Context.— Measles causes serious morbidity in infants, with the highest risk among
those who are 6 to 12 months of age. In the United States, measles vaccine
has been given at age 12 to 15 months to minimize interference by passive
antibodies and to achieve the high seroprevalence required for herd immunity.
Infants of mothers with vaccine-induced immunity may lose passively acquired
antibodies before 12 months, leaving them susceptible to measles infection.
Objective.— To assess the immunogenicity of measles vaccine in infants younger than
12 months.
Design.— Cohort study conducted before and after measles immunization.
Setting.— Pediatric clinic in Palo Alto, Calif.
Participants.— Infants 6 (n=27), 9 (n=26), and 12 (n=34) months of age were enrolled;
72 provided both initial and follow-up samples.
Main Outcome Measures.— Evaluation of immunogenicity before and 12 weeks after measles vaccination,
including measles neutralizing antibody titers, measles-specific T-cell proliferation,
and cytokine profiles.
Results.— Measles neutralizing antibodies were present before vaccination in 52%
(12/23), 35% (7/20), and 0% (0/22) of 6-, 9-, and 12-month-old infants, respectively.
In the absence of detectable passive antibodies, geometric mean titers after
vaccination were significantly lower in 6-month-old infants compared with
9-month-old infants (27 vs 578, P=.01) and 12-month-old
infants (27 vs 972, P=.001). The seroconversion rate,
defined as a 4-fold rise in antibody titer, in these 6-month-old infants was
only 67%, and only 36% of these infants achieved seroprotective neutralizing
antibody titers of 120 or higher after vaccination compared with 100% of 9-
and 12-month-old infants lacking detectable passive antibody prior to vaccination.
T-cell proliferation and cytokine responses to measles did not differ with
age.
Conclusions.— Humoral immunity was deficient in 6-month-old infants given measles
vaccine, even in the absence of detectable passively acquired neutralizing
antibodies. Comparison of their responses with those of 9- and 12-month-old
infants indicates that a developmental maturation of the immune response to
measles may occur during the first year of life, which affects the immunogenicity
of measles vaccine.
THE SUSCEPTIBILITY of infants to serious disease caused by viruses is
recognized during the immediate neonatal period but it also extends through
the first year of life, suggesting that immunocompetence of the host develops
gradually over this time interval. In the case of measles, clinical experience
demonstrates that a critical maturation of the host response occurs between
6 and 12 months, based on the subsequent decline in measles mortality.1-5
The high rate of infant morbidity and mortality observed in developing countries
and during recent outbreaks in the United States has renewed interest in evaluating
measles immunization of infants at the youngest possible age.1,6,7
Past studies showed a high failure rate of measles vaccination in infants
younger than 12 months. Poor immunogenicity was associated with the persistence
of antibodies acquired transplacentally from mothers whose measles immunity
was induced by natural infection.7-13
The recommendation for vaccination at 12 to 15 months of age was made to ensure
that all, or almost all, infants had lost passive antibody when immunized
and that optimal herd immunity was achieved.14
In contrast with the first 3 decades after measles vaccine was introduced,
most infants in the United States are now born to mothers who have vaccine-induced
immunity to measles.15-19
These infants can be expected to lose maternal antibodies by 9 to 12 months
of age.19,20 Our recent study
showed only 29% of 9-month-old infants and 5% of 12-month-old infants had
persistent passive antibodies.20 As a result,
more infants younger than 12 months now lack both passive and active measles
immunity, leaving them unprotected and in the highest-risk group for life-threatening
complications. Maintaining high seroprevalence rates to achieve herd immunity
protects young infants but local epidemics confirm past studies showing that
a small population of susceptible individuals can sustain a measles outbreak.11,20
Little is known about the maturation of virus-specific immune responses
in healthy infants following infection or immunization.21-24
Newborn infants have deficiencies in primary antigen presentation by dendritic
cells, limited T-cell proliferation, impaired B-cell function, and reduced
production of cytokines by helper T cells of the type 1 subset (TH1),
including interleukin 2 (IL-2) and interferon γ (IFN-γ).24-30
Whether these deficiencies, which could diminish the immunogenicity of measles
vaccine, are still present in 6- to 9-month-old infants has not been determined.
Since many infants now have early loss of passive antibodies, it is feasible
to distinguish the relative impact of deficiencies attributed to the maturation
of the immune response from passive antibody inhibition of measles vaccine
immunogenicity.
The purpose of our study was to assess whether there are intrinsic immunologic
barriers to immunization of infants younger than 12 months with measles vaccine,
or whether neutralization of the vaccine virus by passive antibodies constitutes
the only significant obstacle to early vaccination. In the past, potential
interference by passive antibodies prevented the analysis of developmental
changes in the host response to measles.13,31
Subjects included healthy infants, without documented intercurrent illnesses,
who were 6 (n=27), 9 (n=26), or 12 (n=34) months of age and were seen for
their well-child visit at the Palo Alto Medical Foundation, Palo Alto, Calif.
A total of 87 infants were enrolled in the study; 2 infants never participated
after consent was given because their mothers decided against phlebotomy (6-month-olds:
n=1, 12-month-olds: n=1), 13 infants provided only the initial blood sample
(6-month-olds: n=1, 9-month-olds: n=2, 12-month-olds: n=10), and 72 infants
provided both the initial and follow-up samples (6-month-olds: n=25, 9-month-olds:
n=24, 12-month-olds: n=23), but not all T-cell and B-cell assays were performed
for each sample. 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. Children born before 36 weeks' gestation, whose birth weight
was less than 2500 g, or who had chronic underlying illnesses were excluded.
Mothers were grouped by birth date, as those born before 1957 (n=17), between
1957 and 1963 (n=34), after 1963 (n=13), or unknown (n=3). Blood samples (2-5
mL) were collected from infants before vaccination and 12 weeks later. Samples
were also obtained after the Measles, Mumps, and Rubella Virus Vaccine (M-M-R,
Merck & Co Inc, West Point, Pa) (given as routine well-child care at age
12 months) from infants who did not respond to initial measles vaccination.
Healthy adults who had received at least 1 measles vaccination were also evaluated.
No cases of measles were identified in our geographic area during the study
period.
Six- and 9-month-old infants were immunized with Measles Virus Vaccine
Live (Attenuvax; Merck & Co Inc; lot 1002A; expiration, August 15, 1996;
strength, 1000 median tissue culture infective doses [TCID50] of
the US reference measles virus); these infants subsequently received M-M-R
at 12 months. Twelve-month-old infants were immunized with M-M-R Virus Vaccine
Live (Merck & Co Inc; lot 1315A; expiration, October 12, 1996; containing
Measles Virus Vaccine Live; strength, 1000 TCID50 of the US reference
measles virus).
Serum samples were stored at −80°C. Paired specimens from
before and after vaccination were run in parallel when possible and tested
for measles neutralizing antibody using a modified plaque reduction neutralization
(PRN) assay.32 This assay was used instead
of commercially available enzyme-linked immunosorbent assay (ELISA) kits because
of the superiority in detection of low titers of measles antibodies.33 Briefly, serial 4-fold dilutions, starting at 1:4,
of heat-inactivated serum (56°C for 30 minutes) were mixed with an equal
volume of a low-passage strain of Edmonston measles virus containing 25 to
35 plaque-forming units. Each dilution was incubated in duplicate in plastic
24-well plates with Vero cell monolayers for 1 hour 45 minutes at 36°C
and 5% carbon dioxide. A reference serum calibrated against the international
reference was included in duplicate in each run. The PRN titer was defined
as the serum dilution that reduced the number of plaques by 50%. Titers less
than 1:4 were considered negative and assigned a value of 1 for statistical
analysis. A PRN titer of 1:120 shown previously to neutralize infection34 was used as the definition for seroprotection. Seroconversion
was defined as a 4-fold rise in antibody titer after levels prior to vaccination
were corrected for decay over 3 half-lives (1 half-life=1 month); lack of
seroconversion was considered primary vaccine failure.
T-cell Proliferation Assay
Fresh peripheral blood mononuclear cells (PBMCs) were separated from
whole blood by Ficoll-Hypaque gradient and added to 96-well microtiter plates
at concentrations of 3.0 × 105 per well in RPMI 1640 (Gibco,
Gaithersburg, Md), 10% normal human sera (Sigma, St Louis, Mo). Measles antigen,
prepared from infected Vero cell lysates, or an uninfected cell control was
added at dilutions of 1:16 and 1:32 to triplicate wells. T-cell proliferation
was measured by adding tritiated thymidine (2.5 µCi per well) after
5 days for 6 to 18 hours. The stimulation index (SI) was calculated as the
mean counts per minute (cpm) in measles antigen–stimulated wells divided
by the mean cpm in control wells. A positive SI to measles was 3.0 or greater,
based on the mean and SD of responses in infants before vaccination. Phytohemagglutinin
(Difco, Detroit, Mich) was used as a positive control.
Assays for Cytokine Production
Supernatants from PBMCs stimulated with measles antigen prepared from
infected Vero cell lysates or uninfected cell controls were collected from
duplicate wells for 8 consecutive days, stored at −70°C, and tested
using ELISA assays, with sensitivities of detection defined by reference standards
in each assay. The supernatants collected on days 1 through 8 after initial
incubation of T cells with measles antigen were tested in parallel to determine
the peak cytokine response; this peak concentration was used as the value
for statistical analysis. Interleukin 4 and IL-10 production were measured
using assays from Genzyme Inc (Cambridge, Mass). Specimens were also tested
for IL-4 using Cytoscreen ultrasensitive assay (Biosource Inc, Carmillo, Calif).
The ELISA method from Endogen Inc (Cambridge, Mass) was used to measure IL-2
and IFN-γ.
The reciprocals of the measles PRN titers were transformed, and geometric
mean titers (GMTs) were calculated. Differences in antibody titers among groups
were evaluated by the Mann-Whitney U test. Stimulation
indexes and cytokine responses in individual patients before and after vaccination
were compared using the paired Student t test; the
unpaired t test was used to compare study populations,
but only on paired data points. Analysis of variance was performed to evaluate
differences among the means of all 3 groups. The χ2 and Fisher
exact tests were used to compare the number of vaccinees in each cohort who
had antibody or proliferation responses. The Spearman rank coefficient was
used to evaluate correlations between SI and GMTs or cytokine responses. Statistical
significance was defined at P≤.05 for all analyses
performed.
Measles neutralizing antibody titers were determined in 65 infants before
vaccination. Twelve (52%) of 23 6-month-old infants had detectable passive
antibodies compared with 7 (35%) of 20 9-month-old infants and 0 (0%) of 22
12-month-old infants (6 months vs 12 months, P=.003;
9 months vs 12 months, P =.01) (Table 1). There were no statistical differences in measles GMTs
before vaccination when comparing 6- and 9-month-old infants born to the oldest
mothers, who were born before 1957, and the youngest mothers, who were born
after 1963.
Measles-neutralizing antibody titers after vaccination, determined in
the same 65 infants and expressed as GMTs, were 35 (95% confidence interval
[CI], 13-95), 201 (95% CI, 69-585), and 972 (95% CI, 669-1415) in 6-, 9-,
and 12-month-old infants, respectively (6 months vs 9 months, P=.003; 6 months vs 12 months, P<.001;
9 months vs 12 months, P=.01) (Figure 1). The seroconversion rate (4-fold rise in antibody titer)
in 6-month-old infants was only 65% (15/23) compared with 90% (18/20) of 9-month-old
infants and all of the 22 infants who were 12 months old (6 months vs 12 months, P=.01). Six-month-old infants were also less likely than
9- and 12-month-old infants to develop seroprotective neutralizing antibody
titers of 120 or more. Only 10 (43%) of 23 6-month-old infants had seroprotective
titers after vaccination compared with 17 (85%) of 20 9-month-old infants
and 21 (95%) of 22 12-month-old infants (6 months vs 9 months, P=.01; 6 months vs 12 months, P=.001).
In the presence of passive antibodies, determined by PRN, there was
no statistical difference in the seroconversion rates and GMTs among all infants,
regardless of age. Sixty-three percent of 6-month-old infants who had passive
antibody before vaccination seroconverted, with a postvaccination GMT of only
45. This rate of response was not statistically different from the 40% of
9-month-old infants who seroconverted in the presence of passive antibodies
and who had a GMT of 85 after vaccination.
In contrast, age-related differences were observed among infants who
had no detectable passive antibodies by PRN prior to vaccination. Among these
infants, the measles GMTs after vaccination were lower in 6-month-old infants
compared with 9-month-old infants (27 vs 578; P=.01)
and 12-month-old infants (27 vs 972; P=.001) (Figure 2). Analysis of variance showed P=.001. The seroconversion rate in these 6-month-old infants
was 67%, and only 36% of these infants reached seroprotective GMTs after vaccination,
compared with 100% of the 9- and 12-month-old infants lacking detectable passive
antibody prior to vaccination. The GMTs, seroconversion, and seroprotective
rates of the 9-month-old infants who lacked detectable passive antibodies
showed no statistical difference compared with those of 12-month-old infants,
all of whom lacked detectable passive antibodies prior to vaccination.
Six infants who had primary measles vaccine failure at 6 months (n=5)
or 9 months (n=1) were evaluated for neutralizing antibodies up to 2 years
after revaccination with M-M-R. Their GMTs increased significantly, from 4.7
to 403 (P=.02).
No correlations were found between measles GMT and cytokine responses
to measles in any of the infant groups.
T-cell proliferation to measles antigen was measured in 67 infants and
17 vaccinated adults. Infants from all age groups showed a significant increase
in T-cell proliferation to measles antigen after vaccination (6 months, P=.02; 9 months, P=.04; 12 months, P=.006) (Figure 3).
A positive response (SI ≥3) was detected in 15 (63%) of 24 6-month-old
infants, 15 (68%) of 22 9-month-old infants, 12 (57%) of 2112-month-old infants,
and 72% of adults (Table 1). Response
rates were not statistically different among the infant groups and adults.
The mean (SE) SIs after vaccination of 6-, 9-, and 12-month-old infants were
3.8 (0.52), 7.5 (2.80), and 5.0 (1.10), respectively, which were not statistically
significant. These SIs did not differ statistically from vaccinated adults,
who had a mean (SE) SI of 8.0 (1.60) (Table
1). The presence or absence of passive antibody did not influence
T-cell proliferation responses to measles antigen in the 6- or 9-month-old
infants. Measles SI did not correlate with neutralizing antibody titers in
individual patients after vaccination.
Five infants who had serologically defined primary vaccine failure had
SIs of 3 or greater after measles immunization. Among infants who had passive
antibodies prior to vaccination, 8% (1/12) of 6-month-old infants and 14%
(1/7) of 9-month-old infants had neither humoral nor T-cell proliferation
to measles vaccine. All infants who lacked passive antibodies had either humoral
or cell-mediated immunity or both after immunization.
Interleukin 2 production in response to measles antigen was measured
in 41 infants and 8 adults. Before vaccination, the mean (SE) IL-2 concentrations
were 46.2 (18.0), 65.3 (16.59), and 32.5 (9.83) pg/mL in 6-, 9-, and 12-month-old
infants, respectively (Table 1).
A significant rise in IL-2 production was detected after vaccination of only
6- and 12-month-old infants, to 148.6 (25.77) and 99.8 (24.32) pg/mL, respectively
(6 months, P=.003; 12 months, P=.03). No age-related differences were detected among infant groups
but the mean IL-2 concentration in vaccinated adults was 306.3 (60.84) pg/mL,
which was higher than levels among all infants (P=.002).
The production of IFN-γ by T cells stimulated with measles antigen
was measured in 42 infants and 8 adults. Mean (SE) IFN-γ concentrations
before vaccination were 41.4 (10.93), 49.8 (19.69), and 42.5 (13.69) compared
with concentrations of 194 (75.85), 366.0 (125.37), and 110.4 (27.83) pg/mL
after vaccination of 6-, 9-, and 12-month-old infants, respectively (Table 1). However, when responses of individual
infants were evaluated by paired t test, significant
increases were detected after vaccination of 9- and 12-month-old infants but
not 6-month-old infants (6 months, P=.06; 9 months, P=.03; 12 months, P=.04). The
mean (SE) IFN-γ concentration was 300.6 (147.66) pg/mL in vaccinated
adults, which was not significantly different from the infants.
Interleukin 4 release was not detected after stimulation of T cells
from infants or adults with measles antigen. Interleukin 10 production by
PBMC stimulated with measles antigen was evaluated in 38 infants and 8 vaccinated
adults. The mean (SE) IL-10 concentrations before and after vaccination were
not statistically different in all age groups; the responses were 81.9 (15.54)
vs 73.9 (26.44) pg/mL in 6-month-old infants, 84.5 (17.87) vs 77.4 (25.80)
pg/mL in 9-month-old infants, and 59.9 (11.98) vs 50.4 (10.49) pg/mL in 12-month-old
infants. Vaccinated adults had higher IL-10 concentrations than infants with
a mean (SE) of 152.4 (32.03) pg/mL (P=.02).
No age-related differences in the kinetics of cytokine production, defined
as the interval to detection of the peak concentration, were detected. There
was no correlation between SI and cytokine responses in individual patients.
Interference due to passively acquired antibodies among infants younger
than 12 months has been observed since the live attenuated measles vaccine
was introduced in the 1960s.7-13
Mothers born prior to 1957 who had measles immunity from natural disease transferred
more neutralizing antibodies to their infants than mothers with vaccine-induced
immunity to measles.16,19,20,35
Most women of childbearing age in the United States today have been immunized
against measles.19,20,35
Consequently, infants lose measles neutralizing antibody sooner after birth,15-19
and could benefit from measles vaccination before age 12 months to provide
active immunity against infection. Although rare, measles outbreaks in the
United States are associated with high rates of morbidity and mortality among
infants who have not yet received routine measles vaccination.2,6,36,37
Vaccination of infants younger than 12 months is recommended when exposure
to measles is likely.38 However, more information
about the immunogenicity of measles vaccine in younger infants is needed to
reassess the optimal age for routine vaccination against measles, since the
proportion of infants born to mothers with vaccine-induced immunity compared
with natural immunity can be expected to increase.
Since 48% of 6-month-old infants in our population had undetectable
levels of passive antibodies by the most sensitive PRN assay,33
it was possible to evaluate the capacity of the developing immune system to
respond to measles vaccine without the confounding variable of interference
by neutralizing antibodies acquired from the mother. Vaccination of 6-month-old
infants who had no detectable passive antibodies elicited seroconversion in
only 67% and seroprotective titers in only 36% of these infants. In contrast,
100% of 9-month-old infants lacking passive antibodies seroconverted and achieved
titers considered seroprotective; their responses were not statistically different
from those of 12-month-old infants.
Our study demonstrates that the persistence of passive antibodies remains
an obstacle to measles immunization, affecting responses in about one third
of 9-month-old infants and half of 6-month-old infants. Yet, the deficiency
of the humoral immune response to measles vaccine among 6-month-old infants
without detectable passive antibodies in this study, compared with that among
9- or 12-month-old infants, indicates that some component of the immune response
to measles antigens undergoes maturation late in the first year of life. Younger
infants may have a functional defect in the TH-cell response to
measles antigen since IFN-γ production did not increase significantly
after vaccination of 6-month-old infants. Infants infected with herpes simplex
virus and cytomegalovirus also have low or absent IFN-γ.24,39
T-cell recognition of measles antigens, as measured by in vitro proliferation,
was detected among vaccinated infants and adults but the response rates were
less than 75% among all cohorts, as has been described in previous studies
of cell-mediated immunity to measles.40-42
The limited proliferation of measles-specific memory T cells in in vitro assays
may be related to the down-regulation of IL-12 production shown previously
to be triggered by measles.43 Interleukin 12,
which is secreted by monocytes, is important for optimal TH1 differentiation
and plays an integral role in the acquisition of the cell-mediated immune
response.44-46
If infant T cells have a diminished capacity to produce IFN-γ, decreased
IL-12 production after measles infection or immunization would be expected
to further impair the induction of measles-specific cellular immunity.
In vivo, natural measles infection and live attenuated measles vaccine
induce transient, nonspecific immunosuppression, characterized by predominance
of type 2 TH cell responses and associated with an increase in
the spontaneous release of IL-4 and IL-10.42,47-49
Infants may have an age-related susceptibility to the generalized immunosuppression
elicited by measles virus in vivo, including attenuated vaccine strains.50 In contrast with the increased spontaneous release
of these cytokines, our evaluation of the measles-specific production of IL-4
and IL-10 did not demonstrate a shift toward a predominant TH2
cell response. Naive T cells of neonates shift preferentially toward a TH2 cell response when stimulated by foreign antigens, but whether this
pattern persists later in the first year of life has not been determined.39
The decreased synthesis of measles neutralizing antibodies in younger
infants may represent impaired T-cell and B-cell interactions. Specifically,
a maturational deficiency in CD40 ligand expression by activated T cells could
inhibit the development of T-cell–dependent B-cell immunity to measles.27,29,44,46,51,52
It is also possible that the limited immunogenicity of measles vaccine in
6-month-old infants reflects a defect in antigen presentation by dendritic
cells. The switch from naive CD45RA T cells to memory T cells expressing CD45RO
is crucial for acquisition of an effective antigen-specific immune response
and requires antigen processing by dendritic cells, which have been shown
to be functionally immature in neonates.25,26
Finally, diminished humoral immunity to measles in 6-month-old infants could
represent a primary B-cell deficiency, although impaired immunity to viral
pathogens has usually been associated with altered T-cell–dependent
responses. Infants have decreased T-cell–independent B-cell activation
by polysaccharides and heavily glycosylated proteins made by bacteria and
viruses.53
Regardless of the underlying immunologic mechanism, our experience was
that the maturational deficiency in the humoral response to measles vaccine
was transient in individual infants. Revaccination at age 12 to 15 months
resulted in a marked increase in measles neutralizing antibody titers among
infants with serologically defined primary vaccine failure. These observations
suggest that early immunization does not induce tolerance to subsequent doses
of measles vaccine, which was an earlier concern in considering the immunization
of infants younger than 12 months.12,54
Our observations are consistent with recent reports that these infants seroconvert
after a second dose of measles vaccine.55-58
Most 6-month-old infants with poor humoral immune responses to measles
had detectable T-cell proliferation to measles antigen after vaccination.
Whether the presence of measles-specific T cells predicts protection, despite
low or undetectable titers of neutralizing antibodies, is not known. The importance
of cellular immunity against measles is suggested by clinical experience demonstrating
that patients with cellular immunodeficiencies are susceptible to severe or
fatal measles, whereas children with congenital agammaglobulinemia had no
complications from measles and developed immunity to reinfection.14 Nevertheless, seroconversion after measles vaccination,
with induction of measles neutralizing antibody titers greater than 120, correlates
with protection against wild-type measles infection.34
Our study demonstrates that host response of most infants immunized at age
6 months is insufficient to achieve this criterion of protective immunity.
Given the heterogeneity of the population of women of childbearing age
in the United States, which includes women with natural as well as vaccine-induced
immunity to measles, interference by passive antibodies will continue to affect
the responses of many 6- and 9-month-old infants to measles vaccine. Our study
indicates that postnatal maturation of the immune system is also likely to
restrict the immunogenicity of measles vaccine in 6-month-old infants. This
possibility warrants further investigation when considering lowering the recommended
age of measles immunization for infants whose mothers have vaccine-induced
immunity.
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