A range of schedules are recommended for hepatitis B vaccination of premature infants. This open-label study (217744/083) compared the immune response of premature (
Infection with hepatitis B virus (HBV) persists as a worldwide public health problem, with vertical transmission of HBV being responsible for approximately one third of all new cases of hepatitis B. Childhood hepatitis B immunisation has significantly reduced the incidence and prevalence of HBV infection [
The number of infants born prematurely has risen in the last 15 years, and recent advances in the care of premature infants have substantially increased their survival rates [
Concern among parents and paediatricians about the number of injections required during each immunisation visit has contributed to the observation that routine paediatric vaccination is often delayed in preterm infants [
We have previously shown preterm infants less than 37 weeks of gestational age to display satisfactory immune response to all component antigens of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-
This was an open-label study with two parallel groups: preterm subjects (
Preterm subjects were stratified according to clinical characteristics including length of gestation, birth weight, pre- and postnatal steroid use, need for red blood cell transfusion, and weight at 6 months. Length of gestation was determined by date of the last menstrual period and/or early ultrasound scan and subsequently confirmed by neonatal examination. Exclusion criteria comprised major congenital defects or serious chronic illnesses, severe neurologic damage or nontreatable convulsions; known or suspected immune dysfunction, HIV positive or hepatitis B surface antigen (HBsAg) positive mother, acute disease or rectal temperature
All subjects were primed with a DTPa-HBV-IPV/Hib vaccine [
Each dose of DTPa-HBV-IPV/Hib vaccine contained
For infants not responding to primary and booster doses (anti-HBs
Blood samples were drawn before the first dose and one month after the third in primary course and before and one month after the booster dose. Serum samples were stored at
Statistical analysis of the immunogenicity results was performed on the according-to-protocol (ATP) cohort. Seroprotection rates and antibody geometric mean concentrations (GMCs) were calculated with exact 95% confidence intervals (CI) at each time point. Differences in seroprotection rates between the preterm and full-term groups were compared using Fisher’s exact test.
A total of 186 infants were enrolled (94 preterm and 92 full-term), of whom 93 and 89 infants, respectively complied with the criteria for inclusion in the ATP cohort for analysis of immunogenicity of the primary vaccination course. The demographic and neonatal characteristics of the infants have been previously described [
Of the 155 infants who received booster doses, 152 subjects were included in the ATP cohort for analysis of immunogenicity of the booster dose (84 prematurely born subjects and 68 full-term subjects). Mean age at the time of booster vaccination was 18.2
The mean immunogenicity data after primary course and before and after booster dose are included in Table
Anti- HBs seroprotection rates and GMCs in preterm and full-term infants one month after the primary course and before and after the booster dose (ATP cohort for immunogenicity).
Seroprotection | GMC | |||||
% | 95% CI | mIU/ml | 95% CI | |||
Postprimary | ||||||
Preterm | 91 | 85 | 93.4 | 86.2–97.5 | 634.1 | 433.8–927.0 |
Full-term | 84 | 80 | 95.2 | 88.3–98.7 | 867.1 | 576.6–1303.9 |
Prebooster | ||||||
Preterm | 84 | 63 | 75.0 | 64.4–83.8 | 56.8 | 39.6–81.4 |
Full-term | 67 | 54 | 80.6 | 69.1–89.2 | 58.1 | 39.1–86.3 |
Postbooster | ||||||
Preterm | 83 | 76 | 91.6 | 83.4–96.5 | 1771.0 | 1060.3–2958.1 |
Full-term | 68 | 67 | 98.5 | 92.1–100.0 | 1965.0 | 1180.1–3272.0 |
The immunogenicity results by gestational age are shown in Table
Anti-HBs seroprotection rates (SR) and geometric mean concentrations (GMC) by subgroup of preterm infants after primary course and booster dose (ATP cohort for immunogenicity).
Seroprotection | GMC | |||||
Gestational age (weeks) | % | 95% CI | mIU/ml | 95% CI | ||
Primary course | ||||||
34–36 | 27 | 25 | 92.6 | 75.7–99.1 | 955.9 | 461.1–1981.8 |
31–33 | 24 | 20 | 83.3 | 62.6–95.3 | 418.0 | 153.7–1136.4 |
28–30 | 20 | 20 | 100 | 83.2–100 | 1044.5 | 633.9–1721 |
24–27 | 20 | 20 | 100 | 83.2–100 | 364.8 | 184.5–721.5 |
Booster dose | ||||||
34–36 | 24 | 22 | 91.7 | 73.0–99.0 | 2389.1 | 919.4–6207.9 |
31–33 | 23 | 18 | 78.3 | 56.3–92.5 | 1127.2 | 262.2–4845.2 |
28–30 | 18 | 18 | 100 | 81.5–100 | 3555.9 | 1881.1–6721.8 |
24–27 | 18 | 18 | 100 | 81.5–100 | 1054.0 | 508.6–2184.2 |
A nonconsistent response was also seen in the analysis according to birth weight (Table
Post-primary anti-HBs seroprotection rates and GMCs by birth weight (ATP cohort for immunogenicity).
Seroprotection | GMC | |||||
Birth weight (kg) | % | 95% CI | mIU/ml | 95% CI | ||
17 | 14 | 82.4 | 156.6–96.2 | 493.9 | 147.2–1657.0 | |
23 | 22 | 95.7 | 78.1– 99.9 | 933.8 | 418.8–2081.8 | |
26 | 26 | 100 | 86.8–100 | 1294.5 | 882.5–1898.6 | |
25 | 23 | 92.0 | 74.0–99.0 | 250.7 | 122.0–515.1 |
Post-primary anti-HBs seroprotection rates and GMCs were numerically lower in the nine subjects who had received postnatal steroids (88.9% and 188.1, resp.) than the 81 subjects who had not received them (93.9% and 724.6, resp.), but the differences were not significant.
Blood transfusion during the neonatal period did not significantly affect seroprotection rates (anti-HBs
Considering weight at 2 and 6 months as a variable independent of gestational age and birth weight, no significant patterns of differences were observed in seroprotection rates (Table
Post-primary anti-HBs seroprotection rates and GMCs by weight at vaccination and percentile weight at six months (ATP cohort for immunogenicity).
Seroprotection | GMC | |||||
% | 95% CI | mIU/ml | 95% CI | |||
Weight at first vaccination (kg) | ||||||
19 | 16 | 84.2 | 60.4–96.6 | 617.4 | 206.8–1843.8 | |
26 | 25 | 96.2 | 80.4–99.9 | 984.0 | 479.0–2021.6 | |
26 | 26 | 100 | 86.8–100 | 972.6 | 589.2–1605.3 | |
20 | 18 | 90.0 | 68.3–98.8 | 210.7 | 95.4–465.2 | |
Percentile weight at six months | ||||||
29 | 27 | 93.1 | 77.2–99.2 | 1140.8 | 577.6–2253.1 | |
21 | 20 | 95.2 | 76.2–99.9 | 353.7 | 150.8–829.4 | |
14 | 13 | 92.9 | 66.1–99.8 | 561.4 | 205.7–1532.4 | |
27 | 25 | 92.6 | 75.7–99.1 | 566.2 | 280.0–1144.7 |
Before the booster dose, both the seroprotection rates of anti-HBs GMCs were low in both the pre- and full-term groups (Table
Six preterm infants (6.59%) did not respond to primary immunisation and also failed to respond to the booster dose (anti-HBs
Anti-HBs concentrations (mIU/ml) after all HBV doses in subjects who were non-responders to hepatitis B at the end of the primary and booster studies.
Post Extra HBV | HBV | ||||||||||||
Gestational age (Weeks) | Birth weight (kg) | Percentile at birth | Weight at 1st vaccination (kg) | Percentile at 6 months | Weight at 6 months (kg) | Pre-primary | Post-primary | Pre-booster | Post-booster | Dose 1 | Dose 2 | Dose 3 | Persistence at 4 years (mIU/ml) |
33 | 2.1 | 75 | 4.4 | 95 | 8.3 | 690 | 3485 | NG | 176 | ||||
35 | 2.0 | 25 | 4 | 25 | 6.7 | 32 | 128 | ||||||
32 | 0.6 | 1.7 | 4.4 | 141 | NG | 64 | |||||||
31 | 0.8 | 1.7 | 10 | 5.1 | 97 | NA | NG | ||||||
33 | 2.0 | 50 | 4.3 | >90 | 8.4 | ||||||||
35 | 1.7 | 10 | 3.6 | 50 | 6.6 | 1087 | NG | NA |
NA = Not available; NG = Not given.
One infant responded to the 5th HBV dose, two to the 6th, and one to the 7th. Two babies (2.19%) never responded. One was an infant with IUGR who had anti-HBs antibodies before vaccination and the other although born prematurely at 33 weeks weighed 2000 g and did not have risk factors. These 6 infants did show a good response to the other antigens included in the DTPa-HBV-IPV/Hib vaccine.
The American Academy of Pediatrics (AAP) recommends that all infants receive hepatitis B vaccine at birth or before discharge from the hospital. In infants weighing less than 2000 g and born to HbsAg negative mothers, the first dose of hepatitis B vaccine is recommended at 30 days [
Immunogenicity studies indicate that premature children generally respond less well to hepatitis B vaccination than full-term infants, both in terms of seroprotection rates [
Analysis according to birth weight in premature infants has suggested a relationship between reduced immunological response and low birth weight [
Gestational age seems to be a much more objective parameter than weight for assessing immune response in premature babies. After birth dosing, both seroprotection rates and GMCs are generally lower in babies with a reduced gestational age [
Our findings strengthen the notion that the immunological response in premature babies depends on postnatal age of vaccination and not on birth weight or gestational age. Indeed, studies in term infants have demonstrated that very young infants (up to 2 months) achieve lower GMCs after three doses of hepatitis B vaccine compared to infants who are at least 3 months of age at the time of first vaccination [
Low-birth weight has been reported to be associated with an inadequate immune response to early hepatitis B vaccination in premature infants by some workers [
Other factors linked to nonresponse to hepatitis B vaccination in premature babies include hyperbilirubinaemia [
We found no differences in immune response in the infants with either IUGR, or in the different groups stratified according to percentile weight at 6 months, consistent with previous findings [
Three doses of HB vaccines are generally recommended in preterm babies, although 4 doses have been suggested [
Few authors have studied the persistence of anti-HBs in premature infants; however, Kesler et al. [
Many long-term studies of infants indicate that immunisation against hepatitis B induces both antibody-producing-cells and memory cells, and the rapid development of anamnestic responses [
In summary, preterm babies born to HBsAg-negative mothers and vaccinated with a hexavalent DTPa-HBV-IPV/Hib vaccine at 2, 4, and 6 months responded well immunologically and similarly to children born at full term. The response in terms of seroprotection rates was not influenced either by gestational age or birth weight, and these findings strengthen the notion that the immunological response in premature babies depends on postnatal age and not on birth weight or gestational age. Six infants, all with a gestation age above 31 weeks, did not respond, but we did not find any associated risk factors, other than severe intrauterine malnutrition in two babies. After a further vaccination cycle, only 2 remained “true” non-responders. The vaccination schedule used here for preterm babies born to HBsAg-negative mothers offers a single schedule for all infants, with fewer injections and better acceptance.
The authors would like to thank the parents and children who participated in the study and the study nurses M