Hepatitis B virus (HBV) infection is a significant health concern worldwide. Approximately 240 million people are infected with HBV,1 and 100 million are infected in Southeast Asia, accounting for approximately 5.6% of the total population.2 In Thailand, the prevalence of chronic HBV infection was approximately 4% in the population born before 1992 and decreased to 0.6% (2–3 million patients) after the HBV vaccine was implemented in the Thai expanded program on immunization (EPI).3,4 HBV infection can be effectively prevented by vaccination. HBV vaccines are usually combined with diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b vaccines. This has made vaccination more feasible for the prevention of these diseases. Currently, the HBV vaccines contained in combined vaccines are considered highly immunogenic.5,6 The combined HBV-containing vaccine currently used in the Thai EPI is a pentavalent vaccine consisting of diphtheria, tetanus, whole cell pertussis, HBV and Haemophilus influenzae type b vaccines (DTwP-HBV-Hib).7 Hexavalent vaccines consisting of diphtheria, tetanus, acellular pertussis, inactivated polio, HBV and Haemophilus influenzae type b vaccine (DTaP-IPV-HBV-Hib) are not included in Thai EPI and are available as alternative vaccines. Previous studies comparing Hepatitis B surface antibody (anti-HBs) levels between receiving 3 doses of each combined vaccine formula revealed that vaccination with these vaccines could lead to a protective level of anti-HBs antibody (≥10 mIU/mL) in more than 90% of infants who completed the primary vaccination series.6 Some studies have shown that HBV vaccination using 3 doses of DTaP-IPV-HB-Hib vaccines yielded higher anti-HBs antibody levels than vaccination using 3 doses of pentavalent vaccines.8,9 One study showed that high anti-HBs antibody levels correlate with higher anti-HBs antibody levels after a booster dose.10 In addition, the other one demonstrated that higher anti-HBs antibody levels after the primary series of HBV vaccination had more probability of anti-HBs antibody level persistence at 12 years after the vaccination.11 These imply that higher anti-HBs antibody levels after HBV vaccination in the primary series would reflect a higher probability of long-term persistence of positive anti-HBs antibody levels. Currently, for infants aged 0–6 months, the Thai EPI offers a BCG vaccine and a monovalent HBV vaccine at birth, followed by 3 doses of DTwP-HBV-Hib at the ages of 2, 4 and 6 months (a pentavalent regimen), 2 or 3 doses of rota vaccines, 1 dose of IPV at the ages of 4 months and 3 doses of oral polio vaccine (OPV) at the ages of 2, 4 and 6 months. Pneumococcal conjugated vaccines at these ages have not yet been included in Thai EPI. The pentavalent vaccination regimen may lead to lower levels of anti-HBs antibodies in most Thai children compared with those who receive hexavalent HBV-containing vaccines6; however, whether substituting 1 dose with DTaP-IPV-HBV-Hib vaccine in the pentavalent regimen to achieve higher anti-HBs antibody levels is still unknown. We hypothesized that substituting the DTaP-IPV-HBV-Hib vaccine for 1 dose could lead to higher anti-HBs antibody levels. Therefore, the primary objective of this study was to compare anti-HBs antibody levels between infants receiving 1 dose of DTaP-IPV-HBV-Hib vaccines followed by 2 doses of DTwP-HBV-Hib vaccines and those receiving three doses of DTwP-HBV-Hib vaccines in the primary series of HBV vaccination.
METHODS
Study Design
An open-label randomized controlled trial was conducted at the Department of Pediatrics, Ramathibodi Hospital, Mahidol University, between March 2022 and April 2023. Infants (born at a gestational age >36 weeks) aged 30–120 days who received a monovalent HBV vaccine at birth were enrolled. Infants born to HIV- or HBV-infected mothers and those with coagulopathy were excluded. The participants were randomized by block randomization into 2 groups: a combined hexavalent/pentavalent group and a 3-dose pentavalent group. The combined hexavalent/pentavalent group received the DTaP-IPV-HBV-Hib vaccine, whereas the 3-dose pentavalent group received the DTwP-HBV-Hib vaccine and an OPV at the age of 2 months. Both groups received the DTwP-HBV-Hib vaccine, standalone IPV and OPV at 4 and 6 months. The 3-dose pentavalent group was in accordance with the Thai EPI program.
The primary objective was to compare the anti-HBs antibody levels between these 2 groups 3–6 months after the last dose of vaccination. The secondary objective was to compare adverse events after vaccination in these 2 groups. Adverse events were reported by phone on the seventh day after vaccination. Adverse events included fever, irritability, loss of appetite, pain or swelling at the injection site. Severe adverse events were defined as those that led to death, life-threatening events or hospitalization. In addition, factors associated with higher anti-HBs levels were also assessed, including sex, other co-administered vaccines, receiving breast milk and body weight status. This study was approved by the ethical committee of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University (MURA2022/287).
Study Vaccines
Pentavalent vaccine (DTwP-HBV-Hib; Eupenta, LG Chem; Seoul, South Korea) and hexavalent vaccine (DTaP-IPV-HBV-Hib; Infanrix-Hexa, GlaxoSmithKline, Mississauga, Canada) were used in this study. According to the group assigned, the participants received 0.5 ml of the vaccines intramuscularly at 2, 4 and 6 months of age. The components of each vaccine are listed in Table, Supplemental Digital Content 1, https://links.lww.com/INF/F600. Concomitant pneumococcal conjugated vaccination (either with Prevnar, Pfizer, Bruxelles, Belgium or Synflorix, GlaxoSmithKline; Ontario, Canada) at 2-, 4- and 6-month-old and administration of seasonal influenza vaccine were at the discretion of parents.
Determination of Anti-HBs Antibody Level
Blood collected from the participants was subjected to anti-HBs antibody levels. The anti-HBs antibody was analyzed using a chemiluminescent microparticle immune assay (Alinity I anti-HBs microparticles, Abbott Laboratory, Wiesbaden, Germany). The anti-HBs antibody level ≥10 mIU/mL was defined as seroprotective, and the level <10 mIU/mL was defined as nonseroprotective. The anti-HBs antibody level is reported as the geometric mean titer (GMT).
Statistical Analysis
The data were analyzed using per-protocol and intention-to-treat analyses. STATA version 17 (STATA Corp, College Station, TX, USA) was used for all the statistical analyses. Categorical data are expressed as frequencies and percentages, and continuous data as mean [95% confidence interval (CI)] or median with interquartile range (IQR) if the data were normally distributed or not normally distributed, respectively. The groups were compared using the χ2 test for categorical data and Student’s t test or Mann–Whitney U test for continuous data. Univariate analysis, followed by forward stepwise selection linear regression analysis, was performed to identify independent variables associated with anti-HBs antibody levels. Factors with a P value <0.05 in the univariate analysis were selected to fit a model in the multivariate analysis. Statistical significance was set at P < 0.05.
RESULTS
Demographic Characteristics of the Study Population
The flow diagram of the enrolled participants is shown in Figure 1. Seventy-six participants were enrolled, with 38 participants in each group. The demographic characteristics of the 2 groups are shown in Table 1. The final number of participants in each group after exclusion was 33 in 3-dose pentavalent groups and 31 in the combined hexavalent/pentavalent group.
TABLE 1. - Demographic Data of Enrolled Patients
| Characteristics | Combined Hexavalent/Pentavalent Group (n = 31) | 3-dose Pentavalent Group (n = 33) |
|---|---|---|
| Sex; n (%) Male Female | 16 (51.6) 15 (48.4) | 15 (45.5) 18 (54.5) |
| Gestational, week* | 38.7 | 38.4 |
| Birth weight, gram SGA AGA | 1 (3.2) 30 (96.8) | 2 (6) 31 (94) |
| Weight below 10th percentile at any visit, n (%) | 4 (12.9) | 3 (9) |
| Receiving concomitant pneumococcal vaccine, n (%) | 10 (32.3) | 13 (39.4) |
| Receiving Influenza vaccine, n (%) | 2 (6.5) | 5 (15.2) |
| Hct at blood drawn, %† | 34.7 (33.8–35.8) | 34.3 (33.5–35.2) |
| Anemia, n (%) | 7 (22.6) | 8 (24.2) |
| Breast milk feeding, n (%) | 5 (16.1) | 12 (36.4) |
| Age at first dose of vaccination, months† | 2.22 (2.2–2.3) | 2.24 (2.2–2.3) |
| Age at last dose of vaccination, months† | 6.3 (6.2–6.5) | 6.22 (6.1–6.3) |
| Age at blood drawn, month† | 9.6 (9.2–10) | 9.62 (9.3–10) |
| Time between first vaccination and blood drawn, months† | 6.24 (5.7–6.8) | 5.84 (5.3–6.3) |
AGA indicates appropriate for gestational age; Hct, hematocrit; SGA, small for gestational age. *Data are presented as mean (95% confidence interval). †Data are presented as median (IQR).
Anti-HBs Antibody Levels
The anti-HBs antibody levels in each group of participants are summarized in Table 2. In this study, both intention-to-treat and per-protocol analyses were conducted.
TABLE 2. - Anti-HBs Antibody Levels in Each Group of Patients
| Anti-HBs (mIU/mL) | Per-protocol Analysis | ||
|---|---|---|---|
| Combined Hexavalent/Pentavalent Group (n = 22) | 3-dose Pentavalent Group (n = 32) | P value | |
| Absolute level* | 468.75 (210.26–714.27) | 116.24 (42.32–343.3) | 0.03 |
| GMT† | 251.2 (114.8–549.5) | 75.9 (36.3–158.5) | 0.007 |
| <10, n (%) | 1 (4.5) | 5 (16) | 0.203 |
| 10–100, n (%) | 4 (18.2) | 11 (34.4) | 0.192 |
| >100, n (%) | 17 (77.2) | 16 (50) | 0.043 |
| Anti-HBs (mIU/mL) | Intention-to-treat Analysis | ||
| Combined Hexavalent/Pentavalent Group (n = 31) | 3-dose Pentavalent Group (n = 33) | P value | |
| Absolute level* | 418.7 (210.26–1000) | 135.84 (50.94–367.07) | 0.002 |
| GMT† | 316.2 (173.8–575.4) | 81.3 (38.9–169.8) | 0.006 |
| <10, n (%) | 1 (3.2) | 5 (15) | 0.102 |
| 10–100, n (%) | 4 (13) | 11 (33.3) | 0.054 |
| >100, n (%) | 26 (83.9) | 17 (51.5) | 0.006 |
*Data are presented as the median (IQR). †Data are presented as mean (95%CI). GMT, geometric mean titer.
Intention-to-treat Analysis
There were 31 and 33 participants in the combined hexavalent/pentavalent groups and 3-dose pentavalent groups, respectively. There was a significant difference in the GMT of anti-HBs antibody levels in the combined hexavalent/pentavalent and the 3-dose pentavalent groups [316.2 mIU/mL (95% CI: 173.8–575.4 mIU/mL) versus 81.3 mIU/mL (95% CI: 38.9–169.8 mIU/mL), P = 0.006]. In the combined hexavalent/pentavalent group, the proportion of participants with anti-HBs antibody levels higher than 100 mIU/mL (26/31 participants; 83.9%) was significantly higher than that in the 3-dose pentavalent group (17/33 participants; 51.5%) (P = 0.006).
Regarding the factors affecting anti-HBs antibody levels (see Table, Supplemental Digital Content 2, https://links.lww.com/INF/F600), the factor that could increase the anti-HBs antibody level was receiving a combined hexavalent/pentavalent vaccine. Having a body weight below the 10th percentile according to the 2020 Thai pediatric growth curve and receiving the concomitant pneumococcal conjugate vaccines (PCV) were associated with lower anti-HBs antibody levels. Receiving a combined hexavalent/pentavalent regimen had higher anti-HBs antibody levels than receiving 3 doses of pentavalent vaccine with a coefficient of 0.57 (95% CI: 0.21–0.94, P = 0.003), meaning that, on average, replacing pentavalent vaccine with hexavalent vaccine at the age of 2 months could significantly increase the GMT of anti-HBs antibody by 3.72 folds (increase of 0.57 unit of log scale). Body weight below the 10th percentile was associated with lower anti-HBs antibody levels with a coefficient of −0.85 (95% CI: −1.44 to −0.26, P = 0.006). Receiving concomitant PCVs significantly decreased anti-HBs antibody levels with a coefficient of −0.65 (95% CI: −1.04 to −0.27, P = 0.001). Comparisons of anti-HBs antibody levels between participants who received concomitant PCV and those who did not are presented in Table 3.
TABLE 3. - Anti-HBs Antibody Levels in Participants Receiving vs Not Receiving Pneumococcal Conjugated Vaccines
| Anti-HBs (mIU/mL) | Not Receiving PCV Mean (95%CI) | Receiving PCV mean (95%CI) | P value |
|---|---|---|---|
| Combined hexavalent/pentavalent group | 467.7 (281.8–794.3) (n = 21) | 138 (26.9–691.8) (n = 10) | 0.049 |
| 3-dose pentavalent group | 154.9 (75.9–326.2) (n = 20) | 31.6 (6.5–147.9) (n = 13) | 0.031 |
| All participants | 275.4 (177.8–426.6) (n = 41) | 58.9 (20–173.8) (n = 23) | 0.003 |
Data represents mean (95% confidence interval).
Per-protocol Analysis
The GMT of anti-HBs antibody levels in the combined hexavalent/pentavalent group was higher than in the 3-dose pentavalent group; 251.2 mIU/mL (95% CI: 114.8–549.5 mIU/mL) and 75.9 mIU/mL (95% CI: 36.3–158.5 mIU/mL), respectively (P = 0.03). The proportion of participants in the combined hexavalent/pentavalent group with anti-HBs antibody levels higher than 100 mIU/mL (17/22 participants; 77.2%) was higher than in the 3-dose pentavalent group (16/32 participants; 50%), and this also reached a statistically significant difference (P = 0.043).
Of note, participants in the pentavalent group in the intention-to-treat analysis tended to have higher anti-HBs antibody levels than those in the per-protocol analysis.
Adverse Events
The incidence of adverse events did not differ between the 2 groups. Fever was the most common adverse event in both groups. No severe adverse events were observed in this study. Adverse events are shown in Table 4.
TABLE 4. - Adverse Events in Each Group of Participants
| Combined Hexavalent/Pentavalent Group (n = 31) | 3-dose Pentavalent Group (n = 33) | |
|---|---|---|
| Number of episodes at 2 months old Fever Irritability Loss of appetite Pain/redness/swelling | 12 10 2 - - | 12 12 - - - |
| Number of episodes at 4 months old Fever Irritability Loss of appetite Pain/redness/swelling | 10 10 - - - | 10 10 - - - |
| Number of episodes at 6 months old Fever Irritability Loss of appetite Pain/redness/swelling | 12 11 - - 1 | 9 9 - - - |
DISCUSSION
In this study, participants receiving the DTaP-IPV-HBV-Hib vaccine at the age of 2 months, replacing the DTwP-HBV-Hib vaccine provided by the Thai EPI program, followed by receiving the DTwP-HBV-Hib vaccines at the ages of 4 and 6 months, had higher anti-HBs antibody levels than those who received 3 doses of the DTwP-HBV-Hib vaccines. In addition, the proportion of infants with anti-HBs antibody levels greater than 100 mIU/mL, which is regarded as a high level of immunity,12 was higher in infants receiving combined hexavalent/pentavalent vaccines than in those receiving 3-dose pentavalent vaccines.
In this current study, the proportion of participants having anti-HBs antibody levels <10 mIU/mL after 3–6 months after the last vaccination in the 3-dose pentavalent group (16%) was comparable to that in the previous study which reported the proportion of 20% at 12 months after the last vaccination.6 This study also supported the previous study showing that vaccination with hexavalent vaccines gave higher anti-HBs antibody levels.6 Although the significance of having higher anti-HBs antibody levels has not been clear, a study from Gambia demonstrated that children with higher anti-HBs antibody levels had less chance of getting HBV infection.13 Ones with higher anti-HBs levels had a higher probability of persistence of protective anti-HBs levels.11,14 However, one study could not demonstrate a correlation of anti-HBs antibody levels between 1 month and 8 years after vaccination.15 Anti-HBs level could also be a predictive factor for higher postbooster anti-HBs levels.10,16 This may imply that those with higher anti-HBs levels might better mount an immune response against HBV after HBV exposure. Nevertheless, one study indicated that hepatitis B surface antigen-specific T-cell numbers were not different between adults who had completed a series of HBV vaccinations whose anti-HBs antibody levels ≥10 and whose anti-HBs antibody levels <10 mIU/mL,17,18 suggesting that long-lasting cellular immunity was not different between these 2 groups and capability of HBV protection might not be different.
One of the reasons that the DTaP-IPV-HBV-Hib vaccine could enhance the immunogenicity of HBV vaccination was the fact that this vaccine contains a higher amount of adjuvant aluminum hydroxide. The hexavalent vaccine used in this study (Infanrix-Hexa) contains 0.5 mg of aluminum hydroxide and 0.32 mg of aluminum phosphate. The pentavalent vaccine (Eupenta) contains only 0.39 mg of aluminum hydroxide. Shan-5 vaccine, pentavalent vaccine with wP component that contains 0.625 mg of aluminum phosphate gel, could elicit anti-HBs antibody levels comparable to the hexavalent vaccine.9 In addition, that study also showed that participants receiving Quinvaxim, which had 0.3 mg of aluminum, had lower anti-HBs antibody levels compared with those receiving Shan-5 or hexavalent vaccine.9 The higher amount of aluminum adjuvant may thus contribute to the enhanced immune response by increasing the immune response duration and immunogenicity of the antigens.19,20 This is supported by the fact that participants in the 3-dose pentavalent group in the intention-to-treat analysis had higher anti-HBs antibody levels than those in the per-protocol analysis as some of those assigned to receive a 3-dose pentavalent regimen in the intention-to-treat analysis were unintentionally given a hexavalent vaccine, and some of them were given more than 1 dose of the hexavalent vaccines according to parental need. This further reinforces that having at least 1 dose of a hexavalent vaccine could enhance the immunogenicity of HBV vaccination.
Another issue that needed to be addressed was vaccination with OPV because participants would receive concomitant OPV when they received the DTwP-HBV-Hib vaccine. Those who received DTaP-IPV-HB-Hib vaccines would get IPV instead. A previous study indicated that different forms of polio vaccination did not affect the immunogenicity of HBV vaccination.21 However, in that study, the first dose of the polio vaccine was administered 1 month after the second dose of the HBV vaccine. Whether the concomitant administration of OPV, a live-attenuated vaccine, induces viral interference and attenuates the response to other vaccines is still unknown.
This study found that concomitant administration of the pneumococcal conjugate vaccine was associated with a decrease in anti-HBs antibody levels. The finding in the current study supported the findings in previous studies that receiving a pneumococcal conjugated vaccine can decrease anti-HBs antibody levels induced by vaccination; the reason underlying this finding was that co-administration of glycoprotein-containing vaccine could affect another vaccine’s immune response.22–24 Further studies, including larger sample sizes or meta-analyses, are needed to address this question. In addition, whether the administration of hexavalent or pentavalent vaccines and pneumococcal conjugated vaccines at different times increases the immunogenicity of HBV vaccination needs to be addressed.
Malnutrition may be another factor affecting HBV immunogenicity. This study highlighted that participants with body weights lower than the 10th percentile tended to have a lower immune response to HBV after vaccination. Therefore, nutritional support for young infants would also benefit the HBV immune response. Malnutrition is associated with thymic atrophy and decreased numbers of helper and cytotoxic T-cells.25,26 This can lead to decreased T-cell function and eventually an impaired immune response by vaccination. However, a previous review did not demonstrate the adverse impact of malnutrition on the immune response to vaccination.27 Another factor that may have affected anti-HBs levels was cord blood anti-HBs. Maternal anti-HBs antibodies can transplacentally inhibit infants’ immune response to a vaccine.28,29 However, this issue was not explored in this study.
The current study emphasized that substitution of the 2-month-old HBV vaccination with DTaP-HBV-IPV-Hib vaccine could enhance the anti-HBs antibody level when compared with all 3 doses of DTP-HBV-IPV-Hib, even after adjusting for other factors potentially affecting anti-HBs antibody levels. A higher anti-HBs antibody level may imply a longer duration of anti-HBs antibody levels above 10 mIU/mL.11,13,14 The limitations of this study include enrollment in a single institution. A multicenter study is required to generalize these results. Anti-HBs antibody levels at birth may affect subsequent HBV immune responses; however, they were not assessed in this study. This study included only 1 brand of pentavalent and 1 brand of hexavalent vaccines. The generalization to other brands of both vaccines warrants further studies. This study did not enroll groups of participants receiving 2 or 3 doses of hexavalent vaccine, precluding the demonstration of a dose-response relationship. In addition, it would be interesting to explore the immune response to other vaccine components, such as tetanus, pertussis, diphtheria and pneumococci, and whether there would be differences in the antibody levels between these 2 groups. Finally, studies of cellular immune response to HBV in participants receiving these 2 different vaccination regimens would provide more insight in the protection ability of the HBV vaccination conferred by these 2 vaccination regimens.
CONCLUSIONS
Replacing the second HBV vaccination (at the age of 2 months) with the DTaP-IPV-HBV-Hib vaccine in the Thai EPI, which offers 3 doses of the DTwP-HBV-Hib vaccine, could enhance the immunogenicity of the primary series of HBV vaccinations. The adverse events associated with both vaccination regimens were comparable. The impact of concomitant administration of PCV needs to be further explored.
Acknowledgments
We thank all nurses at the Pediatric Outpatient Division, Department of Pediatrics at Ramathibodi Hospital, for their assistance with patient enrollment. We thank Ms. Sasip*rn Sitthisorn for assistance of statistical analyses.
The manuscript was edited by Paperpal Preflight
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Keywords:
anti-HBs antibody level; hexavalent vaccine; pentavalent vaccine; infant vaccination
