
). Blood
samples were collected at birth (cord blood), and at 2, and 4.5 mo of
age (Table I). One hundred fifty-one newborns were enrolled into the
study. One hundred four were studied at 2 mo, including 35, 35, and 34
infants vaccinated with BCG at birth, and at 2, or 4.5 mo of age,
respectively. Eighty-five were studied at 4.5 mo, including 28, 29, and
28 infants vaccinated with BCG at birth, and at 2 or 4.5 mo of age,
respectively. Infants who were lost to follow-up had similar
socio-demographic and clinical characteristics at birth as that of
followed-up infants. Prevaccination T cell responses to BCG and HBV
were measured in a consecutive series of 23 cord blood samples.
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BCG (0.05 ml; Aventis Pasteur, Lyon, France) was given intradermally in the left arm. HBV (0.5 ml, Engerix B; Glaxo SmithKline, Rixensart, Belgium) and whole-cell DPT (0.5 ml; Aventis Pasteur) were injected i.m. in the left arm. OPV (Sabin; Glaxo SmithKline) was given orally.
In vitro lymphocyte responses to vaccine Ags
PBMC were isolated by density gradient centrifugation (Lymphoprep; Nycomed, Oslo, Norway) and were resuspended in complete RPMI 1640 medium supplemented with 10% human AB serum (Sigma-Aldrich, St. Louis, MO). PBMC (2.105/200 µl) were incubated with Ags including purified protein derivative (PPD, RT49, 10 µg/ml; Statens Serum Institut, Copenhagen, Denmark), hepatitis B surface Ag (HbsAg, 2 µg/ml; Glaxo SmithKline) and tetanus toxoid (TT, 2 µg/ml; Chiron Behring, Marburg, Germany), PHA (PHA-L, 10 µg/ml; Sigma Chemicals, Poole, Dorset, U.K.), or medium alone. Methyl-[3H]thymidine (1 µCi/well, Amersham Life Science, Buckinghamshire, U.K.) was added for the final 17 h of culture to assess cell proliferation. Thymidine incorporation was measured by liquid scintillation using a Betaplate reader (LKB1205; LKB Instruments, Turku, Finland).
Cytokine assays
Cytokine concentrations were measured in supernatants collected
on day 2 (PHA) or day 6 (medium and Ags) using commercially available
reagents (IFN-
and IL-5; BioSource Europe, Fleurus, Belgium; IL-13;
Diaclone, Besançon, France).
Ab assays
Neutralizing Abs to poliovirus type 1 were measured as recommended by the World Health Organization (23). Dilutions of heat-inactivated sera were incubated with poliovirus (100 tissue culture infective dose50) for 3 h. The mixture was incubated with Hep-2 cells for 5 days. The serum Ab titer was taken as the highest serum dilution protecting 50% of cultures against virus challenge and was converted into international units. Ab concentrations to TT, DT, and HBsAg were determined by ELISA on plates coated with TT (Chiron Behring), DT (Aventis Pasteur), or HBsAg (Glaxo SmithKline). Incubation of serum samples was followed by successive addition of biotinylated goat anti-human IgG (Sigma Chemicals) and extravidine-peroxidase (for TT and DT Abs) or peroxidase-coupled goat anti-human IgG (Cappell-ICN, Costa Mesa, CA, for HBsAg Abs) and ABTS substrate. Ab concentrations were calculated with the Softmax PRO software (Molecular Devices, Sunnyvale, CA) by comparison with standard curves (4-parameter fitting) using international standards of reference. Values below the assay cutoff (i.e., <100 mIU/ml (tetanus, diphtheria) or 150 mIU/ml (hepatitis B)) were arbitrarily given a value of one-half the cut-off for determination of geometric mean titers.
Statistical analysis
Background production of cytokines measured in control wells was subtracted from that measured in Ag-stimulated wells. After logarithm transformation, data were compared using the t test. Where there were either many nonresponders or persistent skewing of data after log transformation, the Wilcoxon test was used. Multiple regression analysis was conducted to allow for potential confounders. Despite randomization, group 2 infants had a lower birth weight (p = 0.02). Thus, we adjusted for birth weight, ethnicity, date and season of delivery, sex, and parity of mother. Those measurements with many nonresponders were categorized and analyzed by ordinal logistic regression. Tables and figures show adjusted p values for three pairwise comparisons. At 2-mo sampling, groups vaccinated with BCG at 2 or 4.5 mo were combined and compared with the group vaccinated at birth. At 4.5-mo sampling, the group vaccinated with BCG at 4.5 mo was compared with groups vaccinated at birth or 2 mo, separately. Statistical significance was assessed at the two-sided 0.05 level. All statistical analysis was done using Stata software (version 6; Stata, College Station, TX).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first confirmed that BCG induced a Th1-type immune response in
our study population (6, 7). Infants vaccinated at birth
with BCG (group 1) produced high concentrations of IFN- and showed
strong proliferative responses to PPD at 2 and 4.5 mo of age (Fig. 1). In contrast, only low production of
type 2 cytokines, IL-5 and IL-13, was detected. Similar responses were
observed at 4.5 mo in infants who had been vaccinated at 2 mo of age
(group 2), whereas only minimal responses were detected in control
infants who had not received BCG.
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In control infants who had not received BCG, HBV immunization at
birth, and at 2 and 4 mo of age induced the production of both type 1
and type 2 cytokines in response to HBsAg (Fig. 2). Administration of BCG at the time of
priming markedly increased the lymphocyte response to HBV. Cytokine and
proliferative responses to HBsAg were significantly higher in infants
vaccinated at birth (group 1) than in infants who had not received BCG.
The production of type 1, IFN-, and type 2 cytokines, IL-5 and
IL-13, were enhanced by BCG. This effect was already apparent at 2 mo
of age, after a single dose of HBV, and was further enhanced at 4.5 mo
of age. Infants vaccinated with BCG at 2 mo of age (group 2), at the
same time as the second dose of HBV, produced significantly higher
concentrations of IL-5 and IL-13 and had stronger proliferative
responses to HBsAg than infants who had not received BCG. These
responses were similar to those measured in infants who received BCG at
the time of priming. In contrast, BCG vaccination at 2 mo did not
significantly influence IFN- response to HBV. The specificity of
these differences for vaccine Ags was confirmed by the lack of
influence of BCG on responses to PHA in the three groups (data not
shown).
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As shown in Fig. 3, the increased
lymphocyte response to HBV was associated with an increased Ab
response. Infants vaccinated at birth with BCG (group 1) had
significantly higher anti-HBs IgG than control infants who had not
received BCG. This effect was apparent at 2 mo of age and was maximal
after immunization with three doses of HBV. In contrast, administration
of BCG at the same time as the second dose of HBV (group 2) did not
influence the Ab response to HBV. Fig. 4
shows individual data obtained from three representative infants
vaccinated at birth with BCG (group 1) and three representative
controls. In most infants vaccinated at birth with BCG, the increased
Ab response to HBV was associated with an increased production of both
type 1, IFN-, and type 2 cytokines, IL-5 and IL-13, in response to
HBsAg. The effect of BCG on proliferative responses to HBsAg was more
variable.
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). A marked
enhancement of the Ab response to OPV was observed in infants
vaccinated with BCG at 2 mo of age (group 2), at the same time as the
third dose of OPV. In contrast, administration of BCG at the time of
OPV priming (group 1) did not significantly increase the Ab
concentration to poliovirus type 1. Influence of BCG on the cytokine response to TT
DPT immunization at 2, 3, and 4 mo of age induced the production
of both type 1 and type 2 cytokines in response to TT (Fig. 5). BCG vaccination at the time of
priming had a limited but significant influence on this response.
Infants vaccinated with BCG at 2 mo of age (group 2) showed higher
cytokine responses to TT than control infants who had not received BCG,
but these differences were only significant for IL-5 and IL-13. BCG
vaccination also had a limited but significant influence on the
cytokine response to TT when given at birth, 2 mo before the first dose
of DPT. Infants vaccinated at birth with BCG (group 1) showed
significantly higher IL-13 responses to TT than control infants who had
not received BCG (Fig. 5). These IL-13 responses to TT were similar to
those measured in infants who received BCG at 2 mo of age. In contrast,
no significant effect of BCG vaccination at birth was observed on
proliferative, IFN-, or IL-5 responses to TT.
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Relatively high concentrations of anti-TT IgG were detected at
2 mo of age (Fig. 3) as a result of the maternal immunization practice
in The Gambia (10). BCG administration with DPT priming
did not influence the Ab response to TT as measured at 4.5 mo. The Ab
response to DT was also similar in infants who received BCG at 2 mo
(group 2) and in those who had not received BCG (controls). Infants who
received BCG at birth (group 1) also had similar Ab responses to TT and
DT than those who had not received BCG (controls).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effect of BCG on unrelated vaccine Ags injected in the same arm was
found to depend on the vaccine Ag and on the timing of immunization in
relation to BCG administration. The strongest influence of BCG was
observed on responses to HBV, one of the most immunogenic vaccines
administered to infants (1). In infants who had not
received BCG, neonatal HBV vaccination induced the production of both
type 1 and type 2 cytokines in response to HBsAg. This response was
qualitatively similar but of lower magnitude than that measured in
adults (M. O. C. Ota, J. Vekemans,S. E. Schlegel-Haueter,
K. Fielding, H. Whittle, P. H. Lambert,K. P. W. J. McAdam, C. A.
Siegrist, and A. Marchant, manuscript in preparation). The
administration of BCG at the time of HBV priming at birth markedly
increased the cytokine (IFN-, IL-5, and IL-13), proliferative, as
well as Ab responses to HBV. When given at 2 mo of age, at the time of
booster HBV immunization, BCG also increased the production of type 2
cytokines, but not the IFN-, proliferative, or Ab responses. BCG
also had a significant although limited influence on the immune
response to priming with TT. BCG administration at 2 mo of age,
together with the first dose of DPT, increased the production of type 2
cytokines in response to TT, but did not significantly influence
TT-specific IFN-, proliferative, or Ab responses. No significant
effect was observed on the Ab response to DT (for which cellular
responses were not assessed), in keeping with data reported by Simondon
et al. (11) showing no influence of BCG vaccination on Ab
response to pertussis vaccine. A surprising finding was that a similar
increase of TT-specific IL-13 responses was observed when BCG was given
at birth, 2 mo before DTP priming. Thus, BCG may influence T and B cell
responses to unrelated vaccine Ags that are administered at the same
injection site either simultaneously or even several weeks later.
One of the central characteristics of Th1 and Th2 cells is that they reciprocally inhibit their differentiation and function (12). Given the induction of a potent Th1-type response to mycobacterial Ags such as PPD, the observation that BCG promoted both type 1 and type 2 cytokine responses to unrelated vaccine Ags was unexpected. In fact, the production of Th2 cytokines was more frequently increased than that of Th1. The mechanism underlying the stimulation of T cell responses by BCG is likely to be related to its influence on the maturation of neonatal DC, as DC are essential Ag-presenting cells for the priming of naive T cells (13). Mycobacteria, including BCG, activate adult DCs, increasing their production of IL-12 and their expression of costimulatory molecules, which support the induction of Th1 responses (14, 15). However, recent data indicate that DC derived from cord blood monocytes have defective expression of IL-12 (p35) gene as well as of membrane costimulatory molecules (4). Under suboptimal conditions of costimulation, IL-12 was shown to stimulate the production of both type 1 and type 2 cytokines by neonatal CD4 T cells (16). Thus, the promotion of type 1 and type 2 cytokine (or even predominant Th2 cytokine) responses by BCG in early life could be related to a suboptimal state of activation of neonatal DC. Further studies are needed to evaluate whether the promotion of type 2 cytokine responses to unrelated Ags by BCG is a characteristic feature of neonatal responses, or whether it is also observed in adults.
The mechanisms underlying the influence of BCG on the priming of Ab responses to unrelated vaccine Ags is likely to involve enhanced activation of T lymphocytes by APC. In support of this hypothesis, the enhanced HBV Ab response following BCG vaccination at birth paralleled the marked increase in the production of T cell cytokines, whereas the more modest increase in the cytokine response to TT was not associated with significant changes in the TT Ab response. The increased Ab response to HBV priming was marginal when assessed at 2 mo of age, whereas a marked increase was observed at 4.5 mo of age. This indicates that BCG at birth had a limited impact on early life plasmocyte differentiation, but markedly enhanced induction of memory B cells. This is in accordance with studies in mice suggesting that induction of memory B cells occurs much earlier during life than plasmocyte differentiation (1). The enhancement of APC-T cell interactions did not appear to be sufficient to promote the Ab response to booster HBV immunization. Indeed, although a similar increase in the production of type 2 cytokines was observed in infants who received BCG at the time of priming or boosting, the Ab response was not increased by BCG when given at the time of boosting.
BCG considerably influenced the Ab response to mucosally administered OPV. Newborns develop a relatively weak response to OPV (1), and BCG vaccination at birth did not significantly increase OPV Ab responses. In contrast, BCG markedly enhanced OPV Ab response when given at 2 mo of age, together with the third dose of OPV. These data suggest that the maturation of B cell responses to OPV is associated with an increased responsiveness to the influence of BCG. The marked increase in the response to OPV suggests that intradermal BCG vaccination can influence immune responses to unrelated Ags at the systemic level. A systemic modulation of immune responses was recently observed in patients with intestinal helminth infection (17). De Smedt et al. (18) reported that injection of bacterial products induces the migration and the maturation of splenic DC in mice. A similar mechanism could be involved in the up-regulation of systemic immune responses by BCG.
This study has several important implications. First, BCG administration, in its native form or as a live vector, could be a useful strategy in improving the immunogenicity of vaccines in early life (19). Second, BCG vaccination in early life could influence immune responses to unrelated infectious pathogens. A recent report indicating that BCG vaccination is associated with reduced mortality in infants in Guinea-Bissau emphasizes the potential public health relevance of this hypothesis (20). The possible influence of BCG on the development of allergic reactions remains controversial (8, 21, 22). The enhancement of Th2 responses by BCG observed in this study suggests that the influence of BCG on the immune response to allergens is likely to be more complex than a polarization toward Th1 responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Arnaud Marchant at the current address: Human Immunology Unit, Weatherall Institute of Molecular Medicine, OX3 9DS, Oxford, U.K. E-mail address: Arnaud.Marchant{at}btinternet.com
3 Abbreviations used in this paper: BCG, Mycobacterium bovis bacillus Calmette-Guérin; HBV, hepatitis B vaccine; OPV, oral polio vaccine; DPT, diphtheria-pertussis-tetanus toxoids vaccine; PPD, purified protein derivative; HbsAg, hepatitis B surface Ag; TT, tetanus toxoid; DT, diphtheria toxoid; DC, dendritic cell; CI, confidence interval.
Received for publication August 13, 2001. Accepted for publication November 5, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by CD4+ T lymphocytes. Eur. J. Immunol. 31:1531.[Medline]
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,
n = 23); at 2 mo of age, postvaccination in infants
who received BCG at birth (
, group 1, n infants
tested ranged from 30 to 32 depending on the response measured), and
prevaccination in infants scheduled to receive BCG at 2 mo (
, group
2, n = 26–34) or 4.5 mo of age (
, control
infants, n = 27–32), at 4.5 mo of age,
postvaccination in infants who received BCG at birth (
, and 
) and three representative infants vaccinated at 4.5
mo of age (controls, 
, 
, and 