A randomized clinical trial evaluating three dosing strategies for 13-valent pneumococcal vaccine (PCV13) in preterm infants found that more widely spaced priming vaccinations resulted in higher immunoglobulin G (IgG) during the first 12 months of life, but reduced the immune response seen after the 12-month booster was given.
After the primary schedule, the percent of infants lacking seroprotection for more than one half of the serotypes in the PCV13 formulation was 25% on a reduced two-dose schedule, 12% on an accelerated schedule, and 3% on an extended schedule (P less than .001).
Conversely, “A reduced priming schedule of PCV13 resulted in higher post-booster IgG concentrations but lower post-primary concentrations,” wrote Alison Kent, MBChB, and her coinvestigators in the PUNS (Prems Under New Schedule) Study Group (Pediatrics. 2016;138[3]:e20153945).
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“Infants who received the extended schedule had lower fold increases in concentrations after booster vaccination than the other groups,” wrote Dr. Kent of the Pediatric Infectious Diseases Research Group and Vaccine Institute, St. George’s, University of London, and her collaborators. Participants receiving the extended schedule had lower geometric mean concentrations (GMCs) of antibodies than did those on the reduced schedule for nine serotypes and those on the accelerated schedule for four serotypes.
The study enrolled 210 premature infants in a phase IV, controlled, open-label trial at 12 sites in the United Kingdom. Infants of less than 35 weeks gestation, and between 7 and 12 weeks of age, were randomly assigned to receive PCV13 on one of three schedules. The reduced schedule gave two priming doses at 2 and 4 months of age; the accelerated schedule gave the doses at 2, 3, and 4 months of age; and the extended schedule gave doses at 2, 4, and 6 months of age. All infants received a booster vaccination at 12 or 13 months of age, and all received a standard suite of childhood immunizations for other diseases. The entire study was completed by 194 patients.
Serotype-specific IgG concentrations were obtained pre-vaccination, 1 month after the primary vaccination, and before and 1 month after the booster vaccination was given. IgG levels were reported for each PCV serotype; “there was considerable variation between serotypes,” ranging from 0.16 ng/mL for serotype 6b on the reduced schedule to 8.49 ng/mL for serotype 14 on the extended schedule, the investigators said.
Dr. Kent and her collaborators also used logistic regression analysis to explore how the vaccine’s effectiveness was affected by a number of factors. These included gestational length, the receipt of blood transfusions or pre- or post-natal steroids, BCG vaccination, early postvaccination acetaminophen, and the presence of chronic lung disease.
Later gestation was associated with increased seroprotection for four serotypes at 2 months of age, and with an increase in post-primary vaccination IgG concentrations for three others (P-values ranging from P less than .001 to P = .021).
No other factors were associated with protective IgG levels at any point, except that receipt of prenatal steroids had a negative association with seroprotection for several serotypes. “At no time points were antenatal steroids associated with higher antibody concentrations,” wrote the investigators.
Most studies of immunogenicity of infant vaccination schedules have been completed using term infants, with limited knowledge about efficacy in preterm infants. Previous work had shown that preterm infants had lower IgG concentrations after the primary and booster vaccinations for eight serotypes of PCV, compared with term infants. “The lower immunogenicity ... is concerning because premature infants are also less likely to benefit from the protective maternal antibodies transferred during late pregnancy,” Dr. Kent and her coauthors wrote.
The lower booster immunogenicity after the extended schedule is an effect that has been previously observed with other vaccinations and may be related to the formation of immune complexes with previously existing antibodies with the vaccine antigen, said Dr. Kent and her coauthors. The variation in immunogenicity timing for the various priming schedules, they said, will be helpful for those caring for preterm infants, enabling them “to consider this finding in the context of their own immunization programs and epidemiologic situations.”
The study was funded by Pfizer as an investigator-led study, without Pfizer’s input on the conduct of the trial, analysis of data, interpretation of results, or the preparation of this manuscript. Pfizer manufactures Prevnar 13.
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