REVIEW

Human Vaccines & Immunotherapeutics 11:11, 2556--2563; November 2015; 2015 Taylor and Francis Group, LLC

Immunization of preterm infants

Arnaud Gagneur1,*, Didier Pinquier2, and Caroline Quach3
1
Department of Pediatrics; Faculty of Medicine and Health Sciences; University of Sherbrooke; Sherbrooke, Qu
ebec, Canada; 2Rouen University Hospital; Neonatal Pediatric and
Intensive Care Department; IHU, EA4309, Charles Nicolle Hospital; Rouen, France; 3Departments of Pediatrics and Epidemiology; Biostatistics & Occupational Health, McGill Univer-
sity; Montreal, Quebec, Canada

Keywords: immunization, neonate, preterm, vaccines

Abbreviations: DTaP, diphtheria-tetanus-acellular pertussis vaccine; DTwP, diphteria-tetanus-whole cell pertussis vaccine; Hib,
Haemophilus influenzae type b; HBV, Hepatitis B; IPV, Inactivated polio vaccine; OPV, Oral polio vaccine; MenC, meningococcal
group C conjugate vaccine; PCV, pneumococcal conjugate vaccine; MMR, measles-mumps-rubella; GMC, geometric mean
concentration; GMT, geometric mean titer; GA, gestational age

Preterm infants are at increased risk of infections in general

Vaccinations of premature infants are often delayed
despite being at an increased risk of contracting vaccine
preventable diseases. This article reviews the current
knowledge on the immune response to widely used vaccines,
on the protection derived from routine immunization and on
vaccine safety and tolerability in a population of preterm
infants. Available data evaluating the immune response of
preterm infants support early immunization without
correction for gestational age. For a number of antigens, the
antibody response to initial doses of vaccines may be lower
than that of term infants, but protective concentrations are
often achieved and memory successfully induced. Vaccines
are immunogenic, safe and well tolerated in preterm infants.
Preterm infants should be vaccinated using the same
schedules as those usually recommended for full-term
infants, with the exception of the hepatitis B vaccine, where
additional doses should be administered in infants receiving
the rst dose during the rst days of life if they weighed less
than 2000 g because of a documented reduced immune
response.
and from vaccine preventable diseases in particular with increased
incidence and severity.4-6 Consequently, there is a need for timely
vaccination of preterm infants, using the same schedules as rec-
ommended for full-term infants, without correcting for prematu-
rity and regardless of birth weight.3,7,8
Vaccination is often delayed in preterm infants as demon-
strated in a recent Italian study.9 Lack of knowledge about safety
and effectiveness of vaccines in preterm infants among healthcare
workers and parents may explain this delay. Fear or adverse
events could also explain this delay, as an increase in cardiorespi-
ratory events following immunization in the very preterm was
reported.10-14 Accordingly, several recommendations were made
to closely observe hospitalized extremely-low-birth-weight infants
for significant adverse events for up to 72 hours.3,7,8,15 This
review focuses on the immunogenicity, safety and tolerability of
currently used vaccines and the evidence pertaining to their use
in preterm infants.

Premature Infants: Risk Factors for Vaccine

Preventable Diseases

Introduction Over 50% of reported cases of pertussis occur in infants. Low

More than 10% of infants are born prematurely and the rate
of preterm births is increasing steadily worldwide.1 Very preterm
infants (<33 weeks of gestational age) represent 20% of all pre-
mature infants.2 Immunocompetence in newborns depends on
prenatal maturation as each additional week of gestation sees an
increased response to antigens. Postnatal maturation, which
begins upon exposure to environmental antigens, occurs in pre-
term infants at a speed comparable to that of full-term infants.
Moreover, preterm infants have immunologic immaturities that
may impact vaccine response particularly in very premature
infants.3
*Correspondence to: Arnaud Gagneur; Email: arnaud.gagneur@USherbrooke.
ca
Submitted: 03/03/2015; Revised: 07/01/2015; Accepted: 07/14/2015
http://dx.doi.org/10.1080/21645515.2015.1074358
birth weight infants are particularly at risk (RR 1.86; 95% CI
1.33 to 2.38) when compared to normal birth weight infants.5 In
a recent Australian prospective study, a history of prematurity
(OR 5.00, CI 1.2719.71) was independently associated with
severe pertussis infections.6 Invasive pneumococcal diseases
account for up to 11% of neonatal sepsis. Preterm and low birth
weight infants are at increased risk of pneumococcal disease com-
pared to term infants. Comparing to normal birth weight and
term infants, Shinefield et al. reported a risk ratio of 2.6
(pD0.03) and 9.1 for invasive pneumococcal diseases for low
birth weight infants and preterm infants less than 32 weeks of
gestation, respectively.16 Preterm infants are also at higher risk
for complications and hospitalization following rotavirus infec-
tions, compared to infants born at term.17-19 Among children
born preterm, those with a low (<2500 g) or very low birth
weight (<1500 g) present the highest risk of rotavirus hospital-
izations (OR: 2.6, 95 % CI: 1.6 4.1 and OR: 1.6; 95 % CI 1.3

2556 Human Vaccines & Immunotherapeutics Volume 11 Issue 11

 2.1, respectively).17,18 Preterm infants are also at increased risk
of influenza virus infections and complications.20
Immunogenicity of Vaccines in Preterm Infants
Current evidence indicates that immune response in pre-
term infants is directly proportional to gestation age (GA) and
birth weight. Various factors can influence antibody produc-
tion, such as clinical conditions, prescribed therapies, vaccine
composition and vaccination schedules.7 However, regardless
of the variations induced by these factors, vaccines appear to
induce a protective immune response in preterm infants in the
majority of cases.
Tetanus
Tetanus toxoid is an adjuvanted vaccine that generates neu-
tralizing antibodies. Data suggest that individuals with anti-
body levels against tetanus between 0.01 and 0.1 IU/ml are
considered partially protected and that titres of 0.1IU/ml are
required for optimal protection.21 Bernbaum et al. reported the
immunological response of 25 preterm and 38 term infants
(GA 31.0 C/ 1.6 weeks) given DTwP at 2, 4 and 6 months
after birth. All preterm and full-term control infants achieved a
protective antibody concentration measured at 2 months after
the 3rd dose.22 DAngio et al. studied a cohort of extremely
preterm infants (<29 weeks gestation and <1,000 g at birth)
immunized with DTwP, Hib and IPV administered as a 3-dose
schedule. After 3 doses of DTwP, all preterm and term infants
were considered protected.23 Using a hexavalent DTaPHBV-
IPV/Hib vaccine at 2, 4 and 6 months, Vazquez et al. reported
that 98% of preterm infants (GA between 24 and 36 weeks
with a birth weight <2,000 g) developed protective GMTs
(geometric mean titer, defined as a level of 0.1 IU/ml).24
Slack et al. reported no significant difference in anti-tetanus
toxoid GMTs between preterm (<32 weeks gestation) and
term infants using an accelerated 2, 3 and 4 months schedule
with DTaP-Hib vaccine.25 In all, current evidence favors the
use of tetanus toxoid combination vaccines in preterm infants
on a similar schedule to full-term infants.
Diphtheria
Diphtheria toxoid is an adjuvanted vaccine that generates neu-
tralizing antibodies. Data suggest that, similar to tetanus, individ-
uals with antibody levels against diphtheria between 0.01 and
0.1 IU/ml are considered partially protected while titres of
0.1 IU/ml are needed for optimal protection.21 Using a 2, 3
and 4 months immunization schedule, Slack et al. reported no
significant difference in anti-diphtheria toxoid GMTs between
preterm (<32 weeks gestation) and term infants.25 Using a 2, 4
and 6 months schedule, Vazquez et al. reported that at least 98%
of preterm infants achieved protective GMTs against diphtheria
(based on a level of 0.1 IU/ml).24 In summary, standard sched-
ules of diphtheria toxoid combination vaccines appear as effective
in preterm and full-term infants.
www.tandfonline.com Human Vaccines & Immunotherapeutics
Poliovirus
Neutralizing antibodies are required to control for the viremic
phase of poliovirus infection. Plotkin concluded that titres of 1/4
to 1/8 are protective against polioviruses types I, II and III.21
Slack et al. reported no statistically significant difference between
50 preterm infants (mean GA of 28.5 weeks) and 60 term con-
trol infants with a 2, 3 and 4 months immunization schedule
using inactivated polio vaccine (IPV), as part of Pediacel. All pre-
term infants achieved a level 1:8 for serotypes I, II and III.26
DAngio compared the immune response of extremely premature
infants (mean GA 25.9 weeks) and term infants who were given
IPV at 2 months followed by OPV at 4 months. An equivalent
proportion of preterm and term infants were protected (defined
as a neutralizing antibody titer 1:8) against serotype I (85 and
80%) and serotype II (100%). However, fewer preterm infants
were protected against serotype III (31% vs. 90%). 23 In sum-
mary, data suggest IPV offers preterm infants protection against
polioviruses types I, II and III.
Acellular pertussis
Pertussis vaccine can be either a whole cell or an acellular sub-
unit vaccine, which contains 2 to 5 of the following antigens: Per-
tussis Toxin (PT), Filamentous Haemagglutinin (FHA),
Pertactin (PRN) and Agglutinogens 2 and 3 (FIM). Bordetella
pertussis is a mucosal infection and correlates of protection for the
acellular vaccine are not as well established. However, it is reason-
able to think that antibodies against the separate component
would provide the basis for some interpretation of immune cor-
relate. Consensus on protective antibody levels has however not
been reached. 3,21 Schloesser et al. using a 2-component acellular
pertussis vaccine (PT, FHA) compared the immune response of
50 preterm infants (mean GA of 30.8 weeks) and 50 term
infants. A fourfold rise of antibody concentration was obtained
in 93.5% (PT) and 82.6% (FHA) of preterm infants. However,
GMTs were significantly higher in term infants.27 Slack et al.
studied 130 preterm infants and 54 term infants given a trivalent
acellular pertussis vaccine (PT, FHA, PRN) using a 2, 3 and
4 months schedule and found similar geometric mean responses
to FHA and PRN in preterm and term infants. Nevertheless,
reduced geometric mean concentration to PT (21 vs. 33.4,
p < 0.001) was observed.25 Similar observations were made by
Vazquez et al. in a study of 170 preterm infants to whom a hexa-
valent DTaP-HBV-IPV/Hib vaccine was administered using a 2,
4 and 6 months schedule. A lower response to PT was observed,
especially among the very low birth weight group.24 Similarly
Faldella et al. studied antibody response to a combined DTaP-
HBV vaccine given at 3, 5 and 11 months after birth to 34 pre-
term infants (mean GA of 32 weeks) and 28 term infants. After
3 doses, preterm infants with a GA of 31 weeks had antibody
concentrations significantly lower than preterm infants with a
GA of >31 weeks, whose immune response was quite similar to
that of term infants.28 Even after a booster dose, preterm infants
with a GA of 31 weeks had lower antibody levels.29 In sum-
mary, data suggest a decreased immunogenicity in preterm
infants, particularly with regards to PT. However, the signifi-
cance of this is uncertain in the absence of consensus data on
2557
immune correlates of protection, and even lower specific anti-
body level against the different antigens were significantly higher
than those considered protective.28,29 Above all, despite lower
antibody response, primary immunization series were able to
induce antibodies production as reported by Omenaca et al. in a
cohort of 94 preterm infants with vaccine response rates
>98.9%,30 although long-term pertussis-specific immune
responses seems to be lower in preterm infants.29
Haemophilus influenzae type b
Antibody levels 0.15 or 1.0 mg/mL were respectively con-
sidered to be the serological correlates of short-term and long-
term protection.21 Results of studies on preterm infants immune
response to Haemophilus influenzae type b (Hib) vaccines vary.
Some studies did not find any statistically significant differences in
Hib antibody concentrations between preterm and term infants.
Using a 2, 4 and 6 months schedule, similar proportions of pre-
term (<29 weeks gestation) and term infants reached antibody
level 1.0 mg/mL (82 vs. 87%) in Dangio study.23 Similarly,
comparing preterm and term infants Kirmani et al. found the
same proportion of infants who had antibody concentrations
1 mg/mL at 3 and 7-years of age.31 Robinson et al. reported
that 88% of preterm infants (GA 31 weeks) reached antibody level
1.0 mg/mL using a 2, 3 and 4 months schedule.32 On the other
hand, the data collected by Munoz et al. and Kristensen et al.
indicate that antibody levels reached after the administration of
the Hib vaccine are lower in preterm infants. In both studies, Hib
IgG-GMT and the proportion of infants achieving a level of
0.15 or 1.0 mg/mL were lower in preterm than in term
infants.33,34 Slack et al. studied 107 premature infants
(<32 weeks gestation) given Infanrix-Hib as a 2, 3 and 4 months
schedule. The Geometric Mean Concentration (GMC) in pre-
term was significantly lower (0.27 mg/ml) than in a term control
group (0.81mg; p < 0.001). Only 55% of preterm infants
exceeded the population protective level of 0.15 mg/mL com-
pared with 80% for term infants, and 21% had a level >1.0 mg/
mL (compared to 46% for term infants, p < 0.001).35 Baxter
et al., in a prospective case series study of premature infants
32 weeks given DTaP-Hib and MenC or DTwPHib and Men
C using a 2, 3 and 4 months schedule, found that just over one
third had an anti-PRP level >1.0 mg/ml.36 In a cohort of 94 pre-
term infants (2436 weeks), Omenaca et al observed anti-PRP
titers 0.15 and 1.0 mg/mL in 92.5% and 76.3% of preterm
infants and 97.8% and 86.5% of term infants one month after
the third dose.30 Prematurity was the main risk factor identified in
an observational study explaining the failure of the Hib conjugate
vaccine in the UK in the absence of a booster dose.37 However,
any association must be viewed with caution as further analysis of
data indicates that although the risk for vaccine failure is higher, it
does not reach statistical significance (RR, 1.8; p D 0.13).
In all, preterm infants appear to have lower GMC after Hib
conjugate vaccine when compared to full-term infants.
Hepatitis B virus
Antibody level of 10mUI/ml and 100 mUI/ml were respec-
tively considered to be the serological correlates of protection and
2558 Human Vaccines & Immunotherapeutics
long-term protection.3,21 Hepatitis B virus (HBV) vaccine is the
only vaccine for which data clearly indicate a lower response in
preterm infants. A preliminary study published in 1992 reported
lower seroconversion rates and HBV antibody concentrations in
very low birth weight infants who were immunized with HBV
vaccine when they reached a weight of 1000 g, compared with
infants immunized when they weighed 2000 g.38 After the
third dose, seroconversion was confirmed respectively in 79%,
91% and 100% of 10002000 g, >2000 g preterm infants and
term infants. GMC were respectively 61 mUI/mL, 262 mUI/
mL and 679mUI/mL. Subsequent studies reported that preterm
infants seroconverted to HBV vaccine by 30 days of age, regard-
less of their GA and birth weight.39,40 Prematurity per se, rather
than a specific GA or birth weight, was more predictive of
decreased serum HBV surface antibody levels when compared
with full-term infants.7,39-41 Nevertheless, protective concentra-
tions of HBs antibodies are reached in almost all preterm infants
by 912 months of age after the administration of the recom-
mended 3 vaccine doses.42 In the case of children with a birth
weight <2000 g born to HBsAg-positive mothers, the dose
administered at birth cannot be considered as part of the primary
series. It is recommended that such infants receive the complete
vaccine schedule with further doses at appropriate times in order
to be adequately protected.3,7,8 Omenaca et al., using a hexava-
lent DTaP-HBV-IPV/Hib administered at 2, 4 and 6 months,
found protective antibody levels in 93.4% of preterm infants
(GA 31.5 weeks) and 95.2% of term infants.30
Pneumococcal conjugate vaccine
In vaccine trials, the putative protective IgG antibody level
against Pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F and
23F has been defined as  0.35 mg/mL.16,21 Several studies have
demonstrated the immunogenicity of a 7-valent conjugate pneu-
mococcal vaccine (PCV7) when used at different schedules: 2, 4,
6, and 12 months; 3, 5, and 11 months; and 2, 3, and 4 months
of age. Esposito et al. found no significant differences in antibody
levels to PCV7 vaccine serotypes between term and preterm
infants (mean GA 32 weeks) after a 3-dose vaccination schedule
given at 3, 5 and 11 months.43 Similarly, the large PCV7 efficacy
study in the United States that enrolled 4340 infants born before
38 weeks of age, including 167 preterm infants born at less than
32 weeks, demonstrated that the immune response to all vaccine
serotypes was higher in preterm compared to term infants. The
efficacy against invasive pneumococcal disease was equivalent to
that of term infants.16 In contrast, Ruggeberg et al., who admin-
istered PCV-7 to full-term and preterm infants with a mean GA
of 30 weeks at 2, 3, 4 and 12 months of age, found that IgG
GMTs in preterm infants were significantly lower to 6 vaccine
serotypes at 2 and 5 months of age, 5 serotypes at 12 months of
age, and 3 serotypes at 13 months of age. Moreover, using an
IgG level of 0.35 mg/mL as a serological correlate of protection,
a significantly lower proportion of preterm infants achieved a
protective concentration of antibody against serotypes 4, 6B and
9V at 5 months, and against serotypes 4, 6B, 18C, 19F and 23F
at 12 months of age. However, after the booster dose, at least
93% in both cohorts reached IgG levels >0.35 mg/mL.44 In
Volume 11 Issue 11
summary, at least 80% of premature infants given PCV7 develop
protective antibody titres 0.35 mg/mL for 6 of the 7 serotypes
in the vaccine, within one month of vaccination (lower titres are
found with serotype 6B).44 However, because of the replacement
of the 7-valent preparation by a 10- or 13-valent vaccine, it is
necessary to evaluate the immunogenicity of these new vaccines
in premature infants. Omenaca et al. evaluated the immunoge-
nicity of the 10-valent pneumococcal non-typeable Haemophilus
influenzae protein D conjugate vaccine (PHiD-CV) in preterm
infants on a 2, 4, 6 and 16 to 18 months schedule in 2 groups of
preterm infants (group 1: 27 to 31 weeks; group 2: 31 to
37 weeks) and a group of full-term infants. PHiD-CV was
immunogenic for each of the 10 vaccine pneumococcal serotypes:
after the third dose 92.7% of infants reached antibody concentra-
tions >0.2 g/mL and 97.6% of infants after the booster dose. 45
Recently, Martinon-Torres et al. using a 4-dose regimen of
PCV-13 (2, 3, 4 and 12 months) found lower immune IgG
GMTs in preterm infants than in term infants. However, the
majority of preterm infants achieved both pneumococcal sero-
type-specific IgG antibody levels threshold of protection.46 In
summary, lower vaccine pneumococcal serotypes IgG GMTs
were found in preterm infants for primary doses. Accordingly
French and Canadian recommendations advocate a regimen of 4
doses (consisting of 3 primary doses with a toddler booster dose)
of pneumococcal conjugate vaccines for the routine immuniza-
tion of preterm infants rather than the 2 C 1 regimen.3,47
Meningococcal C conjugate vaccine
In vaccine trials, the putative protective antibody level
against Meningococcal C infection, measured as serum bacteri-
cidal antibody (SBA), is  8.21 Several studies have shown Men
C vaccines to be safe and immunogenic. While GMTs follow-
ing primary vaccination were lower in preterm compared to
term infants, differences were not statistically significant and
antibody persistence at 12 months of age was similar for pre-
term and term infants.48-50
Rotavirus
Both available rotavirus vaccines were studied in preterm
infants. Omernaca et al. assessed the immunogenicity and safety
of 2 doses of RIX4414 (Rotarix ) in a population of 1,009 pre-
term infants stratified into 2 groups (group 1: 2730 weeks;
group 2: 3136 weeks). The rotavirus IgA seroconversion rate
(antirotavirus IgA antibody concentration 20 U/mL in subjects
initially seronegative), at 3083 days post-dose 2, was 85.7% in
the vaccine group and 16.0% in the placebo group. Geometric
mean concentrations were 202.2 U/mL (153.1267.1) in the
vaccine group and 20 U/mL in the placebo group. Seroconver-
sion and GMC were lower in the 2730 weeks preterm infants
group. Seroconversion rates in vaccine recipients in groups 1 and
2 were 75.9% and 88.1%, with GMC of 110.2 U/mL (95% CI:
56.1216.5) and 234.8 U/mL (95% CI: 173.4318.0), respec-
tively.51 Goveia et al. studied the efficacy and safety of the penta-
valent human-bovine reassortant rotavirus vaccine (RotaTeq ) in
2,070 preterm infants born between 25 and 36 gestational weeks.
Overall, 3 doses of the pentavalent vaccine reduced the rate of
www.tandfonline.com Human Vaccines & Immunotherapeutics
hospitalizations and emergency department visits in premature
infants due to rotavirus gastroenteritis by 100% (95% CI:
82.2100) compared with placebo. The vaccine also prevented
73.0% (95% CI:-2.295.2) of rotavirus gastroenteritis cases of
any severity.17 In a prospective cohort study, Rou
e et al. reported
a significant effectiveness of the pentavalent rotavirus vaccine on
the number of hospitalizations in a population of preterm infants
younger than 3 years of age. Rotavirus vaccination decreased by
2.6 times [95% CI 1.3 to 5.2] the number of hospitalizations
due to rotavirus diarrhea during the first 2 epidemic seasons fol-
lowing vaccine introduction and by 11 times [95% CI 3.5 to
34.8] during the third season.52 These data support routine vac-
cination of premature infants with rotavirus vaccine using the
same schedule as for term infants, as recommended by the Advi-
sory Committee on Immunization Practices, the American Acad-
emy of Pediatrics and the Canadian immunization guide.8,53,54
Measles-mumps-rubella
Transferred maternal antibodies confer primary protection
against measles during the first few months of life. The majority
of women of childbearing age are now vaccinated and transfer
fewer antibodies than naturally immune mothers, conferring
shorter protection to their offspring.55,56 Moreover, given that
maternal antibody transfer is dependent on GA, passive protec-
tion is lost earlier in preterm infants with a recent study indicat-
ing that antibodies to measles were absent at birth in 62% of
preterm compared to 29% of term infants.57 In another study,
most preterm infants of less than 28 weeks gestation had lost
maternal antibodies by 3 months of age.58 The result of this early
loss of maternal antibodies is the appearance of a critical window
of risk for measles infection during the first year of life, which
should give rise to several modifications in the measles vaccina-
tion program. Therefore, some authors have suggested initiating
the MMR immunization at an earlier age for preterm infants or
for infants in the context of an epidemic.3,59-61 One of the bar-
riers to earlier vaccination, however, is the presumed immaturity
of the neonatal immunological system despite several studies
demonstrating both humoral and cellular responses at an early
age.59 For example, Gans et al. showed that infants T-cells could
be primed with measles antigen as early as 6 months of age,
despite the presence of maternal antibodies. However, MMR
vaccine given to term infants before 9 months of age have
resulted in reduced seroconversion rates.62,63 To avoid adminis-
tration of a supplementary dose, especially with a low mumps
response before one year, numerous major advisory boards pro-
pose to start the MMR vaccine at 12 month of age or to use
before one year a monovalent measles vaccine.3 As yet, there are
no published studies assessing response of preterm infants to early
MMR immunization, and earlier MMR immunization has not
been recommended in infants in the absence of an outbreak.64
Influenza
There is a paucity of data on the safety, immunogenicity,
and efficacy of influenza vaccination in both preterm and
term infants. Preterm infants were shown to develop signifi-
cantly lower antibody and cell mediated immune responses to
2559
influenza vaccine, compared to term infants from 6 months
to 4 years of age. However, almost all infants developed
GMTs of >1:32 (a level thought to correlate with protec-
tion), independent of GA.65 Similarly, DAngio el al. did not
find a difference in the immunogenicity of trivalent influenza
vaccine in premature versus term infants.66 As vaccination in
this age group is currently not recommended, vaccine
induced protection of preterm infants <6 months of age may
be achieved by a cocooning strategy in which all family mem-
bers receive influenza immunization.3,67,68
Safety and Tolerability of Vaccines in Preterm Infants
Vaccine safety assessment in preterm infants is particularly
challenging due to the frequency of adverse events intrinsically
associated with prematurity. The relationship between the
administration of vaccines and the appearance or worsening of
apnea and/or bradycardia has been extensively investigated but
with controversial results. In an observational study evaluating
the safety of hexavalent vaccines (DTaP-IPV-Hib) involving 78
preterm infants, immunization triggered transient cardiorespira-
tory events (apnea, bradycardia, desaturations) in 47% of infants.
Infants with pre-existing cardiorespiratory symptoms appeared to
have a 5-fold to 8-fold increase in risk of cardiorespiratory events
post immunization.10 In a retrospective study involving 53
infants, transient apnea or bradycardia was observed in 13% of
infants following immunization with pentavalent or hexavalent
vaccines.11 While severe episodes of apnea have been reported in
temporal relation to DTwP immunization of preterm infants
<31 weeks of gestation,12 this seems less frequent and less severe
following DTaP.10,13 It appears that the risk of adverse events
following immunization in preterm infants cannot be predicted
by GA or birth weight but rather by the infants clinical condi-
tion (underlying disease that affects cardiorespiratory stability) at
the time of immunization.10 Moreover, Klein et al. studied risk
factors for the development of apnea after immunization and
found that episodes were more frequent in children who had
experienced similar clinical manifestations in the 24 hours prior
to vaccination, the smallest children, and the children with the
most severe illnesses at birth.14 However, no conclusions can be
drawn on the relationship between immunization and the
appearance or accentuation of apnea or bradycardia as most of
the studies are affected by methodological problems (i.e. absence
of a control group, inadequate sample size). However, Carbone
et al., in a randomized study, excluded the association between
the administration of DTaP and subsequent cardiorespiratory
problems, even in extremely preterm infants.70 The authors com-
pared the incidence of apnea and bradycardia in the 48 hours fol-
lowing vaccination in a group of 93 preterm infants (mean GA of
26.9 weeks) who received a dose of DTaP at a mean chronologi-
cal age of 57.5 days and a control group of 98 comparable pre-
term infants who were not vaccinated. There was no between-
group difference for apnea, bradycardia and severe events
(apnea  30 or bradycardia of 60 bpm).69
2560 Human Vaccines & Immunotherapeutics
Well-controlled studies are needed to confirm specific adverse
events in the preterm infant population and to further delineate
the indication, modalities, and duration of monitoring required
following immunization. To date, the American Academy of
Pediatrics has suggested closely observing hospitalized extremely-
low-birth-weight infants for significant adverse events during
72 hours.7 In 2007, Gaudelus et al. published French recom-
mendations that preterm infants <33 weeks should receive the
first vaccine dose while hospitalized, with a 48-hour cardio-moni-
toring.15 These measures can perhaps be considered excessive
when compared to the benefit of early discharge. In fact, a recent
French study showed that vaccination of very preterm infants
was initiated before their return home in only 15% of cases, as
the median duration of hospitalization was less than 60 days.70
In conclusion, monitoring all preterm infants still hospitalised
in neonatal units at the time of immunization seems prudent but
clinicians should be reassured that there are no apparent safety
concerns which may favor delaying administration of preterm
immunization.
Protecting Preterm Infants by Avoiding
Immunization Delay and Immunizing Family
Members and Close Contacts
Fear of adverse events was one of the major reasons for delaying
vaccine administration in preterm infants. Magoon et al. reported
immunization delays in 3070% of infants ranging from 6 to
40 weeks.71 Langkamp et al. found that very low birth weight
infants were less likely to be fully immunized at the ages of 12, 24
and 36 months than infants with higher birth weights.72 This
delay in initiating vaccination has been confirmed in a French
study, in which no very preterm infants had received all 3 doses of
the DTaP-IPV-Hib primary vaccination series by the beginning
of the fifth month and less than half by the end of the sixth
month.70 Recently an Italian population-based cohort study con-
firmed that the initiation of immunization for all vaccines was
considerably delayed in many very preterm infants.9 Several publi-
cations have highlighted the considerable delay before the first vac-
cinations are given and how an initiation of vaccination in hospital
before homecoming might improve the vaccination rate.70-72
The information given to parents during hospitalization of
preterm infants remains an essential stage in the understanding
of the vaccination process for their children. This counselling is
an exceptional opportunity to catch up with the vaccination
schedule of the entire family and close contacts.67,68 The ade-
quate immunization of all close contacts, with an update of the
familys pertussis and flu vaccinations, offers useful indirect pro-
tection to vulnerable preterm infants.73,74 Birth represents a
moment of particular receptiveness on the part of the whole fam-
ily to any suggestion regarding their own vaccinations and to pro-
vide preterm infants additional indirect protection against
vaccine preventable diseases. The challenge of an educational
counselling approach is to make parents full-time partners in vac-
cination and the drivers of their infants immunization
schedule.67,68
Volume 11 Issue 11
 Conclusion
While absolute primary antibody responses may be lower in
preterm compared to term infants vaccinated according to chro-
nological age, the majority achieve antibody concentrations
higher than levels generally accepted to correlate with protection.
Recent data confirm that preterm infants should be vaccinated
using the same schedule as term infants, with the exception of
the HBV vaccine, where the full schedule needs to be repeated in
infants who received their first dose when they weighed less than
2000 g. However, despite this recommendation, routine immu-
nization of preterm infants is often delayed. The most important
factor explaining the delay in administering routine vaccines is
likely the lack of knowledge regarding the safety and effectiveness
of vaccines in preterm infants among healthcare workers and
parents. Every effort should be made to elaborate universal guide-
lines defining modalities and duration of monitoring following
preterm infant immunization, but also to convince pediatricians
and parents that vaccines are immunogenic, safe and well toler-
ated in preterm infants. A cocooning strategy for pertussis and
influenza should also be proposed to parents. Early active immu-
nity is particularly important in preterm infants because they are
among the most vulnerable populations to pediatric infectious
diseases.
Disclosure of Potential Conflicts of Interest
Arnaud Gagneur has previously received funding from Merck,
Sanofi-Pasteur MSD & Pfizer (research grant). Didier Pinquier
has previously received funding from GlaxoSmithKline and
Sanofi-Pasteur MSD (research grant, speaker/honoraria). Caroline
Quach has previously received funding from GlaxoSmithKline,
Pfizer, Sage and AbbVie (for research grant or support for
unrelated research projects).

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