Immunization of preterm infants

Abstract

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 first dose during the first days of life if they weighed less than 2000 g because of a documented reduced immune response.

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

Introduction

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 premature 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 preterm 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

Preterm infants are at increased risk of infections in general 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 recommended for full-term infants, without correcting for prematurity and regardless of birth weight.^3,7,8

Vaccination is often delayed in preterm infants as demonstrated 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 cardiorespiratory 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

Over 50% of reported cases of pertussis occur in infants. Low 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 1.27–19.71) 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 compared to term infants. Comparing to normal birth weight and term infants, Shinefield et al. reported a risk ratio of 2.6 (p=0.03) 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 infections, 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 hospitalizations (OR: 2.6, 95 % CI: 1.6 – 4.1 and OR: 1.6; 95 % CI 1.3 – 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 preterm infants is directly proportional to gestation age (GA) and birth weight. Various factors can influence antibody production, 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 neutralizing antibodies. Data suggest that individuals with antibody 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 +/− 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 D'Angio 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 neutralizing antibodies. Data suggest that, similar to tetanus, individuals 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 schedules of diphtheria toxoid combination vaccines appear as effective in preterm and full-term infants.

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 control infants with a 2, 3 and 4 months immunization schedule using inactivated polio vaccine (IPV), as part of Pediacel. All preterm infants achieved a level ≥1:8 for serotypes I, II and III.²⁶ D'Angio 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 summary, 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 subunit vaccine, which contains 2 to 5 of the following antigens: Pertussis 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 reasonable to think that antibodies against the separate component would provide the basis for some interpretation of immune correlate. 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 hexavalent 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 preterm 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 summary, data suggest a decreased immunogenicity in preterm infants, particularly with regards to PT. However, the significance of this is uncertain in the absence of consensus data on immune correlates of protection, and even lower specific antibody 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 μg/mL were respectively considered 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 preterm (<29 weeks gestation) and term infants reached antibody level ≥1.0 μg/mL (82 vs. 87%) in D'angio study.²³ Similarly, comparing preterm and term infants Kirmani et al. found the same proportion of infants who had antibody concentrations ≥1 μg/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 μg/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 μg/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 preterm was significantly lower (0.27 μg/ml) than in a term control group (0.81μg; p < 0.001). Only 55% of preterm infants exceeded the population protective level of ≥0.15 μg/mL compared with 80% for term infants, and 21% had a level >1.0 μg/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 μg/ml.³⁶ In a cohort of 94 preterm infants (24–36 weeks), Omenaca et al observed anti-PRP titers ≥0.15 and ≥1.0 μg/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 = 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 respectively considered to be the serological correlates of protection and 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 1000–2000 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, regardless 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 concentrations of HBs antibodies are reached in almost all preterm infants by 9–12 months of age after the administration of the recommended 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 hexavalent 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 μg/mL.^16,21 Several studies have demonstrated the immunogenicity of a 7-valent conjugate pneumococcal 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 administered 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 μg/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 μg/mL.⁴⁴ In summary, at least 80% of premature infants given PCV7 develop protective antibody titres ≥0.35 μg/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 immunogenicity 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 concentrations >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 serotype-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 immunization of preterm infants rather than the 2 + 1 regimen.^3,47

Meningococcal C conjugate vaccine

In vaccine trials, the putative protective antibody level against Meningococcal C infection, measured as serum bactericidal antibody (SBA), is ≥ 8.²¹ Several studies have shown Men C vaccines to be safe and immunogenic. While GMTs following 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 preterm 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 preterm infants stratified into 2 groups (group 1: 27–30 weeks; group 2: 31–36 weeks). The rotavirus IgA seroconversion rate (antirotavirus IgA antibody concentration ≥20 U/mL in subjects initially seronegative), at 30–83 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 (153.1–267.1) in the vaccine group and 20 U/mL in the placebo group. Seroconversion and GMC were lower in the 27–30 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: 56.1–216.5) and 234.8 U/mL (95% CI: 173.4–318.0), respectively.⁵¹ Goveia et al. studied the efficacy and safety of the pentavalent 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 hospitalizations and emergency department visits in premature infants due to rotavirus gastroenteritis by 100% (95% CI: 82.2–100) compared with placebo. The vaccine also prevented 73.0% (95% CI:-2.2–95.2) of rotavirus gastroenteritis cases of any severity.¹⁷ In a prospective cohort study, Roué 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 following vaccine introduction and by 11 times [95% CI 3.5 to 34.8] during the third season.⁵² These data support routine vaccination of premature infants with rotavirus vaccine using the same schedule as for term infants, as recommended by the Advisory Committee on Immunization Practices, the American Academy 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 protection is lost earlier in preterm infants with a recent study indicating 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 vaccination 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 barriers 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 administration of a supplementary dose, especially with a low mumps response before one year, numerous major advisory boards propose 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 significantly lower antibody and cell mediated immune responses to 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 protection), independent of GA.⁶⁵ Similarly, D'Angio 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 members 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 cardiorespiratory 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 infant's clinical condition (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 compared the incidence of apnea and bradycardia in the 48 hours following vaccination in a group of 93 preterm infants (mean GA of 26.9 weeks) who received a dose of DTaP at a mean chronological age of 57.5 days and a control group of 98 comparable preterm 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

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 recommendations that preterm infants <33 weeks should receive the first vaccine dose while hospitalized, with a 48-hour cardio-monitoring.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 30–70% 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 confirmed that the initiation of immunization for all vaccines was considerably delayed in many very preterm infants.⁹ Several publications have highlighted the considerable delay before the first vaccinations 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 adequate immunization of all close contacts, with an update of the family's pertussis and flu vaccinations, offers useful indirect protection to vulnerable preterm infants.^73,74 Birth represents a moment of particular receptiveness on the part of the whole family to any suggestion regarding their own vaccinations and to provide preterm infants additional indirect protection against vaccine preventable diseases. The challenge of an educational counselling approach is to make parents full-time partners in vaccination and the drivers of their infant's immunization schedule.^67,68

Conclusion

While absolute primary antibody responses may be lower in preterm compared to term infants vaccinated according to chronological 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 immunization 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 guidelines defining modalities and duration of monitoring following preterm infant immunization, but also to convince pediatricians and parents that vaccines are immunogenic, safe and well tolerated in preterm infants. A cocooning strategy for pertussis and influenza should also be proposed to parents. Early active immunity 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).