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*
Medical Research Council Laboratories, Fajara, The Gambia;
University of Liège, Liège, Belgium;
London School of Hygiene and Tropical Medicine, London, United Kingdom;
§
Pasteur Institute of Brussels, Brussels, Belgium;
¶
Projecto de Saude de Bandim, Bissau, Guinea-Bissau 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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and are considered to be required for protection against
mycobacteria and viruses whereas Th2 responses, characterized by the
production of IL-4, IL-5, and IL-13, protect against helminths and are
involved in atopic reactions (4). A Th2 bias in newborns
would therefore impair their response to vaccines against diseases
caused by mycobacteria or viruses. More recently, several groups have
shown that newborn mice can develop both Th1 and Th2 responses,
depending on the type of APCs, the presence of adjuvants, and the dose
of Ags administered (3, 5, 6, 7, 8).
Our knowledge about T lymphocyte responses in human newborns is
limited. In vitro studies on cord blood mononuclear cells have shown
that newborn lymphocytes have a defective IFN- production in
response to mitogens (9, 10). Recent work by P.G. Holt’s
group indicates that allergens commonly cross the placenta and
induce the differentiation of fetal T lymphocytes into Th2 cells
(11). The ability of human newborns to develop a Th1
immune response upon immunization has not been studied.
Following World Health Organization (WHO) recommendations, newborns are vaccinated with Mycobacterium bovis bacillus Calmette-Guérin (BCG)3 in The Gambia as in other developing countries (12). In adults, BCG triggers a Th1 response that was shown to be necessary for the control of mycobacterial infections (13, 14, 15). This prospective and randomized study was undertaken to evaluate whether a similar response is induced in newborns and whether age at vaccination influences immunogenicity. Immune response to BCG was evaluated in vitro using mycobacterial Ags that are current antituberculosis vaccine candidates (16, 17, 18).
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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 (MRC) Ethical Committee. Neonates were identified at birth by the study field worker at Fajikunda Health Center. The study was explained to the mother, and she was invited to enroll her child. The following were excluded from the study : neonates born to mothers with evidence of systemic infection at the time of delivery, neonates presenting with any congenital defect or a birth weight below 2.5 kg, and twin neonates. If the mother agreed, one of the study pediatricians (T.G. or M.O.) visited the neonate in the family compound within the first 36 h of life. The pediatrician gave BCG immediately to neonates born in compounds with a history suggestive of tuberculosis, and these children were excluded from the study. Enrolled neonates were then randomly allocated in blocks of six to one of three vaccination groups (BCG given at birth or 2 or 4 mo of age). The same dose of BCG vaccine (0.1 ml, lot E61440A, Evans Medical, Leatherhead, England) was given to all infants. BCG immunogenicity was measured 2 mo after vaccination. Prevaccination samples from infants randomized to receive BCG at 2 or 4 mo of age were used as controls for infants vaccinated at birth or at 2 mo of age, respectively. Induction of immunological memory was assessed at 1 yr of age. For ethical reasons, BCG vaccination could not be delayed for more than 4 mo. Therefore, no unvaccinated controls could be studied at one year of age. At vaccination and follow-up visits, all children were examined by one of the study pediatricians and found to be healthy.
In vitro lymphocyte stimulation with mycobacterial Ags
Due to the limited amount of blood available, evaluation of BCG immunogenicity 2 mo after vaccination was performed on heparinized blood diluted in 9 vol of RPMI 1640 medium (BioWittaker, Verviers, Belgium) supplemented with 100 U/ml penicillin and 100 µg/ml streptomycin (Life Technologies, Paisley, Scotland). Evaluation of immunological memory at 1 yr of age was performed on PBMC separated by density gradient centrifugation (Lymphoprep, Nycomed, Oslo, Norway) and resuspended in RPMI 1640 medium supplemented with 100 U/ml penicillin and 100 µg/ml streptomycin, 10 mM HEPES (ICN Biomedicals, Costa Mesa, CA), 2 mM L-glutamine (Life Technologies), and 10% human AB serum (Sigma, St. Louis, MO). Diluted blood or PBMC suspension was incubated for various periods of time in 96-well plates (200 µl/well) (Becton Dickinson, Rutherford, NJ) containing Ag preparations. Mycobacterial Ags included the purified protein derivative (PPD, RT48, Statens Serum Institut, Denmark), extracellular mycobacterial Ags including M. tuberculosis short term culture filtrate (ST-CF, provided by Prof. Peter Andersen, Statens Serum Institut, Copenhagen, Denmark) (18), the Ag 85 complex from BCG (16), and the recombinant Mycobacterium tuberculosis 10-kDa Ag (provided by Dr. Mahavir Singh, WHO Recombinant Protein Bank) (17), as well as an intracellular mycobacterial Ag preparation (K-MTB, M. tuberculosis H37Rv strain autoclaved for 30 min at 120°C). Wells containing medium alone or PHA (PHA-L, Sigma Chemicals) were used as the negative and positive controls, respectively.
Cytokine release and lymphocyte proliferation assays
IFN-, IL-5, and IL-13 concentrations were measured in culture
supernatants collected on day 2 after PHA (5 µg/ml) stimulation and
day 6 after antigenic stimulation (PPD and ST-CF, 1 µg/ml; K-MTB, 100
µg/ml, 10 kDa and Ag 85 complex, 1 and 10 µg/ml) using commercially
available ELISAs (BioSource Europe, Fleurus, Belgium). Lymphocyte
proliferation was evaluated on day 7 after the addition of 1 µCi of
[methyl-3H]thymidine per well (Amersham Life
Science, Little Chalfont, U.K.) during the final 15 h of culture.
Thymidine incorporation was measured by liquid scintillation using a
Betaplate reader (LKB 1205, Turku, Finland).
IL-4 release assay
IL-4 production was measured using an Enzyme-Linked-Immuno-Trapping-Assay as described elsewhere (DW Groote, X. Gevaert, R. Gathy, M. Lopez, S. Benyoucef, and M. Malaise, manuscript in preparation). Briefly, diluted blood or PBMC suspension was incubated in sterile ELISA plates (Maxisorp Immunoplates, Nunc, Roskilde, Denmark) coated with anti-IL-4 capture F(ab')2 mAb (clone 4B3) containing antigenic preparations (PHA, PPD, ST-CF, 10 kDa, and Ag 85 complex, 10 µg/ml; K-MTB, 100 µg/ml). After 4 days, plates were washed, and captured IL-4 was detected using a secondary detecting HRP-conjugate F(ab')2 anti-IL-4 mAb (clone 10H12). IL-4 concentrations were inferred from a recombinant IL-4 standard curve that was included in every plate.
Statistical analysis
Proliferative responses were calculated as stimulation index (SI) dividing geometric mean Ag-stimulated cpm by background cpm (19). For cytokines, background production was subtracted from Ag-stimulated production. We excluded from the analysis postvaccination data from infants who showed evidence of sensitization to mycobacterial Ags before vaccination. Sensitization was defined as proliferation SI above mean + 2 SD of values obtained in a series of 15 cord blood samples collected during the study, for at least two of the following mycobacterial Ag preparations: PPD (SI > 2.6), ST-CF (SI > 2.6), and K-MTB (SI > 7.2). For comparisons between groups, data were logarithm transformed and compared by the one way ANOVA, or Kruskal Wallis nonparametric test, where there were many nonresponders to the Ag. Despite randomization, infants vaccinated at 4 mo were more often males and from the Mandinka ethnic group while infants vaccinated at birth or at 2 mo were more often firstborn and from the Jola ethnic group. Multiple regression analysis was conducted to allow for any confounding effects of these factors. Those measurements with many nonresponders were grouped and analyzed by ordinal logistic regression. Tables and figures show adjusted regression p values. The unadjusted p values are not shown because they were not materially different. Since a total of 88 multiple comparisons were performed among the different immune responses to different mycobacterial Ags, it would be expected for about four p values to be significant at p < 0.05 solely due to chance. All statistical analysis was done using Stata (version 5; Stata Corporation, College Station, TX).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One hundred and thirty-seven neonates were enrolled between November 1996 and April 1997. Fifty-one infants were studied at 2 mo of age, including 27 vaccinated at birth and 24 immediately before vaccination. Forty-two infants were studied at 4 mo of age, including 19 vaccinated at the age of 2 mo and 23 immediately before vaccination. Fifty-eight infants were studied at 1 yr of age, including 23 vaccinated at birth, 19 vaccinated at the age of 2 mo, and 16 vaccinated at the age of 4 mo. Eighty-five infants were not studied at some stage during the follow-up for the following reasons: mother traveling (n = 9), blood sampling refused (n = 31), BCG vaccination given outside the study (n = 23), death (n = 4), technical failure in the blood sampling or processing (n = 12), and evidence of sensitization to mycobacterial Ags prior to vaccination (n = 1 at 2 mo and n = 5 at 4 mo of age, see Materials and Methods).
BCG immunogenicity in infants vaccinated at birth or at 2 mo of age
To evaluate immunogenicity of BCG vaccination at birth or at 2 mo
of life, we measured proliferative and cytokine responses to tuberculin
PPD and compared them to the responses to the mitogen PHA (Fig. 1
). We observed that 2-mo-old infants who
were vaccinated at birth displayed strong proliferative responses to
PPD whereas age-matched unvaccinated controls had only minimal
responses (Fig. 1, left panel). Proliferative responses to
PPD in 4-mo-old infants who were vaccinated at 2 mo were similar to
infants vaccinated at birth, while age-matched unvaccinated infants
again had minimal responses. The proliferative response to PPD was
associated with the production of high levels of IFN- both in
infants vaccinated at birth or at 2 mo of age (Fig. 1, middle panel). The levels of IFN- were lower in infants
vaccinated at 2 mo than in infants vaccinated at birth, but this
difference was not significant. Very low levels of IFN- were
detected in unvaccinated controls at both ages.
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, no significant IL-4 production was induced by
PPD in infants who received BCG at birth (Fig. 1
, right
panel). Surprisingly, between the age of 2 and 4 mo, unvaccinated
infants acquired a significant IL-4 response to PPD. This IL-4
production was partly, although not significantly, prevented by BCG
vaccination at the age of 2 mo. The Ag specificity of these differences
is demonstrated by the similarity of the proliferative and cytokine
responses to PHA observed in all four groups (Fig. 1). In summary,
these data indicate that infants vaccinated at birth and at 2 mo of age
develop a Th1-type response to PPD while a Th2-type response
predominates in unvaccinated infants. Ag specificity of the immune response to BCG in infants
To further characterize the antigenic targets of the immune
response induced by BCG in infants, we studied lymphocyte responses to
extracellular mycobacterial Ags that are considered to be
antituberculosis vaccine candidates. These included an ST-CF, the Ag 85
complex, and the 10-kDa Ag. In parallel, we studied the response to
intracellular Ags represented by a killed M. tuberculosis
preparation (K-MTB). Table I shows that
infants vaccinated at birth or at 2 mo of age had significant
proliferative responses to all extracellular Ags tested when compared
with unvaccinated controls. The intracellular Ag preparation was
also found to be an important target. The proliferative responses to
these Ags were associated with significant IFN- production, although
the levels of IFN- were generally lower in infants vaccinated at 2
mo (table II). The 10-kDa Ag was found to be a weaker
stimulus of IFN- production. As observed for PPD, between the age of
2 and 4 mo, unvaccinated infants acquired a low but significant IL-4
response to mycobacterial Ags, this response being less marked for the
10-kDa Ag (Table III). The
production of IL-4 was not significantly influenced by BCG vaccination
either at birth or at 2 mo of age.
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To evaluate whether the Th1-type response to BCG in newborns is associated with the induction of immunological memory, the cohort was followed up and studied at 1 yr of age. In these experiments, in which the response of PBMC to extracellular and intracellular mycobacterial Ags was evaluated, no significant IL-4 production could be detected (data not shown). As an alternative method to assess Th2 responses, we measured the production of IL-5 and IL-13, two cytokines that are, like IL-4, preferentially produced by human Th2 cells (4, 20). The production of IL-5 and IL-13 could not be measured retrospectively in 2- and 4-mo-old infants due to lack of culture supernatants.
As shown in Fig. 2, a memory Th1-type
response to PPD was detected in infants vaccinated at birth. This
response was characterized by the production of high levels of IFN-
but only low levels of IL-5 and IL-13. A similar Th1 response to PPD
was detected in infants vaccinated at 2 or 4 mo of age. The lymphocyte
response to PHA was equivalent in the three study groups. Table IV
shows that infants vaccinated at birth also display a Th1-type memory
response to the intracellular K-MTB preparation. At the concentration
used in these experiments (1 µg/ml), the extracellular ST-CF
preparation induced only a low and similar lymphocyte response in the
three study groups. A similar phenomenon was observed with the purified
10-kDa and 85 complex Ags, which induced a detectable response in only
a minority of the subjects from the three study groups (data not
shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The Th1-type immune response induced by BCG in newborns is likely to be dependent on the activation of APCs. Dendritic cells are the APCs involved in the initiation of primary immune responses. Mycobacteria, including BCG, infect dendritic cells and markedly increase their ability to present Ags to T cells (21, 22). This higher Ag-presenting capacity is related to an increased expression of costimulatory surface molecules and cytokines like IL-12. In newborn mice, the use of external costimulatory signals, such as IL-12, anti-CD40 mAbs, or adult dendritic cells at the time of immunization, can prevent the differentiation of helper T lymphocytes into Th2 cells and promotes Th1 responses (3, 5, 23). In the presence of IL-12 and optimal costimulatory signals, human newborn T lymphocytes differentiate into Th1 cells whereas, under suboptimal conditions, IL-4-producing cells are generated (24). Similar mechanisms are probably involved in the ability of adjuvants, DNA vaccines, or replicating viruses to promote Th1 responses in newborn mice (7, 8, 25).
The immune response to vaccines can also be influenced by other factors, including the route of vaccination and the dose of Ag administered. The Th1 response induced by BCG in human newborns could have been promoted by the intradermal route of immunization. The poor Th1 response to BCG vaccination observed by Barrios et al. in newborn mice could at least partly be related to the fact that the immunization route they used was i.p. (1). In newborn mice, high doses of Ag preferentially activate Th2 responses whereas Th1 responses are induced by low doses of Ags (6). The dose of Ag is unlikely to have affected the immune response to BCG in our study population since a relatively high dose of BCG was administered, generally that used to immunize individuals above the age of 1 yr.
Unvaccinated infants developed a Th2-type response to mycobacterial Ags between the age of 2 and 4 mo. The production of IL-4 was associated with a detectable proliferative response in only 5 of the 23 4-mo-old infants studied. Although this was not specifically determined in our study, the defective proliferation is likely to be related to a weak IL-2 production but could also be dependent on the type of APCs. In newborn mice immunized with alloantigens, D. Abramowicz et al. described a similar Th2 response associating IL-4 production with no proliferation and no detectable IL-2 production (26). In the absence of IL-2, murine Th2 clones were shown to produce IL-4 when stimulated by both B cells or macrophages, but only B cells could promote a proliferative response (27). The mechanism involved in the induction of the Th2 response in unvaccinated infants is unknown. The Ag specificity of the response suggests that it could be related to exposure to environmental mycobacteria. Indeed, in The Gambia, 2- to 4-mo-old infants are likely to be exposed to environmental mycobacteria through their mucosa. Gastrointestinal immunization was shown to induce preferentially Th2-type responses in animals (28). Further studies are needed to evaluate whether a similar Th2-type response is triggered by other microorganisms colonizing the gastrointestinal tract during early childhood.
The observation that BCG induces a Th1-type response in neonates has
several potential implications. Firstly, since neonatal BCG vaccination
represents one of the first infectious challenges during life, it could
have a strong impact on the development of the immune system. It has
been suggested that the Th1 response induced by mycobacteria could
prevent the development of allergen-specific Th2 responses and atopy
during childhood (29). We have recently observed that BCG
vaccination during the first week of life is associated with a
decreased risk of atopy in children in
Guinea-Bissau.4
Secondly, although protective immunity against mycobacterial infections
is not fully understood, a Th1-type response is known to be necessary
(14, 15). The early IFN- production detected in our
study therefore plays a central role in the ability of the newborns to
control the infection with BCG and allows the safe administration of
the vaccine. In addition, the fact that BCG induces a memory Th1-type
response in newborns supports the recommendation of WHO to give BCG as
soon as possible after birth to prevent tuberculosis during early
childhood (12). Finally, our data indicate that human
newborns can be immunized against pathogens controlled by a Th1
response. In addition to DNA vaccines and adjuvants,
immunization strategies could include the use of BCG as a vector
expressing foreign Ags (30, 31).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Arnaud Marchant, Medical Research Council Laboratories, Post Office Box 273, Banjul, The Gambia, West Africa. E-mail address:
3 Abbreviations used in this paper: BCG, Mycobacterium bovis bacillus Calmette-Guérin; PPD, purified protein derivative; ST-CF, short-term culture filtrate; K-MTB, heat-killed Mycobacterium tuberculosis; SI, stimulation index; CI, confidence interval.
4 P. Aaby, S. O. Shaheen, C. B. Heyes, A. Goudiaby, A. J. Hall, A. W. Shiell, H. Jensen, and A. Marchant. Early BCG vaccination and reduction in atopy in Guinea-Bissau. Submitted for publication.
Received for publication March 22, 1999. Accepted for publication May 19, 1999.
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by human neonatal cells. J. Clin. Invest. 77:860.
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and IL-4/IL-5/IL-13, respectively. J. Immunol. 160:2380.This article has been cited by other articles:
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 E. T. Chang, S. M. Montgomery, L. Richiardi, A. Ehlin, A. Ekbom, and M. Lambe Number of Siblings and Risk of Hodgkin's Lymphoma Cancer Epidemiol. Biomarkers Prev., July 1, 2004; 13(7): 1236 - 1243. [Abstract] [Full Text] [PDF]
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B. Adams, N. Nagy, F. Paulart, M.-L. Vanderhaeghen, M. Goldman, and V. Flamand CD8+ T Lymphocytes Regulating Th2 Pathology Escape Neonatal Tolerization J. Immunol., November 15, 2003; 171(10): 5071 - 5076. [Abstract] [Full Text] [PDF]
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B. M. Buddle, D. N. Wedlock, N. A. Parlane, L. A. L. Corner, G. W. de Lisle, and M. A. Skinner Revaccination of Neonatal Calves with Mycobacterium bovis BCG Reduces the Level of Protection against Bovine Tuberculosis Induced by a Single Vaccination Infect. Immun., November 1, 2003; 71(11): 6411 - 6419. [Abstract] [Full Text] [PDF]
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M. Salio, N. Dulphy, J. Renneson, M. Herbert, A. McMichael, A. Marchant, and V. Cerundolo Efficient priming of antigen-specific cytotoxic T lymphocytes by human cord blood dendritic cells Int. Immunol., October 1, 2003; 15(10): 1265 - 1273. [Abstract] [Full Text] [PDF]
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C. S. Benn, C. Bale, H. Sommerfelt, H. Friis, and P. Aaby Hypothesis: Vitamin A supplementation and childhood mortality: amplification of the non-specific effects of vaccines? Int. J. Epidemiol., October 1, 2003; 32(5): 822 - 828. [Abstract] [Full Text] [PDF]
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 J. M Grange, J. L Stanford, C. A Stanford, and K. F Kolmel Vaccination strategies to reduce the risk of leukaemia and melanoma J R Soc Med, August 1, 2003; 96(8): 389 - 392. [Full Text] [PDF]
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C.-M. Sun, L. Fiette, M. Tanguy, C. Leclerc, and R. Lo-Man Ontogeny and innate properties of neonatal dendritic cells Blood, July 15, 2003; 102(2): 585 - 591. [Abstract] [Full Text] [PDF]
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J. C. Eisenberg, S. J. Czinn, C. A. Garhart, R. W. Redline, W. C. Bartholomae, J. M. Gottwein, J. G. Nedrud, S. E. Emancipator, B. B. Boehm, P. V. Lehmann, et al. Protective Efficacy of Anti-Helicobacterpylori Immunity following Systemic Immunization of Neonatal Mice Infect. Immun., April 1, 2003; 71(4): 1820 - 1827. [Abstract] [Full Text]
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 T. G. Krause, A. Hviid, A. Koch, J. Friborg, T. Hjuler, J. Wohlfahrt, O. R. Olsen, B. Kristensen, and M. Melbye BCG Vaccination and Risk of Atopy JAMA, February 26, 2003; 289(8): 1012 - 1015. [Abstract] [Full Text] [PDF]
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Z. Kabir Is all-cause mortality a useful epidemiological endpoint in vaccine trials? An example of BCG (Bacille-Calmette-Guerine) Int. J. Epidemiol., February 1, 2003; 32(1): 161 - 162. [Full Text] [PDF]
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F. Mascart, V. Verscheure, A. Malfroot, M. Hainaut, D. Pierard, S. Temerman, A. Peltier, A.-S. Debrie, J. Levy, G. Del Giudice, et al. Bordetella pertussis Infection in 2-Month-Old Infants Promotes Type 1 T Cell Responses J. Immunol., February 1, 2003; 170(3): 1504 - 1509. [Abstract] [Full Text] [PDF]
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J. W. Upham, P. T. Lee, B. J. Holt, T. Heaton, S. L. Prescott, M. J. Sharp, P. D. Sly, and P. G. Holt Development of Interleukin-12-Producing Capacity throughout Childhood Infect. Immun., December 1, 2002; 70(12): 6583 - 6588. [Abstract] [Full Text] [PDF]
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S. A. Fadel, D. A. Ozaki, and M. Sarzotti Enhanced Type 1 Immunity After Secondary Viral Challenge in Mice Primed as Neonates J. Immunol., September 15, 2002; 169(6): 3293 - 3300. [Abstract] [Full Text] [PDF]
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M. C. Jaimes, O. L. Rojas, A. M. Gonzalez, I. Cajiao, A. Charpilienne, P. Pothier, E. Kohli, H. B. Greenberg, M. A. Franco, and J. Angel Frequencies of Virus-Specific CD4+ and CD8+ T Lymphocytes Secreting Gamma Interferon after Acute Natural Rotavirus Infection in Children and Adults J. Virol., April 16, 2002; 76(10): 4741 - 4749. [Abstract] [Full Text] [PDF]
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M. T. Hopfenspirger and D. K. Agrawal Airway Hyperresponsiveness, Late Allergic Response, and Eosinophilia Are Reversed with Mycobacterial Antigens in Ovalbumin-Presensitized Mice J. Immunol., March 1, 2002; 168(5): 2516 - 2522. [Abstract] [Full Text] [PDF]
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J. C. Hope, P. Sopp, and C. J. Howard NK-like CD8+ cells in immunologically naive neonatal calves that respond to dendritic cells infected with Mycobacterium bovis BCG J. Leukoc. Biol., February 1, 2002; 71(2): 184 - 194. [Abstract] [Full Text] [PDF]
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M. Rayevskaya, N. Kushnir, and F. R. Frankel Safety and Immunogenicity in Neonatal Mice of a Hyperattenuated Listeria Vaccine Directed against Human Immunodeficiency Virus J. Virol., January 15, 2002; 76(2): 918 - 922. [Abstract] [Full Text] [PDF]
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M. O. C. Ota, J. Vekemans, S. E. Schlegel-Haueter, K. Fielding, M. Sanneh, M. Kidd, M. J. Newport, P. Aaby, H. Whittle, P.-H. Lambert, et al. Influence of Mycobacteriumbovis Bacillus Calmette-Guerin on Antibody and Cytokine Responses to Human Neonatal Vaccination J. Immunol., January 15, 2002; 168(2): 919 - 925. [Abstract] [Full Text] [PDF]
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J. M Grange, J. L Stanford, and C. A Stanford Campbell De Morgan's 'Observations on cancer', and their relevance today J R Soc Med, January 6, 2002; 95(6): 296 - 299. [Full Text] [PDF]
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F. A. Post, C. Manca, O. Neyrolles, B. Ryffel, D. B. Young, and G. Kaplan Mycobacterium tuberculosis 19-Kilodalton Lipoprotein Inhibits Mycobacterium smegmatis-Induced Cytokine Production by Human Macrophages In Vitro Infect. Immun., March 1, 2001; 69(3): 1433 - 1439. [Abstract] [Full Text] [PDF]
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S. Goriely, B. Vincart, P. Stordeur, J. Vekemans, F. Willems, M. Goldman, and D. De Wit Deficient IL-12(p35) Gene Expression by Dendritic Cells Derived from Neonatal Monocytes J. Immunol., February 1, 2001; 166(3): 2141 - 2146. [Abstract] [Full Text] [PDF]
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 I. Kristensen, P. Aaby, H. Jensen, and P. Fine Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa Commentary: an unexpected finding that needs confirmation or rejection BMJ, December 9, 2000; 321(7274): 1435 - 1435. [Abstract] [Full Text]
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A. Corcoran, S. Doyle, D. Waldron, A. Nicholson, and B. P. Mahon Impaired Gamma Interferon Responses against Parvovirus B19 by Recently Infected Children J. Virol., November 1, 2000; 74(21): 9903 - 9910. [Abstract] [Full Text]
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J. Rowe, C. Macaubas, T. M. Monger, B. J. Holt, J. Harvey, J. T. Poolman, P. D. Sly, and P. G. Holt Antigen-Specific Responses to Diphtheria-Tetanus-Acellular Pertussis Vaccine in Human Infants Are Initially Th2 Polarized Infect. Immun., July 1, 2000; 68(7): 3873 - 3877. [Abstract] [Full Text] [PDF]
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