Transplacental Immunization of the Human Fetus
to Tetanus by Immunization of the Mother
THOMAS J. GILL III, CHARLES F. REPETTI, LEON A. METLAY, BRUCE S. RABIN,
FLOYD H. TAYLOR, DOUGLASS S. THOMPSON, and ANDREA L. CORTESE,
Departments of Pathology, Community Medicine, and Obstetrics and
Gynecology, University of Pittsburgh School of Medicine and
Magee-Women's Hospital, Pittsburgh, Pennsylvania 15261
A B S T R A C T
that immunization of the pregnant female led to the
transplacental immunization of her fetuses. The pos-
sibility that this also occurred in humans was explored
by immunizing 42 pregnant women with tetanus tox-
oid (2.5 or 5 Lf) in the fifth and eighth months of
pregnancy and comparing the immune responses of
their offspring with the responses of the offspring of
25 unimmunized mothers. Only the offspring of the
immunized mothers were sensitized to tetanus. IgM
antitetanus antibodies were in their blood before im-
munization with diphtheria, pertussis, tetanus vaccine
(DPT), they had a more rapid (P < 0.01) response to
DPT immunization, and they were still highly sensi-
tized (P < 0.01) to tetanus 13 mo after birth. In ad-
dition, pregnancy had no immunosuppressive effect
(P < 0.05) on the responses of the mothers to tetanus
toxoid. Thus, transplacental immunization occurs in
humans; it enhances the response of the offspring to
subsequent immunization, and it could be used to cir-
cumvent the necessity for immunization in early neo-
Experimental studies in rats showed
Experimental studies in inbred rats (1-5) showed that
transplacental immunization of the fetus occurred: im-
munization of a pregnant animal with an insolubilized
antigen permanently altered the immune response of
its offspring (1, 2) due to the transplacental passage of
antigen and its interaction with the developing im-
mune system of the fetus (3), and the effect was ge-
Address reprint requests to Dr. Thomas J. Gill III, De-
partment of Pathology, University of Pittsburgh, School of
Medicine, Pittsburgh, PA 15261.
Received for publication 22 November 1982 and in re-
vised form 28 April 1983.
netically influenced (2-5). In this study we explore this
phenomenon in humans. The basic significance of the
study would lie in the demonstration that transpla-
cental immunization, which was discovered in a spe-
cies having a labyrinthine hemotrichorial placenta,
occurs in another species, i.e., humans, which has a
hemobichorial villous placenta. The clinical signifi-
cance would lie in the possibility that the technique
of transplacental immunization would provide a unique
and safe approach to immunization in humans.
Tetanus toxoid (TT)' was chosen as the antigen for
this study because it is safe (6) and because there is
extensive experience with tetanus immunization in
humans (7-15). The experimental approach was to im-
munize females with TT at 5 and 8 mo of pregnancy
and to assess the sensitization of their offspring to tet-
anus and their ability to respond to subsequent im-
munization with TT compared with the offspring of
control (unimmunized) mothers. This stage of preg-
nancy was chosen for immunization because organo-
genesis and the major development of the fetus are
finished, so any potential teratogenic effect of immu-
nization would be improbable, and it is the most prac-
tical time from the clinical point of view. The doses
of TT used were those ordinarily employed in im-
munizing adults (2.5 or 5 Lf) rather than the high doses
(30-100 Lf) used in many field studies (9-15) or rec-
ommended for pregnant women exposed to tetanus
(6) in order to avoid the possibility of inducing partial
immunological tolerance in the offspring (4, 5). A sec-
ond question to which this study could contribute is
whether pregnant women can respond normally to im-
munization during pregnancy, which is still a point of
some controversy (16).
' Abbreviations used in this paper: DPT, diphtheria, per-
tussis, tetanus vaccine; PHA, phytohemagglutinin; TT, tet-
J. Clin. Invest.
The American Society for Clinical Investigation, Inc.
screened volunteers from the outpatient clinic at Magee-
Women's Hospital. All of them had received three diphthe-
ria, pertussis, tetanus vaccine (DPT) immunizations in child-
hood, and 12% (8/67) gave a history of one subsequent
immunization with TT in childhood or in adolescence. The
women entering the study were assigned in alternating se-
quence to the control (unimmunized) or immunized groups,
and all of them were assayed for circulating antitetanus an-
tibody. The immunized women were assigned randomly to
receive a standard (5 Lf) or half-standard (2.5 Lf) dose of
adult-type TT in order to test any potential effect of the
amount of antigen used on the immune response. All of the
TT used was from the same batch obtained from the Bio-
logical Laboratories, Massachusetts Department of Health.
The mothers were vaccinated subcutaneously at 5 and 8 mo
of gestation and bled periodically (Fig. 1) thereafter for
serum antibody and tetanus-induced lymphocyte transfor-
mation assays; the control mothers were assayed in parallel.
The babies of both the control and the immunized mothers
were assayed in the same way. Both groups of babies received
the standard three doses of DPT: each dose contained 7.5
Lf diphtheria toxoid. 4 protective units pertussis vaccine,
and 5 Lf TT in 0.5 ml. The details of the experimental design
are summarized in Fig. 1. All babies were normal by pe-
diatric evaluation, both at birth and throughout the period
of observation (3 yr).
The antibody was measured by a ra-
dioimmunoassay that could detect 0.75 ug/ml IgG and 0.4
,ug/ml IgM (17). The mixed lymphocyte reaction was per-
formed as described previously (18). Briefly, heparinized
blood from the mothers and babies was used to obtain lym-
The pregnant women were un-
phocytes by Ficoll-Hypaque separation; the plasma layer
was saved for autologous plasma. One batch of male AB
plasma (BioBee Co., Boston, MA) was used in all studies. An
appropriate dilution of lymphocytes, medium 199, and
plasma (autologous or AB) was prepared. Then 0.01 ml of
TT or phytohemagglutinin (PHA) (Burroughs-Wellcome
Co., Research Triangle Park, NC) at the appropriate dilu-
tioIns was added to each well in a 96-well plate, and 0.2 ml
of the mixture of the cells, medium, and plasma was added.
The mixture was incubated for 72 h and then pulsed with
2 tiCi/well of [3H]thymidine. After a further 5-6 h of in-
cubation, the cells were harvested and counted in a liquid
scintillation counter. With tetanus stimulations, assays hav-
ing <100 unstimulated (background) cpm were discarded,
and with PHA stimulations, assays having <5,000 cpm were
discarded. In either case, if the coefficient of variation of
replicate counts was >30%, a replicate that was an obvious
outlier (>2 SD from the mean) was discarded. Onily 3% of
the data were discarded by these criteria. All of the cultures
were done in duplicate in autologous plasma and in AB
plasma in order to look for potential immunosuppressive
factors in the autologous plasma. The positive controls were
the PHA-stimulated cultures (1:5 and 1:10 dilutions of PHA),
and the negative controls were unstimulated cells. Three
different amounts of TT (0.5, 1.0, 2.9 units) were used to
stimulate the cultures in each of the two types of plasma.
TT-induced lymphocyte reactivity was scored as stimu-
lated or unstimulated by a modification of the method of
Harina et al. (19); the quantitative level of stimulation was
not useful because of the intrinsic variability of the method
(19). Briefly, a square-root transformation was performed on
all control and stimulated counts. The difference da between
the means of the stimulated and control counts was calcu-
lated, and the standard error of da, Var,(dj), was calculated
dures performed on the mothers and on the babies are indicated on the appropriate time axis.
The TT was given to the mothers after the bleedings at 0 and 3 mo, and the first DPT im-
munization was given to the babies after the bleeding at 2 mo.
The experimental design of the maternal immunization study. The various proce-
Gill et al.
from the pooled variances of control and stimulated counts
and the estimated covariances of control and stimulated
counts. The variances were pooled separately for each group
of subjects and for each bleeding. An individual group of
replicates was scored as stimulated
and n - 1 degrees of freedom, and n is the number of rep-
licates pooled in a group. There were no significant differ-
ences in the responses elicited by the three dilutions of TT
or by the two dilutions of PHA, so the responses were treated
Statistical treatment of data. The C-statistic (likelihood
ratio) was used in tests of independence. The McNemar test
of change was used in comparisons among the lymphocyte
transformation reactions when two tests in the same indi-
vidual were compared (20).
Three types of analyses were done to evaluate the data
before using them to answer the experimental questions.
First, the effect of the antibody status of the mothers before
immunization, i.e., whether they had detectable IgG or IgM
antitetanus antibody, was examined to determine its effect
on the antibody and lymphocyte transformation responses
of their offspring. Second, lymphocyte stimulations were
compared in autologous plasma and in AB plasma in order
to test for the presence of any immunosuppressive factors
in the autologous plasma. Third, the effects of immunizing
with a standard or half-standard dose of TT on the antibody
and lymphocyte transformation responses of the mothers and
the babies were examined.
If none of the variables affected the results, the data were
pooled and used to answer two questions. First, are the babies
of immunized mothers sensitized to tetanus by transplacental
immunization? The criteria for sensitization were: the pres-
ence of IgM antitetanus antibody in the cord blood and in
the serum before the first DPT immunization; the level of
responsiveness to DPT immunization as measured by anti-
if da > t,,_
is the critical value of the t-statistic for P = 0.05
body and lymphocyte transformation assays, and the level
of lymphocyte responsiveness 1 yr after birth. Second, can
the pregnant female respond to immunization with TT as
measured by antibody and lymphocyte transformation re-
The demographic data for the mothers in the study
and for their offspring at birth are summarized in Ta-
ble I. There were no significant differences among the
three groups in the study. Seven women who were
tetanus-negative at the beginning of the study were
not immunized, and their antibody levels were fol-
lowed. Six of them subsequently developed measure-
able amounts of antitetanus antibody, so they had been
sensitized to tetanus but their antibody levels at the
beginning of the study were undetectable. Similar ev-
idence for tetanus sensitization in women who were
ostensibly tetanus-negative when the study began was
obtained from lymphocyte transformation studies in
autologous plasma and in AB plasma, which showed
no differences in the responses to stimulation by TT
between mothers who were tetanus negative or tetanus
positive when entering the study (Table II).
To test whether the presence of autologous plasma
or of AB plasma influenced the response of lympho-
cytes to stimulation by TT, assays were performed in
parallel in both plasmas and compared by the Mc-
Nemar test of change: 252 assays were performed with
Demographic Data on the Mothers and Babies'
Number of women with
IgM and/or IgG
Birth weight of
Age of females, gestational age, and birth weight differences were assessed by the F-ratio. All other
variables were assessed by the C-statistic with 0.1 added to each cell to compensate for any values of 0.
No significant differences in sex or feeding pattern (breast or bottle) among offspring in the different
classes (P > 0.2). No significant differences in gravidity, parity, or race (black orwhite) amongthe mothers
in the three groups (P > 0.1).
I +, present; -, absent.
§ No significant differences among groups (P > 0.6).
Transplacental Immunization of the Human Fetus to Tetanus
Effect of the Initial Tetanus Status of the Mothers on the Stimulation of Their Lymphocytes
in AB Plasma and in Autologous Plasnm
Time of bleeding
G = 2.81
P > 0.09
G = 1.93
P > 0.11
G = 0.06
P > 0.80
G = 0.01
P > 0.93
G = 0.003
G = 0.64
G = 0.32
The G-statistic was used for the comparisons between the number of mothers whose lymphocytes were stimulated and those whose
lymphocytes were not stimulated. The mothers were further categorized as being either tetatnus negative or tetanus positive at the
beginning of the study. The counts per minute are for stimulation with 0.5 units of TT. The levels of incorporation with the other two
concentration of TT used (1.0 and 2.0 units) were the same.
t One value only.
lymphocytes from control and immunized mothers;
112 assays, from nonpregnant women, and 212 assays,
from babies born to control and immunized mothers.
None showed any differences in lymphocyte stimula-
tion in the two plasmas; therefore, the data were
pooled and used as replicate assays. There were no
differences in the lymphocyte transformation respon-
ses to TT between women immunized with a standard
or half-standard dose of TT, using the G-statistic for
the comparisons, in 18/19 cases. There were also no
differences in the responses of the babies born to moth-
ers immunized with a standard or half-standard dose
of TT (Fig. 2). Finally, there was no significant effect
of the dose of TT used for stimulation on the lym-
phocyte responses of the mothers or of their babies.
The babies of mothers immunized with TT had IgM
antitetanus antibodies in their cord blood, whereas the
babies of control mothers did not, and the prevalence
and the amount of the antibodies were higher in the
babies of mothers who received a standard dose of TT
(Table III, Fig. 2). The tetanus-induced lymphocyte
stimulation studies also supported the finding of trans-
placental immunization of the offspring. The major
piece of evidence comes from a comparison of the
number of babies from control and immunized moth-
ers whose lymphocytes were stimulated or not stim-
ulated by TT at various times after birth (Table IV).
The babies of immunized mothers responded earlier
(by 7 mo of age) to DPT immunization than did the
babies of control mothers. More of the babies from
immunized mothers had lymphocytes sensitized to TT
at 13 mo of age than had sensitized lymphocytes at
7 mo of age (P < 0.01). By contrast, there was no
significant difference in the number of babies with sen-
sitized lymphocytes at 7 and 13 mo among the off-
spring of control mothers. The level of lymphocyte
stimulation, or lack thereof, as measured by thymidine
incorporation, was the same in the lymphocytes of the
babies from control or immunized mothers (Table V).
A comparison of the percentage of babies with stim-
ulated lymphocytes also shows that more of the babies
of immunized mothers had sensitized lymphocytes at
7 and 13 mo than did the babies of control mothers
(Table V). There was no significant difference in the
Gill et al.
Babies of Immunized Mothers
Months of Age
Months of Age
FIGURE 2 The presence of antitetanus antibodies in the babies of control (unimmunized) and
immunized mothers and the babies' responses to immunization with DPT. Each point represents
data from 12 to 23 babies, and the shaded area delineates the sensitivity of the assay method.
Babies of immunized mothers had IgM in their cord blood and in their blood before the first
immunization with DPT, whereas babies of control mothers did not. In addition, the level of
IgM was higher in the cord blood of babies whose mothers received the standard dose of TT.
The asterisks indicate a significant difference (P < 0.05) between the babies of control mothers
and those of immunized mothers, and the daggers indicate a significant difference (P < 0.05)
between the babies whose mothers received the standard dose of TT and those whose mothers
received the half-standard dose of TT. The solid line is the response of babies whose mothers
received a standard dose of TT, and the broken line is the response of babies whose mothers
received a half-standard dose of TT. There was no difference between the IgG antitetanus
antibody levels in the babies of control and immunized mothers or between babies of mothers
receiving a standard or a half-standard dose of TT. The significance of the differences was
assessed by the G-statistic.
initial levels of IgG antitetanus antibody in the babies
of the control and immunized mothers, as would be
expected because of the transplacental passage of IgG
antibodies from the mothers, or in the IgG response
to DPT immunization (Fig. 2).
The immunized mothers responded quite well to
immunization with TT (Fig. 3). The increase in IgG
antitetanus antibody production was significant both
in the group receiving the standard dose of TT (P
< 0.05) and in the group receiving the half-standard
dose (P < 0.005), and it exceeded the level of IgG in
the control mothers (P < 0.05). The difference in IgM
production between the immunized and control groups
was not statistically significant, although IgM levels
were consistently higher in the immunized mothers.
No untoward effects of immunization with TT were
observed in the mothers or their offspring.
Three lines of evidence show that transplacental im-
munization of the human fetus occurs following im-
Transplacental Immunization of the Human Fetus to Tetanus
Babies of Control Mothers
Prevalence of IgM Antitetanus Antibody in the Offspring of Control and Immunized Mothers
Before Their First DPT Immunization
Offspring with IgM from mothers with different vaccination status
Presence of antibody
in the mother before
Control mothersHalf-standard dose
munization of mothers during the fifth and eighth
months of pregnancy. First, there was IgM antitetanus
antibody in the babies' blood before the first DPT im-
munization, whereas it was not present in the blood
of babies from control (unimmunized) mothers (Table
IV, Fig. 3). Second, there was a higher lymphocyte
transformation response (P < 0.01) to DPT immuni-
zation in the babies of immunized mothers (Table V).
Third, the lymphocytes from babies of the immunized
mothers were still highly sensitized to TT 13 mo after
birth, whereas those from babies of the control (un-
immunized) mothers were not (P < 0.01) (Table V).
These studies in humans reproduce the original ex-
perimental observations in rats upon which the pro-
tocol was based (1-5). They show that active immu-
nization of the pregnant female can sensitize her fetus
and that the difference in placental structure in the
two species does not affect the transplacental passage
of antigen. Studies on pregnant women infected with
influenza (21), leprosy (22, 23), rubella (24, 25), hep-
atitis (26, 27), mumps (28), Escherichia coli (29) or
Salmonella typhosa (30) showed that their offspring
were sensitized to the microbial antigens, but the pos-
sibility of direct infection of the fetus or of placental
damage leading to the sensitization cannot be elimi-
nated in this setting.
It is highly unlikely that the observations reported
here could be due to the transplacental passage of an-
tibodies and sensitized cells from the mother. First,
the concentration of IgM antibody is approximately
the same in the immunized mothers and in their babies
(Figs. 2 and 3). In order for this to occur by transpla-
Comparison of the Number of Babies from Control and Immunized Mothers
Whose Lymphocytes Are Stimulated or Not Stimulated by TT
at Different Times After Birth
Comparison of babies responses at different timest
X2 = 3.81
x2 = 4.39
P < 0.01
P < 0.01
P < 10-4
McNemar test of change was used for the comparisons. The (+) indicates stimulation,
and the (-), lack of stimulation.
t 0 mo is the cord blood, and 7 mo is 1 mo after the last DPT immunization.
Gill et al.
Levels of Thymidine Incorporation into the Lymphocytes of Babies from Control and Immunized Mothers.
Thymidine incorporation by babies' lymphocytes at different ages
O mo (cord blood)
Babies' lymphocyte response
The data for lymphocytes that were either stimulated or not stimulated by TT are given.
cental transport from the mother, there would have
to be free diffusion of IgM across the placenta or se-
lective transport of IgM antitetanus antibodies; there
is substantial evidence that neither occurs (31). Even
if the rate of transport of IgM across the placenta were
proportional to the inverse square root of its molecular
weight, as occurs with smaller proteins (31), the change
in the fetal/maternal plasma concentration ratio of
IgM would be of the order of 10-3/d. This low ratio
and the relatively short half-life of IgM (5 d) would
allow only a few nanograms at most of maternal IgM
antibody to be present in the fetus. Experimental sup-
port for this conclusion comes from the observation
that only the babies of immunized mothers had IgM
antitetanus antibodies in their sera at birth, although
both the control and immunized mothers had com-
parable concentrations of IgM antibodies in their sera
at the time of delivery (Fig. 3). Second, there is no
clear evidence for the passage of maternal lympho-
cytes into the normal fetus during pregnancy, although
it has been reported that passage at delivery occurs in
0-30% of cases (reviewed in references 16 and 33).
Even if it did occur, colonization of the fetus by tet-
anus-sensitized lymphocytes from the mothers could
not explain the findings in the babies. The same per-
centage of babies from control and immunized moth-
ers had sensitized lymphocytes at birth, but the num-
ber of babies from immunized mothers who developed
sensitized lymphocytes after birth increased rapidly,
whereas the number of babies from control mothers
with sensitized lymphocytes decreased after birth
(Table V). Such a change would not occur if the lym-
phocytes in both groups of babies have originated in
the mothers. Evidence from demonstrated maternal
against maternal colonization of the babies in this
in other circumstances also militates
study. In patients with severe combined immunode-
ficiency disease, where there should be relatively little
resistance to maternal lymphocytic colonization, only
4/16 patients showed engraftment (32), and the en-
grafted lymphocytes did not respond to stimulation
with mitogens, antigens, or allogeneic cells (32, 33).
Following intrauterine transfusion of male infants with
maternal lymphocytes, only 5/46 infants had maternal
lymphocytes present at birth, and they persisted to 1
yr of age (34). Following postnatal exchange trans-
fusion, 34/82 babies had detectable donor lympho-
cytes at birth, but only 1/82 had donor lymphocytes
detectable at 4 mo of age (34). Thus, the persistance
of maternal lymphocytes in the babies could not ex-
plain the presence of tetanus-sensitized cells in 88%
of the offspring of immunized mothers at 13 mo of age
(Table V). From studies in animals in which transpla-
cental passage of rnaternal lymphocytes occurred, one
would expect to see a graft-vs.-host reaction (35) or
immunosuppression (36) in the offspring, and, indeed,
at least several such cases have been reported in hu-
mans (32, 37-39). Neither phenomenon was observed
in any of the babies in our study. Finally, stimulation
of the lymphocytes cannot be due to a mitogenic effect
of TT, at least to any significant degree. If TT were
acting as a mitogen, the percentage of babies from
control mothers whose lymphocytes were stimulated
would not decrease with the age of the babies nor
would there be the marked differences between the
percentages of babies from control and immunized
mothers whose lymphocytes were stimulated by TT
The genetic control of the responsiveness to TT (40,
41) could not be examined in this study because the
mother and father would have to be either homozygous
responders or homozygous nonresponders in order to
Transplacental Immunization of the Human Fetus to Tetanus
Months after first immunization
FIGURE 3 The production of IgG and IgM antitetanus antibodies in control (unimmunized)
and immunized mothers. Each point represents data from 12 to 24 mothers, and the shaded
area delineates the sensitivity of the assay method. The mothers receiving TT responded to
immunization (P < 0.05-< 0.005), and there was no significant difference between the responses
of those receiving a standard (5 Lf) and a half-standard (2.5 Lf) dose of TT. The asterisks
indicate a significant difference (P < 0.05) between the control and immunized mothers in IgG
antitetanus antibody production. Although there was no statistically significant difference in
IgM antibody production between the control and immunized mothers, the level of IgM an-
tibody in the immunized mothers remained higher than in the control mothers. The significance
of the differences was assessed by the G-statistic.
detect a genetic influence on the immune response of
the offspring: a heterozygous offspring would have an
intermediate response that would be difficult to clas-
sify. It is fortunate that matings between homozygous
responders are probably uncommon in human popu-
lations, because the probability of maternal immuni-
zation's causing decreased responsiveness to tetanus in
the offspring due to the induction of partial tolerance
(4, 5) is remote.
Two observations indicate that there is no functional
evidence for an immunosuppressive effect during
pregnancy. First, the pregnant females responded well
to immunization with TT (Fig. 3); a similar finding
was noted following immunization with influenza vac-
cine (42, 43). Second, the lymphocyte responses were
not different in autologous plasma and in AB plasma.
Thus, there do not appear to be any physiologically
active, immunosuppressive plasma factors in the preg-
nant female, at least during the fifth and eighth months
of gestation and at delivery. This observation contrib-
utes to the body of evidence supporting the hypothesis
that the acceptance of the fetal homograft is not due
to immunosuppression in the mother, although argu-
ments can still be made for local (uterine) effects of
immunosuppressive substances that may not be re-
The technique of transplacental immunization may
provide a unique and safe approach to immunization
Gill et al.
in humans, and it may be especially useful in those
populations where neonatal care is not readily avail-
able. It has substantial potential for clinical use to pro-
tect the offspring during the neonatal period and to
enhance its response to subsequent immunization or
to exogenous infection. It also circumvents the neces-
sity for immunization in the early postnatal period,
when the levels of maternal IgG antibody in the new-
born are still high and could interfere with the efficacy
of the immunization procedures. The enhanced im-
munity due to transplacental immunization, at least
as judged by the persistence of sensitized lymphocytes
(Tables IV and V), lasts longer than 1 yr, but the total
duration of its protective effect can only be judged by
long-term population studies. Transplacental immu-
nization may also be useful with other clinically im-
portant vaccines, such as those against the Strepto-
coccus and the Meningococcus, since they are inert
polysaccharides which can pass through the placenta
(44). This approach might even be useful with vaccines
against diseases that occur in later life, such as gono-
coccal infection, if the transplacentally induced im-
munity lasts long enough and if effective vaccines are
We thank Mr. Leo Levine of the Biological Laboratories,
Massachusetts Department of Health, for providing the tet-
anus toxoid; Dr. Gurmukh Singh, Dr. Jerome Sachs, and Dr.
Paul M. Taylor for helpful discussions; and Ms. Katherine
Rumin, Ms. Mary Ann Kofke, Mr. Bruce Hyde, Ms. Dorothy
Crowell, and Ms. Megan B. Taylor for technical assistance.
This study was supported by National Institutes of Health
grant HD 09880.
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