We have shown that infants ≤1000 grams birth weight, when compared with larger premature infants, have similar antibody responses to most, but not all, PCV-7 vaccine serotypes. Postnatal glucocorticoid exposure, lower weight at blood drawing and Caucasian race were also risk factors for lower antibody concentrations to serotypes 6B and/or 23F, which appeared to have the poorest immunogenicity overall.
The efficacy and immunogenicity of PCV-7 have been tested previously in larger premature infants. As part of an efficacy study, in which PCV-7 was administered at 2, 4 and 6 months, some 4340 premature infants (born at <38 weeks gestation) and 1756 LBW infants (<2500 grams) were evaluated.3
The vaccine had 100% efficacy in those populations. However, only 167 infants <32 weeks and 131 VLBW infants were included, and the immunogenicity of PCV-7 in these infants was incompletely addressed. In a study of 46 infants born at 32–36 weeks gestation and given PCV-7 at 3, 5 and 11 months of age, premature infants had antibody concentrations equivalent to the concentrations of full term infants following the third vaccine dose.21
All premature infants in that study achieved concentrations ≥0.15 µg/mL against all 7 vaccine antigens after 3 doses of vaccine, but that small study did not include extremely preterm infants. In a recent study of a population more similar to ours, 69 premature infants, of whom 42 were <32 weeks gestation at birth, and 68 full-term controls received PCV-7 at 2, 3 and 4 months of age.22
Lower proportions of premature infants had concentrations ≥0.35 µg/mL against serotypes 4, 6B and 9V than full-term controls following the primary vaccine series, although both premature and full-term infants responded similarly to a polysaccharide pneumococcal vaccine booster at 12 months old.
Studies of full-term infants receiving PCV-7, regardless of schedule, describe greater than 90% of infants achieving concentrations ≥0.15 – 0.2 µg/mL against each vaccine serotype.17, 22
Greater than 90% of full-term infants receiving PCV-7 on an accelerated 2, 3 and 4 month schedule achieve concentrations ≥0.35 µg/mL against all serotypes except 6B (to which 79% achieve these concentrations).22
Full-term infants receiving PCV-7 on a 2, 4, and 6 month schedule achieve concentrations ≥1.0 µg/mL in proportions ranging from 51% (serotype 9V) to 89% (serotype 14), in a pattern similar to that seen among even the most immature infants in the current study.17
The current study complements previous studies in suggesting that, under circumstances predisposing to reduced vaccine immunogenicity (e.g. less immunogenic serotypes or accelerated vaccine schedules), PCV-7 may be less immunogenic in ELBW (<1000 grams birth weight) infants. As antibody concentrations decay over time, lower concentrations may become clinically significant prior to a booster dose of vaccine.21, 22
The finding in our population of an independent effect of postnatal glucocorticoid administration on the immunogenicity of serotype 6B in premature infants agrees with findings for several other vaccines.23–25
Contrary to the findings of others regarding Hib vaccine,9, 10
glucocorticoid administration, rather than the presence of BPD for which glucocorticoids were administered, appeared in our study to be more strongly associated with poor vaccine immunogenicity. We recognize the possibility that receipt of postnatal glucocorticoids could be a marker for severe BPD; our analysis did not consider severity of BPD.
Other authors have reported an elevated risk of local vaccine reactions in premature or low-birth-weight infants receiving PCV-7.3
We did not analyze local reactions, but found a low incidence (<1%) of fever >40°C in our vaccine recipients. Others have reported a 2.3% incidence of temperature >39°C following PCV-7 in premature infants.3
Similarly, apnea or other respiratory compromise has been reported following several types of vaccines in hospitalized premature infants.6, 26–31
In a preliminary report, Sumner described a 17% incidence of recurrent apnea within 72 hours after PCV-7 in hospitalized VLBW infants who had had no apnea in the 3 days preceding immunization.32
Among our hospitalized infants, a lower proportion (4%) suffered recurrent episodes of apnea following PCV-7, although our study used a more restrictive definition of recurrent apnea. We detected no incidents of post-vaccine apnea in non-hospitalized subjects, although our surveillance for this event was less comprehensive than for in-hospital apnea. Our data support apnea monitoring of hospitalized infants receiving PCV-7 and provide some limited reassurance about apnea in non-hospitalized infants.
Our study was designed to measure PCV-7 immunogenicity over a range of birth weights in VLBW, premature infants only, without the use of a full-term control group. This limits comparisons to historic data on full-term infants from other studies, which may have used differing methodologies. When the current study was designed, agreement was lacking on a meaningful antibody concentration associated with protection from pneumococcal disease, and a concentration of 0.15 µg/mL was used to generate hypotheses. Since that time, a reference antibody concentration of 0.35 µg/mL, based on meta-analysis of major trials, has been established by the World Health Organization.19
The findings of the current study remained consistent using antibody cutoffs ranging from 0.15 µg/mL to 1.0 µg/mL, including 0.35 µg/mL. With the exception of a few infants with low antibody concentrations whose parents desired repeat testing at 12–15 months, we did not measure antibody concentrations following the booster dose of vaccine. This limited our ability to assess responses to the 4th
dose of vaccine, which may be important for long-term protection.22
In summary, in this study of PCV-7 immunogenicity among VLBW infants, even the smallest and least mature infants usually achieved antibody concentrations similar to those described in full-term infants. The favorable immunogenicity of PCV-7 among VLBW infants supports current recommendations to immunize premature infants at the same postnatal ages as full-term infants. In keeping with our hypothesis, however, lower birth weight appeared to be an independent risk factor for poorer vaccine immunogenicity, especially for less immunogenic serotypes. It may be particularly important to offer a timely booster dose of PCV-7 to infants who have multiple risk factors (extremely low birth weight, postnatal glucocorticoid exposure, poor weight gain and/or Caucasian race) for poorer vaccine immunogenicity.