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, and T Cell Proliferation to Measles in Immunized Infants1
*
Infectious Diseases Division, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305;
Department of Health and Human Services, Division of Viral Products, Office of Vaccine Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20867; and
Department of Pediatrics, Palo Alto Medical Foundation, Palo Alto, CA 94301
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. Whether young infants can be immunized
effectively against measles is an important public health issue. We
evaluated Ag-specific IL-12, IFN-, and T cell responses of infants
at 6 (n = 60), 9 (n = 46), or
12 mo (n = 56) of age and 29 vaccinated adults.
IL-12 and IFN- release by PBMC stimulated with measles Ag increased
significantly after measles immunization in infants. IL-12 and IFN-
concentrations were equivalent in younger and older infants, but IL-12
concentrations were significantly lower in infants than in adults
(p = 0.04). IL-12 production by monocytes was
down-regulated by measles; the addition of recombinant human IL-12
enhanced IFN- production by PBMC stimulated with measles Ag, but
infant T cells released significantly less IFN- than adult T cells
under this condition. Of particular interest, the presence of passive
Abs to measles had no effect on the specific T cell proliferation or
IFN- production after measles stimulation. Cellular immunity to
measles infection and vaccination may be limited in infants compared
with adults as a result of less effective IFN- and IL-12 production
in response to measles Ags. These effects were not exaggerated in
younger infants compared with effects in infants who were immunized at
12 mo. In summary, infant T cells were primed with measles Ag despite
the presence of passive Abs, but their adaptive immune responses were
limited compared with those of adults. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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are diminished, and NK
cell function is reduced (9, 10, 11, 13, 14, 15, 16, 17, 18, 19). In addition, nonspecific,
spontaneous release of IL4 by circulating PBMC and total IgE
concentrations are increased (11, 20).
Measles virus infects monocytes through binding to the CD46
surface protein, which acts as a measles-specific entry mediator
(21, 22, 23). Karp et al. (24) have demonstrated that measles binding to
CD46 results in down-regulation of IL-12 production. Based on the
Th1/Th2 model of CD4+ T cell responses, decreased IL-12
release would be expected to favor predominance of a Th2-like response,
because IL-12 is a crucial early stimulus for Th1 clonal expansion.
IL-12 stimulates resting and activated T cells, induces the production
of IFN- by T cells, activates NK cells, and inhibits IL-4 production
(25, 26, 27, 28, 29, 30, 31). Since IL-12 promotes the rapid induction of Ag-specific T
cells in the naive host, decreased IL-12 production could impair the
acquisition of adaptive immunity to measles and facilitate a
generalized immunosuppression by failure to regulate IL-4 production.
The purpose of this study was to compare virus-specific T cell
responses in infants and adults with vaccine-induced measles immunity,
using assays for IL-12 production, T cell proliferation, and IFN-
release by PBMC stimulated with measles. Our hypothesis was that
infants might have a limited Th1-like response to measles compared with
adults.
The evaluation of adaptive immunity to measles vaccination in
infants who are younger than 12 mo has important clinical relevance
because it would be advantageous to achieve protective immunity as
early as possible during the first year of life. Potential obstacles to
immunization of younger infants against measles include neutralization
of the live attenuated vaccine virus by measles Abs acquired
transplacentally and immaturity of the immune system (32, 33, 34, 35, 36, 37, 38, 39). We and
others have shown that passive Abs to measles interfere with
vaccine-induced humoral immunity, but little is known about the effects
of maternally derived measles Abs on induction of virus-specific
cell-mediated immunity (40, 41, 42, 43). Infants whose mothers have measles
vaccine-induced immunity lose passive Abs at a shorter interval after
birth than those who receive higher concentrations of measles Abs
because their mothers have had natural measles (37, 42, 43, 44, 45, 46). In a
recent study, we showed that the humoral response to measles vaccine
was deficient in 6-mo-old infants compared with 9 and 12-mo-old infants
even when passively acquired Abs were not detectable (41). This further
evaluation of measles-specific T cell responses in infants was
undertaken to assess whether there are differences in proliferation,
IL-12 or IFN- responses when younger infants are immunized with
measles vaccine, and whether passive Abs affect these cell-mediated
immune responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The study subjects were 162 healthy infants, without intercurrent illnesses, who were 6 mo (n = 60), 9 mo (n = 46), or 12 mo old (n = 56) and healthy adults (n = 29; age 20–40 yr). Infants were enrolled if they were 6 mo (range, +3 wk), 9 mo (range, ±3 wk), or 12 mo (range, +3 wk). Children born before 36 wk gestation, whose birth weight was <2500 g, or who had chronic underlying illnesses were excluded. Among the infants who were enrolled, 2 infants were withdrawn as participants before blood samples were obtained and 26 infants were evaluated only before measles immunization, including 7 who were 6 mo old, 4 who were 9 mo old, and 15 who were 12 mo old. Prevaccine specimens as well as samples taken 12 ± 3 wk after measles vaccination were available from 134 infants; because of limitations in the numbers of PBMC recovered, not all assays were performed in all infants. The study was approved by the Stanford University Committee for the Protection of Human Subjects and the Institutional Review Board of the Palo Alto Medical Foundation; written consent was obtained from parents or guardians and adult participants. No cases of measles were identified in our geographic area during the study period.
Infants 6 and 9 mo old were immunized with measles virus vaccine live (Attenuvax (Merck, West Point, PA)) containing 1000 median tissue culture-infective doses (TCID50) of the U.S. reference measles virus. Twelve-month-old infants were immunized with M-M-R virus vaccine live (Merck; containing measles virus vaccine live, 1000 TCID50). Adults had received at least one measles vaccination years before evaluation.
T cell proliferation assay
PBMC were separated from whole blood by Ficoll-Hypaque gradient and added to 96-well microtiter plates at concentrations of 3.0 x 105/well in RPMI 1640 (Life Technologies, Gaithersburg, MD), and 10% normal human sera (Sigma, St. Louis, MO). Measles Ag, prepared from lysates of Vero cells inoculated with Attenuvax measles vaccine (more attenuated Enders’ strain, Merck) or an uninfected cell control were added at dilutions of 1:16 and 1:32 to triplicate wells for testing infant PBMC and in quadruplicate wells for adults. Adult PBMC were also incubated with Ag and control at a 1:64 dilution. Preliminary studies were performed with multiple measles Ag dilutions (range, 1:16–1:512); dilutions of 1:16 and 1:32 stimulated T cells from all positive donors. The highest stimulation index (SI)3 from either concentration was used for statistical analysis, since subjects respond to Ag concentrations differently. The measles Ag used in these studies was not inactivated because pilot experiments documented no differences when T cells were stimulated with live or inactivated measles Ag. Recombinant human IL-12 (rhIL-12), with a bioactivity of 7.7 x 107 U/ml, was generously provided by Genetics Institute (Cambridge, MA). In some experiments, rhIL-12 was added to PBMC stimulated with measles Ag or uninfected cell control at 20, 40, and 60 U/ml or 1.2, 2.4, and 3.5 ng/ml, respectively. Preliminary studies were performed with multiple concentrations of rhIL-12, based on published experience and consultation with the manufacturer; additional concentrations above and below these standards were also tested. The optimal rhIL-12 concentrations were used for subsequent assays. T cell proliferation was measured by adding [3H]thymidine after 5 days (1.25 µCi/ml) for 6–18 h. The SI was calculated as the mean cpm in measles Ag-stimulated wells divided by the mean cpm in control wells. The highest SI from either concentration of measles Ag in the presence or absence of rhIL-12 was used for statistical analysis. An SI of 3.0 or higher was considered positive, based on the mean SI + SD of responses in infants before measles vaccination. The mean cpm in background wells were compared between infant groups to assure that no significant age-related differences existed that might influence SI results. PBMC were also stimulated with PHA, 0.01 mg/ml (Difco, Detroit, MI).
Cytokine production
Supernatants from PBMC stimulated with measles Ag or uninfected
cell control were collected from wells on days 4–8, stored at
-70°C. Supernatants were tested for the p40 and p70 subunit of human
IL-12 using the ELISA ultrasensitive assay (Biosource, Camarillo, CA)
and for IFN- using the ELISA method from Endogen (Cambridge, MA).
Supernatants from PBMC stimulated with measles Ag or uninfected cell
control, in the presence or absence of rhIL-12 (added at 50 or 100 U/ml
or 2.9 and 5.8 ng/ml, respectively), were collected on days 4–8,
stored at -70°C, and tested for IFN-. The optimal concentrations
of rhIL-12 were established in preliminary assays and used for all
subsequent tests; peak values from either concentration were used for
statistical analysis. Sensitivities of cytokine detection were defined
by reference standards in each assay.
Monocyte isolation and stimulation
Monocytes were isolated by density gradient centrifugation from whole blood from adult subjects and incubated with measles at a multiplicity of infection of 5, or with an uninfected Vero cell control, under nonadherent conditions. Monocytes were then enriched by adherence to culture flasks and added to 96-well plates at concentrations of 2 x 105/well in RPMI 1640 (Life Technologies), and 10% normal human sera (Sigma). Staphylococcus aureus Cowan strain 1, 0.0075% (Calbiochem, La Jolla, CA), was added to monocyte cultures after 60 h; after 24 h, supernatants were collected and tested for the p40 and p70 subunit of human IL-12 using the ELISA ultrasensitive assay (Biosource). All cell reagents were LPS free to the limits of detection of the Limulus amebocyte lysate pyrogen kit (1–2.3 pg/ml) (BioWhittaker, Walkersville, MD).
Measles Ab assays
Sera were obtained from infant participants on the day that vaccine was given to determine whether passive Abs were present at the time of immunization. Sera were stored at -80°C and tested for measles-neutralizing Ab using a modified plaque reduction neutralization (PRN) assay (47). The PRN assay was used because of its superiority in detection of low titers of measles Abs compared with commercial ELISA methods (48). Briefly, serial fourfold dilutions of heat-inactivated serum (1:4–1:4096) were mixed with an equal volume of a low passage strain of Edmonston measles virus containing 25–35 PFU. Each serum dilution was incubated in duplicate in 24-well plates with Vero cell monolayers for 1 h and 45 min at 36°C in 5% CO2. The PRN titer was defined as the serum dilution that reduced the plaque number by 50%. Titers <1:4 were considered negative and were assigned a value of 1 for statistical analysis. Seroconversion was defined as a fourfold rise in Ab titer after levels before vaccination were corrected for decay over three half-lives.
Statistical analysis
Comparison of T cell and cytokine responses in the same patient
were evaluated by Student’s paired t test, whereas
comparisons between patients were analyzed using a Student’s unpaired
t test. ANOVA was performed to discern differences in the
means between more than two groups. The 
2 and
Fisher exact tests were used to compare the number of vaccinees
in each cohort with proliferation responses. Values of
p 
0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cell proliferation after stimulation of PBMC with measles Ag was
evaluated in 119 infants who were 6 mo (n = 49), 9 mo
(n = 36), or 12 mo (n = 34) old and in
29 adults (Fig. 1
A). T cell
responses to measles were detected after immunization in all of the
infant age groups; the mean SI ± SE increased from 2.0 ±
0.2 to 6.1 ± 0.8 in 6-mo-old (p = 0.001),
from 2.1 ± 0.3 to 6.6 ± 1.6 in 9-mo-old
(p = 0.01), and from 1.4 ± 0.1 to
5.6 ± 0.9 in 12-mo-old (p = 0.0002)
infants. The mean SI after vaccination did not differ by age cohort. In
addition, there were no age-related differences among the infants when
the percentage who had detectable T cell proliferation to measles,
defined as SI > 3.0, was compared. Responses were detected in
71% of 6-mo-old, 69% of 9-mo-old, and 62% of 12-mo-old infants. The
percentage of adults with SI > 3.0 was 86%, which was not
significantly higher than the 68% in infants. However, the mean SI in
vaccinated infants was 6.1 ± 0.66, which was significantly lower
than the mean SI of 11.3 ± 1.9 in adults
(p = 0.002) (Fig. 1A).
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IL-12 production elicited by measles Ag was evaluated in 67
infants, including 37 who were 6 mo old, 16 who were 9 mo, and 14 who
were 12 mo old, and in 13 adults. Mean IL-12 concentrations (±SE)
before vaccination were 6.2 ± 2.4, 3.0 ± 1.1, and 7.0
± 3.8 pg/ml compared with levels after vaccination of 21.3 ±
7.5, 17.9 ± 7.2, and 13.2 ± 5.9 pg/ml, in the 6-, 9-, and
12-mo-old infants, respectively (Fig. 1
B). When the infants
were evaluated as one group, there was a significant increase in IL-12
levels after compared with before measles vaccine
(p = 0.01). No significant differences were
seen when IL-12 responses were compared between the infant groups but
the mean IL-12 concentration after vaccination of infants was 19.6
± 4.4, which was statistically lower than the mean IL-12 concentration
of 41.4 ± 11.7 pg/ml measured in adults
(p = 0.04) (Fig. 1B).
IFN- production to measles in relation to age at immunization
IFN- concentrations were measured in 65 infants who were 6 mo
(n = 30), 9 mo (n = 23), or 12 mo
(n = 12) old and in 13 adults. An Ag-specific response
was observed in each infant age group (Fig. 1C). IFN-
concentrations (±SE) before and after vaccination were 21.1 ±
5.5 pg/ml vs 197.7 ± 59.7 pg/ml (p =
0.002), 38.9 ± 16 pg/ml vs 304.3 ± 100.7 pg/ml
(p = 0.01), and 42.6 ± 13.7 pg/ml vs
110.5 ± 27.8 pg/ml (p = 0.04) in the 6-,
9-, and 12-mo-old infants, respectively. No significant differences
were found when IFN- concentrations were compared among the infant
groups or when the mean of 213.2 ± 43.4 pg/ml for all infants was
compared with the mean IFN- concentration of 404.7 ± 124.7
pg/ml measured in adults (Fig. 1C).
Effect of passive Abs to measles on measles-specific T cell proliferation and cytokine responses in infants
The presence of passive Abs did not affect the frequency with
which T cell proliferation to measles was elicited after vaccination of
infants (Fig. 2A). Twenty-six of 42 infants
who were 6 mo old had passive Abs, compared with 15 of 35 infants 9 mo
old and 0 of 36 infants 12 mo old. No significant differences were
detected when the mean SI of infants with passive Abs within each age
cohort was compared with the mean SI in infants with no detectable Abs.
When data for all age groups were combined, the mean SI of infants who
had passive Abs was 5.7 ± 0.92 compared with 5.8 ± 1.1 in
those who had none (p = 1.0). Cohorting 6- and
9-mo-old infants according to titer of passive Ab present before
vaccination, at both 1:25 and 1:80, did not correlate with decreasing T
cell responses, as has been described with humoral immune responses in
infants (49, 50).
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B). The mean IL-12
concentration was 29.2 ± 9.5 in 17 infants who had passive Abs
compared with 9.2 ± 1.9 among 22 infants who had none
(p = 0.03).
Passive Abs had no significant effect on IFN- production in response
to measles Ag after immunization (Fig. 2C). Of 16 infants
who had passive Abs, the mean IFN- concentration was 105.9 ±
36.5 compared with 235.1 ± 62.6 among 32 infants who had none
(p = 0.2).
Effect of measles immunization on mitogen-induced T cell proliferation in relation to age
Infants were tested for T cell proliferation to PHA responses just
before and 3 mo after vaccination. The mean cpm ± SE in
PHA-stimulated cultures of PBMC were not statistically different among
the infant groups or when measured before immunization and 3 mo later
(data not shown). The mean cpm for all infants tested after
immunization was 43,500 ± 2,900, which was significantly lower
than the mean cpm of 58,000 ± 6,700 observed in adults
(p = 0.03) (Fig. 3).
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The experiment described by Karp et al. was repeated to confirm that the measles virus used to prepare measles Ag for T cell proliferation and cytokine assays had the capacity to suppress IL-12 production by monocytes to concentrations equivalent to those measured in control wells. Furthermore, addition of S.aureus Cowan strain 1 stimulated IL-12 production in control Vero cell cultures but had no effect on human monocytes cultured with measles Ag (data not shown).
Effects of rhIL-12 on measles-specific T cell proliferation and
IFN- production
T cell proliferation was measured in 11 vaccinated adults after stimulation with measles Ag alone and with the addition of rhIL-12. All the adults had a positive SI to measles (SI > 3), with a mean SI ± SE of 14.1 ± 2.9. No difference in measles-induced T cell proliferation was demonstrated when rhIL-12 was added. The mean SI was 7.4 ± 1.5 (p = 0.06).
IFN- release by T cells from 6 adults was measured at Days 1, 3, 5,
and 7 after incubation with measles Ag alone, measles and rhIL-12, or
rhIL-12 alone. IFN- concentrations were higher when PBMC were
stimulated with measles in the presence of rhIL-12 compared with
measles Ag alone (p = 0.02) or rhIL-12 alone
(p = 0.0003) (Fig. 4). The peak
difference was observed on Day 7, with mean IFN- concentrations of
1634.12 ± 196.0 in the measles-stimulated wells with rhIL-12
added.
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production by T cells (Fig. 5).
The mean IFN- concentrations in measles-stimulated wells were
151.8 ± 55.6 pg/ml compared with 747.3 ± 180.2 in the
presence of rhIL-12 and measles Ag (p = 0.01)
(Fig. 5). The peak IFN- concentration after rhIL-12 and measles
stimulation in children was 747.3 ± 180.2 which was significantly
lower than the peak of 1634.2 ± 196 from adult PBMC stimulated
with measles and rhIL-12 (p = 0.01).
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Measles-neutralizing Ab titers before vaccination were 13 (95% confidence interval, 7–26), 4 (95% confidence interval, 2–8), and 1 (95% confidence interval, 1–1) in the 6-, 9-, and 12-mo-old infant, respectively. Twelve weeks after measles vaccination, neutralizing Ab titers rose to 76 (95% confidence interval, 37–156), 353 (95% confidence interval, 164–756), and 1023 (95% confidence interval, 756-1704) in the 6-, 9-, and 12 mo-old-infants, respectively (6 vs 9 mo, p = 0.0002; 6 vs 12 mo, p = 0.0001; 9 vs 12 mo, p = 0.01). As previously reported, in the absence of detectable passive Abs, seroconversion and neutralizing Ab titers of 6-mo-old infants were statistically lower than those of 9- or 12-mo-old infants. There was no statistical difference in the humoral immune responses between 9- and 12-mo-old infants who lacked detectable passive Abs (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, have been documented in infants with
herpes simplex infections during the first few weeks of life (52, 54).
Descriptions of the age-dependent immunogenicity of certain vaccines
suggests that the limited immune responses seen in neonates may extend
beyond the first year, but when immune maturation takes place is not
known and is likely to vary depending on the antigenic stimulus (33, 55, 56). Animal experiments indicate that newborn responses to Ags are
associated with diminished levels of TNF-
and IFN- production and
are shifted toward a Th2-type cytokine pattern (34, 35). Since measles
infection and measles vaccine have been associated with spontaneous
IL-4 release by circulating PBMC and other Th2-like responses,
immunization of young infants could enhance their predominance relative
to the induction of antiviral Th1-like responses (6, 9, 10, 12). This
issue is of practical importance because protection of younger infants
against serious or life-threatening measles would be beneficial in
geographic areas where measles remains endemic (1, 2). Our experiments
addressed these questions with a comparative analysis of cellular
immunity elicited by measles immunization of infants at 6, 9, and 12 mo
of age. We found that T cell recognition of measles Ag was elicited in
71, 69, and 62%, respectively, and no age-related decreases in IL-12
or IFN- production among younger infants were detected. However,
measles-specific T cell proliferation and IL-12 responses of infants
were significantly lower than those of adults with vaccine-induced
immunity to measles.
IL-12 is critical for the induction of IFN-, a major Th1 T cell
cytokine which is involved in the clonal expansion of Ag-specific T
cells (25, 26, 27, 28, 29, 30, 31, 57, 58). Earlier studies have shown that
measles-specific IFN- release and T cell-proliferative responses are
lower after measles infection or immunization than those induced by
other viruses (6, 59, 60). Diminished IL-12 production, associated with
the direct binding of measles to its monocyte receptor, may account for
these differences (24). Our hypothesis was that infants may be
particularly susceptible to the effects of low IL-12 production to
measles Ag because their T cells may be inherently less efficient at
IFN- gene transcription (34, 54, 55, 56, 61). First, we confirmed the
block of IL-12 production by monocytes exposed to high concentrations
of measles. Second, we demonstrated that the addition of rhIL-12 to
PBMC cultures along with measles Ag was associated with a dramatic
increase in IFN- release by T cells from adults with vaccine-induced
measles immunity. Finally, we showed that whereas IL-12 also enhanced
IFN- production by infant T cells stimulated with measles Ag, the
IFN- concentrations were significantly lower than those produced by
T cells from immune adults under these conditions. Taken together,
these observations suggest that despite some measles-specific induction
of IL-12 release, the quantities of IL-12 made may not be sufficient to
induce concentrations of IFN- high enough to promote the maximal
expansion of infant T cells that recognize measles Ags. The increased
susceptibility of infants to severe measles is likely to be
multifactorial and may be mediated in part by lower IL-12 responses
than with adults, associated with a more limited capacity to produce
IFN-.
An increased susceptibility to secondary infections is an important reason for the high rates of infant morbidity and mortality associated with measles (2, 3). These complications are attributed to generalized immunosuppression caused by measles infection (6). Immunization with live attenuated measles vaccine has been followed by a transient decrease in mitogen-induced T cell proliferation for a few weeks after vaccination (16, 17). We found no suppression of proliferation to PHA when the responses of infants tested just before immunization were compared with those measured 3 mo later. There was no evidence that generalized immunosuppression persisted for this time interval regardless of the age at measles immunization; PHA responses of 6-mo-old infants were equivalent to those of infants who were 9 and 12 mo old.
Interference by passively acquired measles Abs with the immunogenicity
of measles vaccine has been a deterrent to immunization of infants
younger than 12 mo (4, 37, 42, 43, 62, 63, 64). In addition to documenting
the effects of passive Abs on active induction of neutralizing Abs in
infants immunized at 6 and 9 mo, we found impaired humoral immunity
among infants who had no detectable neutralizing Abs when immunized at
6 mo of age (41). Impaired humoral immune responses reflect inherent
deficiencies in the host response as well as neutralization of vaccine
virus by passively acquired Abs, but T cell responses appear to be
intact even in younger infants. As has been reported for DNA
vaccination (32), passive Abs did not influence whether
measles-specific T cell proliferation or IFN- was induced by
immunization of infants with live attenuated measles vaccine. Whether
these virus-specific T cell responses result in protection is not
known, but successful immunization of infants as young as 3 mo has been
described during measles outbreaks or in endemic areas (65). Priming of
helper T cells could support the more rapid expansion of adaptive
immune responses when the measles Ags are encountered again. How B
cells and T cells interact to create protective immunity against
measles has not been determined but the clinical experience points to
an essential contribution of cell-mediated immunity (66, 67). The
deficiency in neutralizing Ab production in infants immunized at 6 mo
who had no interference attributable to passive Abs may represent an
age-related impairment in a T cell-independent B cell sensitization
pathway, or a deficiency in the communication between immature T cells
and B cells. Determining what these mechanisms are and how to reverse
them in vivo, as we were able to enhance IFN- release by IL-12 in
vitro, may allow an approach to measles immunization that is more
appropriate for the immune system of young infants.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hayley Gans, Stanford University Medical Center 300 Pasteur Drive G312, Stanford, CA 94305-5208. E-mail address:
3 Abbreviations used in this paper: SI, stimulation index; rhIL-12, recombinant human IL-12; PRN, plaque reduction neutralization.
Received for publication October 16, 1998. Accepted for publication February 9, 1999.
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K. Luzuriaga, M. McManus, M. Catalina, S. Mayack, M. Sharkey, and M. Stevenson Early Therapy of Vertical Human Immunodeficiency Virus Type 1 (HIV-1) Infection: Control of Viral Replication and Absence of Persistent HIV-1-Specific Immune Responses J. Virol., August 1, 2000; 74(15): 6984 - 6991. [Abstract] [Full Text]
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) and 12 wk after (
) measles
vaccination in infants who were 6, 9, or 12 mo of age at time of
immunization and in vaccinated adults. Error bars represent SEs. A
positive SI is defined as 3 or greater. B, IL-12
concentration (pg/ml) before (
), IL-12 (