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Association of Routine Infant Vaccinations With Antibody Levels Among Preterm Infants

Educational Objective
To understand the immunogenicity of routine vaccinations administered to preterm infants.
1 Credit CME
Key Points

Question  What is the association between receipt of a routine schedule of vaccinations and subsequent antibody levels among preterm infants over the first year of life?

Findings  In this prospective observational study that included 296 preterm infants and 66 historical control term-born infants, administration of a routine schedule of vaccinations was associated with 95% or more of preterm infants across all gestational ages achieving protective IgG levels for most vaccine antigens on completion of the primary series and the booster dose. However, after the primary series and booster, 40.6% and 88.1% of preterm infants, respectively, achieved protective levels against Haemophilus influenzae type b. In general, postimmunization antibody levels were significantly lower in preterm infants than in the historical control group, with the lowest values in extremely premature infants.

Meaning  Among preterm infants, administration of a routine schedule of vaccinations during the first year was associated with protective antibody levels against most antigens, except for Haemophilus influenzae type b.


Importance  The standard schedule of national immunization programs for infants may not be sufficient to protect extremely and very preterm infants.

Objective  To evaluate the immunogenicity of routine vaccinations administered to preterm infants.

Design, Setting, and Participants  A multicenter, prospective, observational cohort study of preterm infants stratified according to gestational age recruited from 8 hospitals across the Netherlands between October 2015 and October 2017, with follow-up until 12 months of age (October 2018). In total, 296 premature infants were enrolled and compared with a control group of 66 healthy term infants from a 2011 study, immunized according to the same schedule with the same vaccines.

Exposures  Three primary doses of the diphtheria–tetanus toxoids–acellular pertussis–inactivated poliomyelitis–Haemophilus influenza type b–hepatitis B combination vaccine were given at 2, 3, and 4 months after birth followed by a booster at 11 months and a 10-valent pneumococcal conjugate vaccine at 2, 4, and 11 months after birth.

Main Outcomes and Measures  Primary end points were (1) proportion of preterm infants who achieved IgG antibody against vaccine antigens at concentrations above the internationally defined threshold for protection after the primary series and booster dose and (2) serum IgG geometric mean concentrations after the primary series and booster vaccination. Proportions and geometric mean concentrations were compared in preterm infants and the control group of term infants.

Results  Of 296 preterm infants (56.1% male; mean gestational age, 30 weeks), complete samples before vaccination, 1 month after the primary series, and 1 month after the booster were obtained from 220 preterm infants (74.3%). After the primary series, the proportion of preterm infants across all gestational age groups who achieved protective IgG antibody levels against pertussis toxin, diphtheria, tetanus and 6 of 10 pneumococcal serotypes varied between 83.0% and 100%, Haemophilus influenzae type b between 34.7% and 46.2% (40.6% among all preterm infants overall), and pneumococcal serotypes 4, 6B, 18C, and 23F between 45.8% and 75.1%. After the booster dose, protective antibody levels were achieved in more than 95% of all preterm groups, except for Haemophilus influenzae type b (88.1%). In general, geometric mean concentrations of all vaccine-induced antibodies were significantly lower in all preterm infants vs term infants, except for pertussis toxin and pneumococcal serotypes 4 and 19F after the primary series and booster vaccination.

Conclusions and Relevance  Among preterm infants, administration of routine vaccinations during the first year of life was associated with protective antibody levels against most antigens in the majority of infants after the primary series and booster, except for Haemophilus influenzae type b. However, antibody concentrations were generally lower among preterm infants compared with historical controls.

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Article Information

Corresponding Author: Elsbeth D. M. Rouers, MD, Centre for Infectious Disease Control, National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, the Netherlands (elsbeth.rouers@rivm.nl).

Accepted for Publication: June 24, 2020.

Author Contributions: Dr Rouers had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Bruijning-Verhagen, Sanders, Berbers.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Rouers, Sanders.

Critical revision of the manuscript for important intellectual content: Bruijning-Verhagen, van Gageldonk, van Dongen, Berbers.

Statistical analysis: Rouers, Bruijning-Verhagen.

Obtained funding: Bruijning-Verhagen, Berbers.

Administrative, technical, or material support: van Gageldonk, van Dongen.

Supervision: Bruijning-Verhagen, Sanders, Berbers.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by the Dutch Ministry of Health, Welfare, and Sport.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank all participants and their parents/guardians who made this research possible by participating in this study. We also thank all members of the PRIEMA study group for the help with the recruitment of the preterm infants. We thank all study nurses in the hospitals and clinical staff at the Centre for Infectious Disease Control, Bilthoven, the Netherlands, and the participating hospitals. Members of the PRIEMA study group were Marlies van Houten, MD, Department of Paediatrics, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands; Anne van Kempen, MD, Department of Paediatrics, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands; Obbe Norbuis, MD, Department of Paediatrics, Isala clinics, Zwolle, the Netherlands; Dasja Pajkrt, MD, Department of Paediatrics, Amsterdam Medical Centre, Amsterdam, the Netherlands; Jacqueline van der Sluijs, MD, Department of Paediatrics and Neonatology, Máxima Medical Centre, Veldhoven, the Netherlands; Hans Schipper, MD, Department of Paediatrics, St Antonius Hospital, Nieuwegein, the Netherlands; and Gijs van Well, MD, Department of Paediatrics, Maastricht University Medical Centre, Maastricht, the Netherlands. None of these individuals received compensation for their role in the study.

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