At the 1-year and 2-year follow-up time points for preterm and term infants, pneumococcal OPA geometric mean titers (GMTs) were higher than or similar to those before the toddler dose for all serotypes. Compared with 1 month after the toddler dose, however, OPA GMTs at the 1-year and 2-year follow-up visits in both groups were lower for all serotypes. Formerly preterm infants had statistically significantly lower OPA GMTs at the 1-year follow-up for serotypes 6A, 18C, 19A and 23F and at the 2-year follow-up for serotypes 5 and 19A when compared with GMTs for term infants (Table 3 and Fig., Supplemental Digital Content 3, http://links.lww.com/INF/C607).
Immunogenicity: Preterm Subgroups
In all subgroups at the 1-year and 2-year follow-up time points, GMCs were higher than or similar to those before the toddler dose for all serotypes except serotype 7F (lower than before the toddler dose). GMCs in all subgroups for all serotypes declined from 1 month after the toddler dose to the 1-year follow-up (Table, Supplemental Digital Content 4, http://links.lww.com/INF/C608, which shows pneumococcal IgG GMCs through 2 years after the toddler dose). At both follow-up time points, no discernable patterns were observed in IgG GMCs for any serotype across preterm subgroups based on GA.
For both follow-up time points, OPA GMTs for all serotypes were higher than or similar to those before the toddler dose and lower than GMTs 1 month after the toddler dose. At both follow-up time points, no discernable patterns were observed in OPA GMTs for any serotype across preterm subgroups based on GA (Table, Supplemental Digital Content 5, http://links.lww.com/INF/C609, which shows pneumococcal OPA GMTs through 2 years after the toddler dose).
This study is the first to examine the persistence of immune responses to PCV13 serotypes in preterm and term infants. The vaccination phase of the study demonstrated that preterm infants are able to generate an immune response to PCV13 that is likely to protect against invasive pneumococcal disease. However, IgG GMCs were lower in preterm than term infants for nearly half of the serotypes at all time points. Differences in OPA GMTs between term and preterm infants were not as great, suggesting that despite the quantitative differences observed for IgG antibody, the functionality of the antibody raised by immunization of preterm infants is more closely similar to that of a term infant.10
The lower IgG GMCs observed shortly after vaccination persisted in preterm infants 1 and 2 years after the last vaccine dose. Consistent with the first phase of the study, fewer differences were noted in OPA responses between the study groups at both the 1-year and 2-year follow-ups. These observations suggest comparable retention of functional antibodies in both groups up to 2 years after the toddler dose.
The few studies assessing immunogenicity of PCVs in preterm infants have evaluated mostly PCV7 and have reported inconsistent results, possibly owing to heterogeneity in vaccination schedules and GA of enrolled infants. Two studies including infants with a GA ≥32 weeks identified no differences in PCV7 immune responses between preterm and term infants,1,2 whereas a third study reported comparable proportions of responders above a given antibody concentration threshold in preterm and term infants, except for 1 serotype.3 However, Ruggeberg et al.4 observed significantly lower IgG GMCs in preterm infants 1 month after the toddler dose for 3 serotypes. Similar to that study, the current study also enrolled extremely premature infants (GA: ≥26 weeks) and reported significantly lower pneumococcal IgG GMCs in preterm subjects 1 month after the toddler dose.10
Antibody persistence is an important component of both direct and herd protection.13 However, relatively few studies have evaluated persistence of vaccine immune responses in formerly preterm infants. Antibody persistence has been reported for children up to 7 years of age for antigens in other routine pediatric vaccines, including H. influenzae type b polyribosylribitol phosphate, hepatitis B surface antigen, polio antigens (serotypes 1, 2 and 3), diphtheria toxoid, pertussis antigens (filamentous hemagglutinin, pertactin and pertussis toxoid) and tetanus toxoid. Although antibody levels were frequently lower in formerly preterm infants, continued seroprotection was inferred for those antigens for which minimal protective thresholds have been established.6,14,15
Polysaccharide conjugate vaccines stimulate circulating antibody production and induce anamnestic immune responses.16 A limitation of the current study is the measurement of only circulating antibody and not immune memory. However, the report by Ruggeberg et al.4 in which preterm infants were vaccinated with an infant series of PCV7 followed by a 23-valent pneumococcal polysaccharide vaccine (PPSV23) booster provides clinical evidence that PCV7 establishes immune memory and suggests that PCV13, by extension, is likely to induce immune memory as well. Other studies in term infants provide further evidence for the establishment of immune memory by conjugate pneumococcal vaccines after a booster dose of PPSV2317,18 or PCV13.19 Immune memory responses to natural pneumococcal challenge, although not tested in this study, may also play an important role in assuring protection against disease.
Circulating antibody levels in preterm and term infants fluctuated by serotype between the 1-year and 2-year follow-up time points, which may indicate natural boosting through exposure to circulating pneumococci. Moreover, capsular polysaccharides may stimulate antibody production differently than exposure to the PCV13 conjugate protein at the toddler dose, leading to heterogeneity in serotype-specific IgG levels with time. Heterogeneity in persistence may stem from potential differences in quality and quantity of B cells elicited by intact bacteria compared with pneumococcal conjugate vaccine antigens.20 In a study of infants immunized with the meningococcal serogroup C protein conjugate vaccine (MnC-CRM197), MnC-specific memory B cells and antibody levels after priming correlated with antibody persistence at 1 year of age, suggesting that initial responses predict antibody persistence.21 In addition, the strength of immune responses to pneumococcal antigens may vary with age and serotype.22
Differences between preterm and term infants for certain serotypes may have been less evident 1 month after the toddler dose because of the postbooster spike in antibody concentrations that possibly muted any between-group differences. Differences may only become apparent as antibody levels wane with time. Nevertheless, the antibody concentrations achieved after PCV13 vaccination of preterm infants are protective and similar to those detected in term infants.
A strength of this study is its parallel-group design, which allowed direct comparisons between preterm and term subjects. Moreover, the 2-year follow-up period provided an extended analysis window after vaccination in which to evaluate the persistence of antibody responses in subjects born as early as 26-week gestation. Although circulating antibody concentrations were significantly lower in preterm infants for 7 serotypes, antibody concentrations at the 1- and 2-year follow-ups generally remained higher than those before the toddler dose, and no trends were observed toward decreased antibody concentrations with increasing prematurity. A larger sample size, however, may be necessary to identify significant trends in immune responses based on GA.
Further study of long-term antibody persistence and additional epidemiologic studies are still needed to confirm that antibody persistence correlates with long-term protection against S. pneumoniae by PCV13 vaccination of preterm infants. Because of a lack of expert consensus regarding the threshold of protection for individual pneumococcal serotypes, the current study defined the threshold of protection as the aggregate correlate of protection established by the World Health Organization (IgG concentrations ≥0.35 µg/mL based on prelicensure studies).23 Two studies have evaluated protection based on IgG titers by individual serotype,24,25 but a lack of official guidance regarding which criteria to use prompted the application of the World Health Organization–recommended threshold.
Immune responses elicited by PCV13 in preterm and term infants persisted up to 2 years after the toddler dose, although differences were observed between the 2 groups. Antipneumococcal IgG levels in preterm infants were generally lower than in term infants, but fewer differences in OPA were seen between the groups. A recent study by Voysey et al.26 reported generally higher IgG levels and OPA titers among girls than boys up to 1 year after the toddler dose. The current study was not designed to evaluate immune responses by sex, and while the proportion of female preterm (45%) and term (60%) subjects was slightly different, the majority of subjects in both groups had IgG levels and OPA titers at 1 and 2 years after the toddler dose that are likely to confer protection against vaccine-type pneumococcal disease.
Preterm infants may be at a relative disadvantage when vaccinated in infancy, but generate persistent pneumococcal antibody responses that are functionally comparable to those of term infants. While it might have been possible to identify pneumococcal disease occurring among study participants by virtue of protocol-specified safety reporting requirements, the number of such infections would likely be low. Moreover, determining the etiology of infections among this group of children was not a specific objective of the current study, which was designed to effectively capture antibody responses. However, responses observed in preterm infants are likely to afford protection; this may be confirmed with epidemiologic studies.
Overall, these results emphasize the need for timely vaccination of infants against S. pneumoniae starting at the chronologic age of 2 months, regardless of GA or weight at birth, and reinforce the importance of giving the toddler dose at the earliest possible opportunity. A routine vaccination schedule including a 3-dose primary series followed by a toddler dose at approximately 12 months is likely to offer long-term protection against invasive pneumococcal disease in preterm infants as well as their term infant counterparts.
The authors would like to thank the infants who participated in the study and their families and the clinical staff who assisted each investigator during the study. The authors would also like to thank the other investigators and team members who contributed to the successful conduct and completion of this study, including: Susana Ares and Esperanza Escribano (Hospital La Paz, Madrid, Spain); Enrique Bernaola Iturbe, Maria Concepción Goñi Orayen and Elisabet Burillo-Sanchez (Complejo Hospitalario de Navarra, Pamplona, Spain); Marta Bouzon Alejandro, Maria Lopez Sousa, Olalla Elena Lopez Suarez, Nazareth Martinon Torres and Lorenzo Redondo Collazo (Complejo Hospitalario Universitario de Santiago, A Coruña, Spain); Jose Luis Gomez Llorente (Complejo Hospitalario de Torrecárdenas, Almería, Spain); Aleksandra Matyla-Radzewska (Specjalistyczny ZOZ nad Matka i Dzieckiem Przychodnia Wieku Rozwojowego, Poznań, Poland); Agnieszka Spychalowicz (Hanna Czajka Indywidualna Praktyka Lekarska, Kraków, Poland); Marzena Ambicka-Ciba, Magdalena Orzechowska and Henryk Szymanski (Szpital im Sw Jadwigi Slaskiej Oddzial Dzieciecy, Trzebnica, Poland); Tomasz Czerniak, Agnieszka Jalowska, Julia Seniuta, Kinga Sikorska-Socha, Karolina Szel-Bernach, Zofia Szymanska-Toczek, Izabela Zaleska and Kamila Zyzak (Samodzielny Publiczny Szpital Kliniczny nr 1 we Wroclawiu, Wroclaw, Poland); Oscar Blanco Barca, Eva Gonzalez Colmenero and Maria Suarez Albo (Complexo Hospitalario Xeral Cies, Pontevedra, Spain); Maria Isabel Gonzalez Tome, Pablo Rojo Conejo, Jesus Ruiz Contreras and Maria Jose Torres Valdivieso (Hospital 12 de Octubre, Madrid, Spain); Jerzy Pejcz (Hospital Swietej Jadwigi Slaskiej, Trzebnica, Poland) and Natacha Ledren-Narayanin, Katarzyna Juszczak and Enrique Ramos (Pfizer Inc).
1. Shinefield H, Black S, Ray P, et alEfficacy, immunogenicity
and safety of heptavalent pneumococcal conjugate vaccine
in low birth weight and preterm infants
.Pediatr Infect Dis J200221182–186
2. Esposito S, Pugni L, Bosis S, et alImmunogenicity, safety and tolerability of heptavalent pneumococcal conjugate vaccine
administered at 3, 5 and 11 months post-natally to pre- and full-term infants.Vaccine2005231703–1708
3. Moss SJ, Fenton AC, Toomey JA, et alResponses to a conjugate pneumococcal vaccine in preterm infants
immunized at 2, 3, and 4 months of age.Clin Vaccine Immunol2010171810–1816
4. Ruggeberg JU, Collins C, Clarke P, et alImmunogenicity and induction of immunological memory of the heptavalent pneumococcal conjugate vaccine
in preterm UK infants.Vaccine200725264–271
5. Omeñaca F, Garcia-Sicilia J, García-Corbeira P, et alResponse of preterm newborns to immunization
with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio and Haemophilus influenzae
type b vaccine: first experiences and solutions to a serious and sensitive issue.Pediatrics20051161292–1298
6. Omeñaca F, Garcia-Sicilia J, Boceta R, et alAntibody persistence and booster vaccination during the second and fifth years of life in a cohort of children who were born prematurely.Pediatr Infect Dis J200726824–829
7. Bonhoeffer J, Siegrist CA, Heath PTImmunisation of premature infants.Arch Dis Child200691929–935
8. Omeñaca F, Merino JM, Tejedor JC, et alImmunization of preterm infants
with 10-valent pneumococcal conjugate vaccine
9. Trück J, Pollard AJChallenges in immunisation against bacterial infection in children.Early Hum Dev201086695–701
10. Martinón-Torres F, Czajka H, Center KJ, et al13-valent pneumococcal conjugate vaccine
(PCV13) in preterm versus term infants.Pediatrics2015135e876–e886
12. Chan IS, Zhang ZTest-based exact confidence intervals for the difference of two binomial proportions.Biometrics1999551202–1209
13. Isaacman DJ, Fletcher MA, Fritzell B, et alIndirect effects associated with widespread vaccination of infants with heptavalent pneumococcal conjugate vaccine
14. Kirmani KI, Lofthus G, Pichichero ME, et alSeven-year follow-up of vaccine response in extremely premature infants.Pediatrics2002109498–504
15. Esposito S, Faldella G, Giammanco A, et alLong-term pertussis-specific immune responses to a combined diphtheria, tetanus, tricomponent acellular pertussis and hepatitis B vaccine in pre-term infants.Vaccine2002202928–2932
16. O’Brien KL, Steinhoff MC, Edwards K, et alImmunologic priming of young children by pneumococcal glycoprotein conjugate, but not polysaccharide, vaccines.Pediatr Infect Dis J199615425–430
17. Russell FM, Carapetis JR, Balloch A, et alHyporesponsiveness to re-challenge dose following pneumococcal polysaccharide vaccine at 12 months of age, a randomized controlled trial.Vaccine2010283341–3349
18. Sigurdardottir ST, Davidsdottir K, Arason VA, et alSafety and immunogenicity
of CRM197-conjugated pneumococcal-meningococcal C combination vaccine (9vPnC-MnCC) whether given in two or three primary doses.Vaccine2008264178–4186
19. Sigurdardottir ST, Center KJ, Davidsdottir K, et alDecreased immune response to pneumococcal conjugate vaccine
after 23-valent pneumococcal polysaccharide vaccine in children.Vaccine201432417–424
20. Snapper CMDifferential regulation of polysaccharide-specific antibody responses to isolated polysaccharides, conjugate vaccines, and intact Gram-positive versus Gram-negative extracellular bacteria.Vaccine2016343542–3548
21. Blanchard Rohner G, Snape MD, Kelly DF, et alThe magnitude of the antibody and memory B cell responses during priming with a protein-polysaccharide conjugate vaccine in human infants is associated with the persistence of antibody and the intensity of booster response.J Immunol20081802165–2173
22. Laferriere CThe immunogenicity
of pneumococcal polysaccharides in infants and children: a meta-regression.Vaccine2011296838–6847
24. Trück J, Snape MD, Tatangeli F, et alPneumococcal serotype-specific antibodies persist through early childhood after infant immunization
: follow-up from a randomized controlled trial.PLoS One20149e91413
25. Andrews NJ, Waight PA, Burbidge P, et alSerotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine
: a postlicensure indirect cohort study.Lancet Infect Dis201414839–846
26. Voysey M, Barker CI, Snape MD, et alSex-dependent immune responses to infant vaccination: an individual participant data meta-analysis of antibody and memory B cells.Vaccine2016341657–1664
preterm infants; pneumococcal conjugate vaccine; immunization; immunogenicity
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