Increased Poliovirus-Specific Intestinal Antibody
Response Coincides with Promotion of
Bifidobacterium longum-infantis and
Bifidobacterium breve in Infants: A Randomized,
Double-Blind, Placebo-Controlled Trial
CATHERINE MULLIÉ, ASMAE YAZOURH, HÉLÈNE THIBAULT, MARIE-FRANÇOISE ODOU,
ELISABETH SINGER, NICOLAS KALACH, ODILE KREMP, AND MARIE-BÉNÉDICTE ROMOND
Unité d’étude de la translocation bactérienne [C.M.], Faculté de Pharmacie d’Amiens, Université de
Picardie, 80037 Amiens Cedex 1, France; Laboratoire de Bactériologie-Virologie [A.Y., M.-F.O., E.S.,
M.-B.R.], Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2, 59006 Lille Cedex,
France; Conservatoire National des Arts et Métiers [H.T.], 75015 Paris, France; and Hôpital Pédiatrique
St Antoine [O.K.], Université Catholique de Lille, 59000 Lille, France
To determine whether the size of the intestinal bifidobacterial
population can influence the immune response to poliovirus
vaccination in infants, we set up a randomized, placebo-
controlled trial. From birth to 4 mo, infants were given a fer-
mented infant formula (FIF) or a standard formula (placebo).
Bifidobacteria were quantified monthly in infant stools. Antipo-
liovirus IgA response to Pentacoq? was assessed before and 1
mo after the second vaccine injection. Thirty infants were ran-
domized, and 20 completed the study (nine in the placebo group
and 11 in the FIF group). Fecal bifidobacterial level was signif-
icantly higher with the FIF group at 4 mo of age (p ? 0.0498).
Furthermore, B. longum/B. infantis carriage was higher at 4 mo
in the FIF group (p ? 0.0399). Antipoliovirus IgA titers in-
creased after Pentacoq? challenge (p ? 0.001), and the rise was
significantly higher in the FIF group (p ? 0.02). Antibody titers
correlated with bifidobacteria, especially with B. longum/B. in-
fantis and B. breve levels (p ? 0.002). Infants who harbored B.
longum/B. infantis also exhibited higher levels of antipoliovirus
IgAs (p ? 0.002). In conclusion, the present results indicate that
antipoliovirus response can be triggered with a fermented for-
mula that is able to favor intestinal bifidobacteria. Whether this
effect on the immune system is achieved through the bifidogenic
effect of the formula (mainly through B. longum/B. infantis and
B. breve stimulation) or directly linked to compounds (i.e. pep-
tides) produced by milk fermentation remains to be investigated.
(Pediatr Res 56: 791–795, 2004)
FIF, fermented infant formula
IPV, inactivated poliovirus vaccine
Breast milk is known to protect newborns from infection. As
secretory IgA is the predominant immunoglobulin in breast
milk (1), it supposedly acts locally in the infant gut as a first
line of defense against foreign antigens. Secretory IgA is well
adapted to persist in the gastrointestinal tract because it is
resistant to digestive enzymes (1) as shown by its detection in
feces (2). It thus can bind to gastrointestinal pathogens and
interfere with their attachment to mucosal cells (2–4).
Paradoxically, breast-fed infants have been found to produce
their own intestinal secretory IgA sooner than formula-fed
infants (4). This stimulation of the immune system might be
related to bacteria that highly colonize the intestinal tract of
breast-fed infants, such as bifidobacteria (5–7). Indeed, exper-
imental gut colonization of germ-free mice with human bi-
fidobacteria have already shown an enhanced immune response
to rotavirus by increasing anti-rotavirus IgA production (8).
Therefore, bifidobacteria are possibly involved in the priming
of the infant immune system.
To establish whether high colonization with bifidobacteria
can trigger intestinal immune response, we attempted to en-
hance the bifidobacterial flora of healthy bottle-fed newborns.
To this purpose, we used an infant formula that contains new
bifidogenic factors generated through a fermentation process
Received July 16, 2003; accepted May 7, 2004.
Correspondence: Marie-Bénédicte Romond, Ph.D., Laboratoire de Bactériologie-
Virologie, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2,
Rue du Pr Laguesse 59000 Lille, France; e-mail: email@example.com
Financial support was provided by Blédina SA.
Copyright © 2004 International Pediatric Research Foundation, Inc.
Vol. 56, No. 5, 2004
Printed in U.S.A.
implying Bifidobacterium breve strain C50 and Streptococcus
thermophilus. The fermented formula did not contain viable
bacteria but bifidogenic factors previously shown to promote
intestinal bifidobacteria in human flora–associated mice as well
as in adults (9,10). In this clinical trial, the possible immuno-
modulative properties of intestinal bifidobacteria were investi-
gated by quantifying fecal bifidobacterial levels and fecal IgA
titers (as markers of mucosal immune stimulation) before and
after vaccination with the inactivated poliovirus vaccine (IPV).
IPV is known to protect people from illness by inducing
circulating neutralizing antibodies, but it elicits poor mucosal
IgA response in the intestine (11). An increase in antipoliovirus
mucosal IgA would then indicate specific stimulation of the
intestinal immune system.
Case definition. Inclusion criteria were 1) vaginal delivery,
2) gestational age between 38 and 42 wk, 3) birth weight
?2500 g, 4) bottle feeding previously decided by parents, 5)
follow-up by one of the study pediatricians, and 6) written
informed consent of the two parents or the legal guardian.
Exclusion criteria were 1) caesarean delivery, 2) twins or
multiple births, 3) breast-feeding started before inclusion, 4)
associated disease requiring antibiotic administration or likely
to interfere with the course of the study, and 5) prescription of
a specific diet.
Data set. Infants (n ? 34) who were born between August
1999 and January 2000 at the maternité Pavillon de la Sainte
Famille (Clinique du Bois, Lille, France) were assessed for
enrollment within the first days after birth. Of them, 30 (seven
boys and 23 girls) met inclusion criteria and entered the study
Study design. This study was a randomized (block random-
ization), double-blind, placebo-controlled trial. The study pro-
tocol and consent procedures were approved by the local ethics
committee (Comité Consultatif des Personnes se prêtant à la
Recherche Biomédicale de Lille). The infant formulas were
supplied as powder in numbered containers (Blédina SA,
Steenvoorde, France). They had the same basal nutrient com-
position (1.45 g of protein, 8.3 g of carbohydrates, and 3.5 g of
fat per 100 mL). Newborns received the placebo or the fer-
mented infant formula (FIF) from inclusion until 4 mo of age.
Respecting the French vaccination program, they received an
injection of Pentacoq? (vaccine against diphtheria and tetanus
toxoids, poliomyelitis virus, Haemophilus influenzae, and Bor-
detella pertussis; Pasteur Mérieux Serums and Vaccines, Lyon,
France) at 2, 3, and 4 mo. Infants were followed up to the age
of 5 mo. Experienced pediatricians carefully collected the
history of any gastrointestinal and respiratory infections during
monthly visits, as well as filled in a form with children’s
clinical history, anthropometric data, tolerance, acceptability,
and volumes of milk taken at each monthly visit. The pedia-
tricians who monitored tolerance during the study and the
people who handled the samples were not aware of which milk
the infants were receiving.
Fecal IgA titer determination. Stools were collected for IgA
quantification at 3 (before the second Pentacoq? vaccine in-
jection), 3.5, and 4 mo (after the second Pentacoq? vaccine
injection). They were immediately frozen until further analysis.
Dry stool weight was determined after freeze-drying, and
protein content was quantified using the Lowry method (12).
Total IgA and anti–poliomyelitis-specific IgA titers were mea-
sured by ELISA. Briefly, dry stools were suspended (wt/10
vol) in 0.1 M of PBS buffer (pH 7.4) with protease inhibitors
(Sigma Chemical Co., Saint Quentino-Fallavier, France) pep-
statin and leupeptin (1 mg/mL), 4-(2-aminoethyl) benzenesul-
fonyl fluoride (50 ?g/mL), and dry milk powder (0.05 g/mL).
For the total fecal IgA detection, microplates were coated with
goat anti-human secretory component (IgA) antibody (Sigma
Chemical Co.) 1:100 (vol/vol) diluted in coating buffer [20 mM
NaHCO3(pH 9.5)]. For antipoliovirus antibody detection,
microplates were coated with 1:100 (vol/vol) diluted Sabin
vaccine (Copper, Lille, France). After incubation overnight at
4°C, the wells were washed three times. They were then
saturated with 0.1 M of PBS buffer (pH 7.4) that contained 1%
(wt/vol) BSA and 0.025% (vol/vol) Tween-20. After three
washings, the samples were added to the wells and incubation
(1 h, 37°C) was carried out in duplicate for each sample. On
each microplate, a negative control [0.1 M of PBS buffer (pH
7.4)] was included as well as a positive control (IgA from
human colostrum). Detection of total or antipoliovirus fecal
Figure 1. Trial profile.
MULLIÉ ET AL.
IgA was carried out using horseradish peroxidase–labeled
sheep anti-human IgA (?-chain; ICN, Coger, France). The
reading was taken at a wavelength of 492 nm.
Rectal flora analysis. Fecal samples to enumerate cultivable
bifidobacteria and total cultivable fecal flora were collected at
1, 2, 3, and 4 mo, on swabs that allow for the survival of
anaerobic bacteria. Appropriate dilutions of the samples were
plated onto 1) horse blood agar (Columbia agar base; Oxoid,
Dardilly, France) supplemented with glucose (0.5%) and cys-
teine · HCl (0.03%) to enumerate eubacteria, cocci, and clos-
tridia; 2) Beerens and MRS agar for bifidobacteria and lacto-
bacilli; and 3) EMB for enterobacteria. Each type of colony
was subcultured on Rosenow broth, Gram-stained, and tested
for aerobic susceptibility and catalase production. The sum of
the various bacteria recovered gave the total cultivable flora
expressed as colony forming units (CFU)/mL. The counts in
cultivable bifidobacteria were expressed as the percentage of
the total cultivable flora. Bacteria are considered to belong to
the dominant flora when their proportion is ?1% of the total
cultivable flora (13). The detection limit of the method was
0.01%. Bifidobacteria were identified at the species level by a
multiplex PCR technique using species-specific primers previ-
ously described (14).
Statistical analysis. IgA titers and total cultivable bifidobac-
terial proportions were analyzed by nonparametric ANOVA
for repeated measures (Conover’s method). Fisher exact test
was used to evaluate the difference in colonization percentages
by the various bifidobacterial species between the feeding
groups. Mann-Whitney test was used to compare antipoliovirus
IgA titers between infants who harbored B. longum-infantis at
4 mo and those who did not. Spearman rank correlation
coefficient was used to correlate fecal bacterial counts with IgA
concentration. Bacterial proportions are reported as mean ?
SD, and IgA titers are expressed as the median.
Infants. Twenty of 30 infants completed the study (Fig. 1).
Causes of premature ending were similar in the two groups:
infants lost to follow-up (two placebos and one FIF) did not
complete the study protocol (the 4-mo visit was usually
missed). Regurgitations, diarrhea, and colics were alleviated by
a change in the infant formula administered (two placebos and
three FIF). Two placebo infants experienced rhinopharyngitis
followed by bronchitis. Their medical treatment included an-
tibiotic administration (amoxicillin/clavulanic acid association
for one of them and josamycin for the other), leading to their
exclusion from the study. No link between the formula admin-
istered and the occurrence of health problems could be estab-
lished. All of the infants recovered without further troubles.
The two final groups (nine placebos and 11 FIF) were compa-
rable for sex ratio, weight, length, head circumference at birth,
age at each monthly visit, clinical tolerance, formula intake,
Fecal IgA titers. Total IgA titers were similar in both groups
and did not increase after vaccination (data not shown). Anti-
poliovirus IgA titers were similar at 3 and 3.5 mo (median: 160
and 200 U/g of dry stools and 80 and 160 U/g of dry stools in
the placebo and the FIF groups, respectively; Fig. 2). At 4 mo,
antipoliovirus IgA titers were significantly increased in both
groups after vaccination (median: 1280 U/g of dry stools and
507 U/g of dry stools for the FIF and placebo groups, respec-
tively; p ? 0.001, nonparametric ANOVA for repeated mea-
sures). Moreover, the increase in antipoliovirus IgA titers was
greater in the FIF group (p ? 0.02, nonparametric ANOVA for
repeated measures; Fig. 2).
Intestinal colonization with bifidobacteria. Bifidobacteria
were detected in all infants. Infants who received the FIF had
a higher mean proportion of cultivable bifidobacteria (p ?
0.0498, nonparametric ANOVA for repeated measures; Fig. 3).
Species identification was carried out successfully for all but
one strain, subsequently referred to as Bifidobacterium sp.
(Table 1). Whatever the feeding, the most frequently isolated
species were B. bifidum, B. breve, and B. longum-infantis.
Carriage of B. longum-infantis was shown to be susceptible to
the type of feeding. In the placebo group, it decreased, whereas
it rose over time in the FIF group. In addition, a higher number
Figure 2. Mucosal antipoliovirus IgA response to vaccination in placebo (n
? 9) and FIF (n ? 11) infants. The solid black bar represents the median value
in each group. *Significant rise in antipoliovirus IgA at 4 mo in placebo and
FIF infants (p ? 0.001, nonparametric ANOVA for repeated measures).
Figure 3. Proportion of cultivable bifidobacteria within the total cultivable
flora. Results are expressed as mean with SD. □, placebo (n ? 9); ?, FIF (n
? 11). *Percentage of bifidobacteria significantly higher in FIF infants (p ?
0.0498, nonparametric ANOVA for repeated measures).
BIFIDOBACTERIA AND ANTI-POLIOVIRUS IgA
of FIF-fed infants were colonized with B. infantis-longum at 4
mo of age (p ? 0.0399, Fisher exact test; Table 1). Also at 4
mo, FIF infants harbored significantly fewer bifidobacteria that
belong to a group of species that are more frequently found in
the adult intestinal flora: B. angulatum, B. adolescentis, B.
catenulatum, B. dentium, B. pseudocatenulatum, and Bi-
fidobacterium sp. (p ? 0.038, Fisher exact test).
A positive correlation between total bifidobacteria and anti-
poliovirus IgA titers was observed on the whole population (r
? 0.46, p ? 0.05, Spearman test; Fig. 4A). The B. breve/B.
longum-infantis subgroup was the sole subgroup within the
bifidobacterial species that correlated with antipoliovirus IgA
titers (r ? 0.73, p ? 0.002, Spearman test; Fig. 4B). In any
case, whichever group to which they belonged, infants who
harbored detectable levels of B. longum-infantis showed higher
antipoliovirus IgA titers at 4 mo than those without (p ? 0.002,
Breast-feeding was previously shown to stimulate response
to vaccination. Pickering et al. (15) observed that 2 mo of
breast-feeding specifically enhanced antibody responses to oral
poliovirus immunization compared with infant formulas. Dif-
ferent mechanisms have been suggested to explain this adju-
vant effect (16). One of them might involve the gastrointestinal
flora, as breast-feeding predominantly stimulates the growth of
B. breve and B. longum-infantis (5–7), and as gastrointestinal
flora is described as a major stimulator of the gut associated
lymphoid system (17–21).
In the present study, FIF induced a rise in the proportion of
cultivable intestinal bifidobacteria and specifically favored the
carriage of B. longum-infantis. At the same time, a greater rise
in IgAs was observed in the FIF group, and the response to
poliovirus vaccination was related to the bifidobacterial pro-
portion in the total flora. The species B. longum-infantis and B.
breve were strongly suspected of supporting the priming of the
antipoliovirus response as their proportion in the flora corre-
lated with antibody titers. More specific, B. longum-infantis
carriage was linked with higher IgA titers in the infant stools,
whatever the feeding group. Contrasting, the most common
bifidobacterial species found in infants, B. bifidum, was not
associated with higher IgA titers. Thus, only a subgroup of the
bifidobacterial genus that colonized the infant gut correlated
with antipoliovirus IgA response. These results suggest that the
immune effect is linked to a specific bifidobacterial population.
However, it is also conceivable that some FIF compounds
might directly participate in the elicitation of the immune
response. Indeed, the oral feeding of peptides derived from
milk fermentation with Lactobacillus helveticus has been re-
ported to increase the number of IgA-producing cells in the
mouse small intestine (22). Hence, Bifidobacterium breve C50
might also produce peptides such as these immunomodulative
ones during the milk fermentation process.
The analysis of IgA synthesis after vaccination could pro-
vide us with some clues as to the mechanism(s) involved in the
antipoliovirus antibody elicitation observed in the present sur-
vey. Humans and monkeys are the only natural hosts for
poliovirus. It is commonly accepted that recognition of CD155
(poliovirus receptor) by poliovirus is the first event in the
triggering of specific antipoliovirus IgA production. Indeed,
transgenic mice that bear the human receptor for poliovirus
showed that the expression of CD155 was necessary for a
virus-specific mucosal IgA response (23). In fact, some degree
of mucosal immunity can be measured in IPV vaccinees (24),
indicating that the first steps of mucosal responses are primed
by the inactivated poliovirus vaccine, although the intramus-
cular administration route avoids close contact with the recep-
tors exhibited on the intestinal cell surfaces. Buisman et al.
(25) showed that poliovirus administered to transgenic mice by
the peritoneal route was transported to the gut lumen by
macrophages, hence inducing local IgA production. A similar
transport of vaccinal poliovirus strains is likely to occur in
infants after Pentacoq? vaccination. In the present study, spe-
cific IgA production cannot be related to recognition between
CD155 and either bifidobacteria or compounds of FIF. Other-
wise, the increase in fecal antipoliovirus IgA titers would occur
independent of vaccination. Consequently, the increased anti-
poliovirus response observed in the FIF group is possibly the
result of an adjuvant effect mediated either through compounds
contained in FIF or through intestinal B. longum/B. infantis.
To support this claim, reports of an adjuvant effect on Peyer’s
patches have already been published for bifidobacteria (26,27),
and uptake of bifidobacteria by the digestive tract has previously
been shown in infants (28). Bifidobacteria could subsequently be
processed and presented to lymphocytes in Peyer’s patches (29),
result in higher antipoliovirus IgA titers (30).
In conclusion, the feeding of infants with FIF gave promising
results in eliciting intestinal immunity. Moreover, the present
study supports the view that increased poliovirus-specific intesti-
Table 1. Carriage of Bifidobacterium species throughout the study (placebo, n ? 9; FIF, n ? 11)
Month 1Month 2Month 3 Month 4
PlaceboFIFPlaceboFIF PlaceboFIF PlaceboFIF
* Number of infants carrying the mentioned species (%).
† Others include strains belonging to B. angulatum, B. adolescentis, B. catenulatum, B. dentium, B. pseudocatenulatum, and Bifidobacterium sp.
‡ Significantly different from the placebo group (p ? 0.0399, Fisher exact test).
§ Significantly different from the placebo group (p ? 0.038, Fisher exact test).
MULLIÉ ET AL.
nal antibody response coincides in infants with the promotion of
B. longum-infantis and B. breve but not with B. bifidum. These
findings should encourage the performing of a complete analysis
of intestinal bifidobacteria at the species level when manipulating
immune system activation can be drawn remains to be elucidated.
On the one hand, a positive correlation is clearly observed be-
tween antipoliovirus IgA titers and B. longum/B. infantis species
a possible mechanism involving FIF compounds (i.e. peptides)
be excluded from immune system activation. Indeed, promotion
of some bifidobacterial species might only be a “side effect” of
FIF compound activity. Further studies thus are needed to deter-
mine the extent of each alternative contribution to specific IgA
at the Maternité de la Sainte Famille for contribution to newborn
inclusions and monthly consultations. We also thank Patrick
Devos for providing statistical advice and carrying out part of the
statistical analysis, Nathalie Derensy and Fatiha N’Zerwalt for
skillful technical assistance, and Cécile Aubert-Jacquin for her
help in preparing the manuscript.
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Figure 4. (A) Correlation between the percentage of cultivable bifidobacteria
within the total cultivable flora and antipoliovirus IgA titers. E, infant from the
placebo group; F, infant from the FIF group. r ? 0.46; p ? 0.05, Spearman test.
(B) Correlation between the percentage of cultivable B. longum-infantis and B.
breve within the total cultivable flora and antipoliovirus IgA titers. E, infant from the
placebo group; F, infant from the FIF group. r ? 0.73 ; p ? 0.002, Spearman test.
BIFIDOBACTERIA AND ANTI-POLIOVIRUS IgA