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

Premature Infants: Risk Factors for Vaccine


Preventable Diseases

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


birth weight infants are particularly at risk (RR 1.86; 95% CI
More than 10% of infants are born prematurely and the rate 1.33 to 2.38) when compared to normal birth weight infants.5 In
of preterm births is increasing steadily worldwide.1 Very preterm a recent Australian prospective study, a history of prematurity
infants (<33 weeks of gestational age) represent 20% of all pre- (OR 5.00, CI 1.2719.71) was independently associated with
mature infants.2 Immunocompetence in newborns depends on severe pertussis infections.6 Invasive pneumococcal diseases
prenatal maturation as each additional week of gestation sees an account for up to 11% of neonatal sepsis. Preterm and low birth
increased response to antigens. Postnatal maturation, which weight infants are at increased risk of pneumococcal disease com-
begins upon exposure to environmental antigens, occurs in pre- pared to term infants. Comparing to normal birth weight and
term infants at a speed comparable to that of full-term infants. term infants, Shinefield et al. reported a risk ratio of 2.6
Moreover, preterm infants have immunologic immaturities that (pD0.03) and 9.1 for invasive pneumococcal diseases for low
may impact vaccine response particularly in very premature birth weight infants and preterm infants less than 32 weeks of
infants.3 gestation, respectively.16 Preterm infants are also at higher risk
for complications and hospitalization following rotavirus infec-
*Correspondence to: Arnaud Gagneur; Email: arnaud.gagneur@USherbrooke. tions, compared to infants born at term.17-19 Among children
ca born preterm, those with a low (<2500 g) or very low birth
Submitted: 03/03/2015; Revised: 07/01/2015; Accepted: 07/14/2015
http://dx.doi.org/10.1080/21645515.2015.1074358 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 Poliovirus
of influenza virus infections and complications.20 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
Immunogenicity of Vaccines in Preterm Infants Slack et al. reported no statistically significant difference between
50 preterm infants (mean GA of 28.5 weeks) and 60 term con-
Current evidence indicates that immune response in pre- trol infants with a 2, 3 and 4 months immunization schedule
term infants is directly proportional to gestation age (GA) and using inactivated polio vaccine (IPV), as part of Pediacel. All pre-
birth weight. Various factors can influence antibody produc- term infants achieved a level 1:8 for serotypes I, II and III.26
tion, such as clinical conditions, prescribed therapies, vaccine DAngio compared the immune response of extremely premature
composition and vaccination schedules.7 However, regardless infants (mean GA 25.9 weeks) and term infants who were given
of the variations induced by these factors, vaccines appear to IPV at 2 months followed by OPV at 4 months. An equivalent
induce a protective immune response in preterm infants in the proportion of preterm and term infants were protected (defined
majority of cases. 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-
Tetanus
mary, data suggest IPV offers preterm infants protection against
Tetanus toxoid is an adjuvanted vaccine that generates neu-
polioviruses types I, II and III.
tralizing antibodies. Data suggest that individuals with anti-
body levels against tetanus between 0.01 and 0.1 IU/ml are
Acellular pertussis
considered partially protected and that titres of 0.1IU/ml are
Pertussis vaccine can be either a whole cell or an acellular sub-
required for optimal protection.21 Bernbaum et al. reported the
unit vaccine, which contains 2 to 5 of the following antigens: Per-
immunological response of 25 preterm and 38 term infants
tussis Toxin (PT), Filamentous Haemagglutinin (FHA),
(GA 31.0 C/ 1.6 weeks) given DTwP at 2, 4 and 6 months
Pertactin (PRN) and Agglutinogens 2 and 3 (FIM). Bordetella
after birth. All preterm and full-term control infants achieved a
pertussis is a mucosal infection and correlates of protection for the
protective antibody concentration measured at 2 months after
acellular vaccine are not as well established. However, it is reason-
the 3rd dose.22 DAngio et al. studied a cohort of extremely
able to think that antibodies against the separate component
preterm infants (<29 weeks gestation and <1,000 g at birth)
would provide the basis for some interpretation of immune cor-
immunized with DTwP, Hib and IPV administered as a 3-dose
relate. Consensus on protective antibody levels has however not
schedule. After 3 doses of DTwP, all preterm and term infants
been reached. 3,21 Schloesser et al. using a 2-component acellular
were considered protected.23 Using a hexavalent DTaPHBV-
pertussis vaccine (PT, FHA) compared the immune response of
IPV/Hib vaccine at 2, 4 and 6 months, Vazquez et al. reported
50 preterm infants (mean GA of 30.8 weeks) and 50 term
that 98% of preterm infants (GA between 24 and 36 weeks
infants. A fourfold rise of antibody concentration was obtained
with a birth weight <2,000 g) developed protective GMTs
in 93.5% (PT) and 82.6% (FHA) of preterm infants. However,
(geometric mean titer, defined as a level of 0.1 IU/ml).24
GMTs were significantly higher in term infants.27 Slack et al.
Slack et al. reported no significant difference in anti-tetanus
studied 130 preterm infants and 54 term infants given a trivalent
toxoid GMTs between preterm (<32 weeks gestation) and
acellular pertussis vaccine (PT, FHA, PRN) using a 2, 3 and
term infants using an accelerated 2, 3 and 4 months schedule
4 months schedule and found similar geometric mean responses
with DTaP-Hib vaccine.25 In all, current evidence favors the
to FHA and PRN in preterm and term infants. Nevertheless,
use of tetanus toxoid combination vaccines in preterm infants
reduced geometric mean concentration to PT (21 vs. 33.4,
on a similar schedule to full-term infants.
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-
Diphtheria valent DTaP-HBV-IPV/Hib vaccine was administered using a 2,
Diphtheria toxoid is an adjuvanted vaccine that generates neu- 4 and 6 months schedule. A lower response to PT was observed,
tralizing antibodies. Data suggest that, similar to tetanus, individ- especially among the very low birth weight group.24 Similarly
uals with antibody levels against diphtheria between 0.01 and Faldella et al. studied antibody response to a combined DTaP-
0.1 IU/ml are considered partially protected while titres of HBV vaccine given at 3, 5 and 11 months after birth to 34 pre-
0.1 IU/ml are needed for optimal protection.21 Using a 2, 3 term infants (mean GA of 32 weeks) and 28 term infants. After
and 4 months immunization schedule, Slack et al. reported no 3 doses, preterm infants with a GA of 31 weeks had antibody
significant difference in anti-diphtheria toxoid GMTs between concentrations significantly lower than preterm infants with a
preterm (<32 weeks gestation) and term infants.25 Using a 2, 4 GA of >31 weeks, whose immune response was quite similar to
and 6 months schedule, Vazquez et al. reported that at least 98% that of term infants.28 Even after a booster dose, preterm infants
of preterm infants achieved protective GMTs against diphtheria with a GA of 31 weeks had lower antibody levels.29 In sum-
(based on a level of 0.1 IU/ml).24 In summary, standard sched- mary, data suggest a decreased immunogenicity in preterm
ules of diphtheria toxoid combination vaccines appear as effective infants, particularly with regards to PT. However, the signifi-
in preterm and full-term infants. cance of this is uncertain in the absence of consensus data on

www.tandfonline.com Human Vaccines & Immunotherapeutics 2557


immune correlates of protection, and even lower specific anti- long-term protection.3,21 Hepatitis B virus (HBV) vaccine is the
body level against the different antigens were significantly higher only vaccine for which data clearly indicate a lower response in
than those considered protective.28,29 Above all, despite lower preterm infants. A preliminary study published in 1992 reported
antibody response, primary immunization series were able to lower seroconversion rates and HBV antibody concentrations in
induce antibodies production as reported by Omenaca et al. in a very low birth weight infants who were immunized with HBV
cohort of 94 preterm infants with vaccine response rates vaccine when they reached a weight of 1000 g, compared with
>98.9%,30 although long-term pertussis-specific immune infants immunized when they weighed 2000 g.38 After the
responses seems to be lower in preterm infants.29 third dose, seroconversion was confirmed respectively in 79%,
91% and 100% of 10002000 g, >2000 g preterm infants and
Haemophilus influenzae type b term infants. GMC were respectively 61 mUI/mL, 262 mUI/
Antibody levels 0.15 or 1.0 mg/mL were respectively con- mL and 679mUI/mL. Subsequent studies reported that preterm
sidered to be the serological correlates of short-term and long- infants seroconverted to HBV vaccine by 30 days of age, regard-
term protection.21 Results of studies on preterm infants immune less of their GA and birth weight.39,40 Prematurity per se, rather
response to Haemophilus influenzae type b (Hib) vaccines vary. than a specific GA or birth weight, was more predictive of
Some studies did not find any statistically significant differences in decreased serum HBV surface antibody levels when compared
Hib antibody concentrations between preterm and term infants. with full-term infants.7,39-41 Nevertheless, protective concentra-
Using a 2, 4 and 6 months schedule, similar proportions of pre- tions of HBs antibodies are reached in almost all preterm infants
term (<29 weeks gestation) and term infants reached antibody by 912 months of age after the administration of the recom-
level 1.0 mg/mL (82 vs. 87%) in Dangio study.23 Similarly, mended 3 vaccine doses.42 In the case of children with a birth
comparing preterm and term infants Kirmani et al. found the weight <2000 g born to HBsAg-positive mothers, the dose
same proportion of infants who had antibody concentrations administered at birth cannot be considered as part of the primary
1 mg/mL at 3 and 7-years of age.31 Robinson et al. reported series. It is recommended that such infants receive the complete
that 88% of preterm infants (GA 31 weeks) reached antibody level vaccine schedule with further doses at appropriate times in order
1.0 mg/mL using a 2, 3 and 4 months schedule.32 On the other to be adequately protected.3,7,8 Omenaca et al., using a hexava-
hand, the data collected by Munoz et al. and Kristensen et al. lent DTaP-HBV-IPV/Hib administered at 2, 4 and 6 months,
indicate that antibody levels reached after the administration of found protective antibody levels in 93.4% of preterm infants
the Hib vaccine are lower in preterm infants. In both studies, Hib (GA 31.5 weeks) and 95.2% of term infants.30
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 Pneumococcal conjugate vaccine
infants.33,34 Slack et al. studied 107 premature infants In vaccine trials, the putative protective IgG antibody level
(<32 weeks gestation) given Infanrix-Hib as a 2, 3 and 4 months against Pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F and
schedule. The Geometric Mean Concentration (GMC) in pre- 23F has been defined as  0.35 mg/mL.16,21 Several studies have
term was significantly lower (0.27 mg/ml) than in a term control demonstrated the immunogenicity of a 7-valent conjugate pneu-
group (0.81mg; p < 0.001). Only 55% of preterm infants mococcal vaccine (PCV7) when used at different schedules: 2, 4,
exceeded the population protective level of 0.15 mg/mL com- 6, and 12 months; 3, 5, and 11 months; and 2, 3, and 4 months
pared with 80% for term infants, and 21% had a level >1.0 mg/ of age. Esposito et al. found no significant differences in antibody
mL (compared to 46% for term infants, p < 0.001).35 Baxter levels to PCV7 vaccine serotypes between term and preterm
et al., in a prospective case series study of premature infants infants (mean GA 32 weeks) after a 3-dose vaccination schedule
32 weeks given DTaP-Hib and MenC or DTwPHib and Men given at 3, 5 and 11 months.43 Similarly, the large PCV7 efficacy
C using a 2, 3 and 4 months schedule, found that just over one study in the United States that enrolled 4340 infants born before
third had an anti-PRP level >1.0 mg/ml.36 In a cohort of 94 pre- 38 weeks of age, including 167 preterm infants born at less than
term infants (2436 weeks), Omenaca et al observed anti-PRP 32 weeks, demonstrated that the immune response to all vaccine
titers 0.15 and 1.0 mg/mL in 92.5% and 76.3% of preterm serotypes was higher in preterm compared to term infants. The
infants and 97.8% and 86.5% of term infants one month after efficacy against invasive pneumococcal disease was equivalent to
the third dose.30 Prematurity was the main risk factor identified in that of term infants.16 In contrast, Ruggeberg et al., who admin-
an observational study explaining the failure of the Hib conjugate istered PCV-7 to full-term and preterm infants with a mean GA
vaccine in the UK in the absence of a booster dose.37 However, of 30 weeks at 2, 3, 4 and 12 months of age, found that IgG
any association must be viewed with caution as further analysis of GMTs in preterm infants were significantly lower to 6 vaccine
data indicates that although the risk for vaccine failure is higher, it serotypes at 2 and 5 months of age, 5 serotypes at 12 months of
does not reach statistical significance (RR, 1.8; p D 0.13). age, and 3 serotypes at 13 months of age. Moreover, using an
In all, preterm infants appear to have lower GMC after Hib IgG level of 0.35 mg/mL as a serological correlate of protection,
conjugate vaccine when compared to full-term infants. a significantly lower proportion of preterm infants achieved a
protective concentration of antibody against serotypes 4, 6B and
Hepatitis B virus 9V at 5 months, and against serotypes 4, 6B, 18C, 19F and 23F
Antibody level of 10mUI/ml and 100 mUI/ml were respec- at 12 months of age. However, after the booster dose, at least
tively considered to be the serological correlates of protection and 93% in both cohorts reached IgG levels >0.35 mg/mL.44 In

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summary, at least 80% of premature infants given PCV7 develop hospitalizations and emergency department visits in premature
protective antibody titres 0.35 mg/mL for 6 of the 7 serotypes infants due to rotavirus gastroenteritis by 100% (95% CI:
in the vaccine, within one month of vaccination (lower titres are 82.2100) compared with placebo. The vaccine also prevented
found with serotype 6B).44 However, because of the replacement 73.0% (95% CI:-2.295.2) of rotavirus gastroenteritis cases of
of the 7-valent preparation by a 10- or 13-valent vaccine, it is any severity.17 In a prospective cohort study, Roue et al. reported
necessary to evaluate the immunogenicity of these new vaccines a significant effectiveness of the pentavalent rotavirus vaccine on
in premature infants. Omenaca et al. evaluated the immunoge- the number of hospitalizations in a population of preterm infants
nicity of the 10-valent pneumococcal non-typeable Haemophilus younger than 3 years of age. Rotavirus vaccination decreased by
influenzae protein D conjugate vaccine (PHiD-CV) in preterm 2.6 times [95% CI 1.3 to 5.2] the number of hospitalizations
infants on a 2, 4, 6 and 16 to 18 months schedule in 2 groups of due to rotavirus diarrhea during the first 2 epidemic seasons fol-
preterm infants (group 1: 27 to 31 weeks; group 2: 31 to lowing vaccine introduction and by 11 times [95% CI 3.5 to
37 weeks) and a group of full-term infants. PHiD-CV was 34.8] during the third season.52 These data support routine vac-
immunogenic for each of the 10 vaccine pneumococcal serotypes: cination of premature infants with rotavirus vaccine using the
after the third dose 92.7% of infants reached antibody concentra- same schedule as for term infants, as recommended by the Advi-
tions >0.2 g/mL and 97.6% of infants after the booster dose. 45 sory Committee on Immunization Practices, the American Acad-
Recently, Martinon-Torres et al. using a 4-dose regimen of emy of Pediatrics and the Canadian immunization guide.8,53,54
PCV-13 (2, 3, 4 and 12 months) found lower immune IgG
GMTs in preterm infants than in term infants. However, the Measles-mumps-rubella
majority of preterm infants achieved both pneumococcal sero- Transferred maternal antibodies confer primary protection
type-specific IgG antibody levels threshold of protection.46 In against measles during the first few months of life. The majority
summary, lower vaccine pneumococcal serotypes IgG GMTs of women of childbearing age are now vaccinated and transfer
were found in preterm infants for primary doses. Accordingly fewer antibodies than naturally immune mothers, conferring
French and Canadian recommendations advocate a regimen of 4 shorter protection to their offspring.55,56 Moreover, given that
doses (consisting of 3 primary doses with a toddler booster dose) maternal antibody transfer is dependent on GA, passive protec-
of pneumococcal conjugate vaccines for the routine immuniza- tion is lost earlier in preterm infants with a recent study indicat-
tion of preterm infants rather than the 2 C 1 regimen.3,47 ing that antibodies to measles were absent at birth in 62% of
preterm compared to 29% of term infants.57 In another study,
Meningococcal C conjugate vaccine most preterm infants of less than 28 weeks gestation had lost
In vaccine trials, the putative protective antibody level maternal antibodies by 3 months of age.58 The result of this early
against Meningococcal C infection, measured as serum bacteri- loss of maternal antibodies is the appearance of a critical window
cidal antibody (SBA), is  8.21 Several studies have shown Men of risk for measles infection during the first year of life, which
C vaccines to be safe and immunogenic. While GMTs follow- should give rise to several modifications in the measles vaccina-
ing primary vaccination were lower in preterm compared to tion program. Therefore, some authors have suggested initiating
term infants, differences were not statistically significant and the MMR immunization at an earlier age for preterm infants or
antibody persistence at 12 months of age was similar for pre- for infants in the context of an epidemic.3,59-61 One of the bar-
term and term infants.48-50 riers to earlier vaccination, however, is the presumed immaturity
of the neonatal immunological system despite several studies
Rotavirus demonstrating both humoral and cellular responses at an early
Both available rotavirus vaccines were studied in preterm age.59 For example, Gans et al. showed that infants T-cells could
infants. Omernaca et al. assessed the immunogenicity and safety be primed with measles antigen as early as 6 months of age,
of 2 doses of RIX4414 (Rotarix ) in a population of 1,009 pre- despite the presence of maternal antibodies. However, MMR
term infants stratified into 2 groups (group 1: 2730 weeks; vaccine given to term infants before 9 months of age have
group 2: 3136 weeks). The rotavirus IgA seroconversion rate resulted in reduced seroconversion rates.62,63 To avoid adminis-
(antirotavirus IgA antibody concentration 20 U/mL in subjects tration of a supplementary dose, especially with a low mumps
initially seronegative), at 3083 days post-dose 2, was 85.7% in response before one year, numerous major advisory boards pro-
the vaccine group and 16.0% in the placebo group. Geometric pose to start the MMR vaccine at 12 month of age or to use
mean concentrations were 202.2 U/mL (153.1267.1) in the before one year a monovalent measles vaccine.3 As yet, there are
vaccine group and 20 U/mL in the placebo group. Seroconver- no published studies assessing response of preterm infants to early
sion and GMC were lower in the 2730 weeks preterm infants MMR immunization, and earlier MMR immunization has not
group. Seroconversion rates in vaccine recipients in groups 1 and been recommended in infants in the absence of an outbreak.64
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- Influenza
tively.51 Goveia et al. studied the efficacy and safety of the penta- There is a paucity of data on the safety, immunogenicity,
valent human-bovine reassortant rotavirus vaccine (RotaTeq ) in and efficacy of influenza vaccination in both preterm and
2,070 preterm infants born between 25 and 36 gestational weeks. term infants. Preterm infants were shown to develop signifi-
Overall, 3 doses of the pentavalent vaccine reduced the rate of cantly lower antibody and cell mediated immune responses to

www.tandfonline.com Human Vaccines & Immunotherapeutics 2559


influenza vaccine, compared to term infants from 6 months Well-controlled studies are needed to confirm specific adverse
to 4 years of age. However, almost all infants developed events in the preterm infant population and to further delineate
GMTs of >1:32 (a level thought to correlate with protec- the indication, modalities, and duration of monitoring required
tion), independent of GA.65 Similarly, DAngio el al. did not following immunization. To date, the American Academy of
find a difference in the immunogenicity of trivalent influenza Pediatrics has suggested closely observing hospitalized extremely-
vaccine in premature versus term infants.66 As vaccination in low-birth-weight infants for significant adverse events during
this age group is currently not recommended, vaccine 72 hours.7 In 2007, Gaudelus et al. published French recom-
induced protection of preterm infants <6 months of age may mendations that preterm infants <33 weeks should receive the
be achieved by a cocooning strategy in which all family mem- first vaccine dose while hospitalized, with a 48-hour cardio-moni-
bers receive influenza immunization.3,67,68 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
Safety and Tolerability of Vaccines in Preterm Infants the median duration of hospitalization was less than 60 days.70
In conclusion, monitoring all preterm infants still hospitalised
Vaccine safety assessment in preterm infants is particularly in neonatal units at the time of immunization seems prudent but
challenging due to the frequency of adverse events intrinsically clinicians should be reassured that there are no apparent safety
associated with prematurity. The relationship between the concerns which may favor delaying administration of preterm
administration of vaccines and the appearance or worsening of immunization.
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 Protecting Preterm Infants by Avoiding
preterm infants, immunization triggered transient cardiorespira- Immunization Delay and Immunizing Family
tory events (apnea, bradycardia, desaturations) in 47% of infants. Members and Close Contacts
Infants with pre-existing cardiorespiratory symptoms appeared to
have a 5-fold to 8-fold increase in risk of cardiorespiratory events Fear of adverse events was one of the major reasons for delaying
post immunization.10 In a retrospective study involving 53 vaccine administration in preterm infants. Magoon et al. reported
infants, transient apnea or bradycardia was observed in 13% of immunization delays in 3070% of infants ranging from 6 to
infants following immunization with pentavalent or hexavalent 40 weeks.71 Langkamp et al. found that very low birth weight
vaccines.11 While severe episodes of apnea have been reported in infants were less likely to be fully immunized at the ages of 12, 24
temporal relation to DTwP immunization of preterm infants and 36 months than infants with higher birth weights.72 This
<31 weeks of gestation,12 this seems less frequent and less severe delay in initiating vaccination has been confirmed in a French
following DTaP.10,13 It appears that the risk of adverse events study, in which no very preterm infants had received all 3 doses of
following immunization in preterm infants cannot be predicted the DTaP-IPV-Hib primary vaccination series by the beginning
by GA or birth weight but rather by the infants clinical condi- of the fifth month and less than half by the end of the sixth
tion (underlying disease that affects cardiorespiratory stability) at month.70 Recently an Italian population-based cohort study con-
the time of immunization.10 Moreover, Klein et al. studied risk firmed that the initiation of immunization for all vaccines was
factors for the development of apnea after immunization and considerably delayed in many very preterm infants.9 Several publi-
found that episodes were more frequent in children who had cations have highlighted the considerable delay before the first vac-
experienced similar clinical manifestations in the 24 hours prior cinations are given and how an initiation of vaccination in hospital
to vaccination, the smallest children, and the children with the before homecoming might improve the vaccination rate.70-72
most severe illnesses at birth.14 However, no conclusions can be The information given to parents during hospitalization of
drawn on the relationship between immunization and the preterm infants remains an essential stage in the understanding
appearance or accentuation of apnea or bradycardia as most of of the vaccination process for their children. This counselling is
the studies are affected by methodological problems (i.e. absence an exceptional opportunity to catch up with the vaccination
of a control group, inadequate sample size). However, Carbone schedule of the entire family and close contacts.67,68 The ade-
et al., in a randomized study, excluded the association between quate immunization of all close contacts, with an update of the
the administration of DTaP and subsequent cardiorespiratory familys pertussis and flu vaccinations, offers useful indirect pro-
problems, even in extremely preterm infants.70 The authors com- tection to vulnerable preterm infants.73,74 Birth represents a
pared the incidence of apnea and bradycardia in the 48 hours fol- moment of particular receptiveness on the part of the whole fam-
lowing vaccination in a group of 93 preterm infants (mean GA of ily to any suggestion regarding their own vaccinations and to pro-
26.9 weeks) who received a dose of DTaP at a mean chronologi- vide preterm infants additional indirect protection against
cal age of 57.5 days and a control group of 98 comparable pre- vaccine preventable diseases. The challenge of an educational
term infants who were not vaccinated. There was no between- counselling approach is to make parents full-time partners in vac-
group difference for apnea, bradycardia and severe events cination and the drivers of their infants immunization
(apnea  30 or bradycardia of 60 bpm).69 schedule.67,68

2560 Human Vaccines & Immunotherapeutics Volume 11 Issue 11


Conclusion preterm infant immunization, but also to convince pediatricians
and parents that vaccines are immunogenic, safe and well toler-
While absolute primary antibody responses may be lower in ated in preterm infants. A cocooning strategy for pertussis and
preterm compared to term infants vaccinated according to chro- influenza should also be proposed to parents. Early active immu-
nological age, the majority achieve antibody concentrations nity is particularly important in preterm infants because they are
higher than levels generally accepted to correlate with protection. among the most vulnerable populations to pediatric infectious
Recent data confirm that preterm infants should be vaccinated diseases.
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 Disclosure of Potential Conflicts of Interest
2000 g. However, despite this recommendation, routine immu- Arnaud Gagneur has previously received funding from Merck,
nization of preterm infants is often delayed. The most important Sanofi-Pasteur MSD & Pfizer (research grant). Didier Pinquier
factor explaining the delay in administering routine vaccines is has previously received funding from GlaxoSmithKline and
likely the lack of knowledge regarding the safety and effectiveness Sanofi-Pasteur MSD (research grant, speaker/honoraria). Caroline
of vaccines in preterm infants among healthcare workers and Quach has previously received funding from GlaxoSmithKline,
parents. Every effort should be made to elaborate universal guide- Pfizer, Sage and AbbVie (for research grant or support for
lines defining modalities and duration of monitoring following unrelated research projects).

References frequent but mostly benign cardiorespiratory events. J Archives of pediatrics & adolescent medicine 2000;
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