https://orcid.org/0000-0002-9023-581X
ABSTRACT
Since the introduction of Haemophilus Influenzae type b (Hib) conjugate vaccines, invasive Hib disease has strongly declined worldwide, yet continued control of Hib disease remains important. In Europe, currently three different hexavalent combination vaccines containing Hib conjugates are marketed. In this phase IV, single-blind, randomized, controlled, multi-country study (NCT04535037), we aimed to compare, in a 2 + 1 vaccination schedule, the immunogenicity and safety and show non-inferiority, as well as superiority, of DTPa-HBV-IPV/Hib (Ih group) versus DTaP5-HB-IPV-Hib (Va group) in terms of anti-polyribosylribitol phosphate (PRP) antibody geometric mean concentrations (GMCs) and proportion of participants reaching anti-PRP antibody concentrations greater than or equal to a threshold of 5 µg/mL. One month after the booster vaccination, the anti-PRP antibody GMC ratio (Ih group/Va group) was 0.917 (95% CI: 0.710–1.185), meeting the non-inferiority criteria. The difference in percentage of participants (Ih group – Va group) reaching GMCs ≥5 µg/mL was -6.3% (95% CI: -14.1% to 1.5%), not reaching the predefined non-inferiority threshold. Interestingly, a slightly higher post-booster antibody avidity was observed in the Ih group versus the Va group. Both vaccines were well tolerated, and no safety concerns were raised. This study illustrates the different kinetics of the anti-PRP antibody response post-primary and post-booster using the two vaccines containing different Hib conjugates and indicates a potential differential impact of concomitant vaccinations on the anti-PRP responses. The clinical implications of these differences should be further studied.
Plain Language Summary
Vaccination against Haemophilus influenzae type b (Hib) is included in the majority of national immunization programs worldwide and has shown to be effective in preventing Hib disease. In Europe, different vaccines containing Hib components are marketed. We compared the immune response and safety of 2 of these (DTPa-HBV-IPV/Hib, Ih group) and DTaP5-HB-IPV-Hib, Va group) in infants and toddlers, when used in a 2 + 1 schedule, i.e. two primary vaccination doses (at 2 and 4 months of age of the infant), followed by one booster dose at the age of one year. One month after the booster vaccination, the antibody concentration ratio between both groups (Ih group/Va group) was 0.917 (95% CI: 0.710–1.185) showing the DTPa-HBV-IPV/Hib vaccine was non-inferior to the DTaP5-HB-IPV-Hib vaccine; the difference in percentage of participants (Ih group – Va group) with antibody concentrations above 5 µg/mL was -6.3% (95% CI: −14.1% to 1.5%), which did not meet the pre-defined criterion for non-inferiority. In the Ih group, the quality of antibodies produced was somewhat higher versus the Va group. Both vaccines were well tolerated, and no safety concerns were raised. The kinetics of the immune response are different between the 2 vaccines. Since both vaccines contain different additional components (conjugated proteins), a possible effect of concomitant (simultaneously administered) vaccines was studied. Further investigations to confirm our findings are needed.
Introduction
Prior to the availability of effective vaccines, Haemophilus influenzae type b (Hib) was a major cause of pneumonia and the most important cause of bacterial meningitis in children <5 years of age, often resulting in death or serious long-term consequences such as hearing loss or intellectual impairment.Citation1 The introduction of Hib vaccines in the national immunization programs of over 90% of countries worldwide has since led to an important decrease in Hib disease incidence.Citation2
In Europe, there is evidence of successful Hib disease control with a hexavalent vaccine combining diphtheria, tetanus, pertussis, hepatitis B, inactivated poliovirus and Hib antigens (DTPa-HBV-IPV/Hib, Infanrix hexa, GSK) using 3 + 1 and 2 + 1 schedules, which also includes data between 2005 and 2013 when it was the only hexavalent vaccine available.Citation1–3 Two other hexavalent combination vaccines are licensed in Europe: DTaP2HBIPVHib (Hexyon/Hexacima/Hexaxim, registered by Sanofi Pasteur in 2013) and DTaP5-HB-IPV-Hib (Vaxelis, registered by MCM Vaccine BV in 2016).
Data from persons given unconjugated Hib vaccine suggest that, in the absence of induction of immunological memory, the concentration of serum antibodies to the capsular polysaccharide of Hib, polyribosylribitol phosphate (PRP), is indicative of the level of protection. A concentration of 0.15 µg/mL is indicative of short-term protection, while 1 µg/mL is considered indicative of long-term protection.Citation4,Citation5 The acquisition of Hib or the prolonged Hib carriage in the nasopharynx is reported to occur only below a threshold concentration of serum or mucosal anti-PRP antibodies.Citation6 Other literature reports that high anti-PRP antibody concentrations above the established correlates of clinical protection may be needed to reduce Hib nasopharyngeal colonization and carriage.Citation5,Citation7 Protection against colonization seems to be well correlated with anti-PRP antibody concentrations ≥5 µg/mL.Citation8 Children who experience Hib disease despite vaccination appear to have a defect in immunological priming, leading to a qualitative difference in Hib-specific memory B cells.Citation9 Low anti-PRP antibody avidity decreases their functional activity in children experiencing vaccine failure, leading to disease susceptibility.Citation9
In all three hexavalent vaccines used in Europe, the PRP polysaccharide is conjugated to a carrier protein to enhance the immune response. DTPa-HBV-IPV/Hib and DTaP2HBIPVHib use a tetanus toxoid carrier protein (Hib-TT),Citation10,Citation11 while DTaP5-HB-IPV-Hib uses the outer membrane protein complex of Neisseria meningitidis serogroup B (Hib-OMP).Citation12,Citation13 These different conjugate vaccines have shown different immunological properties with regard to antibody concentrations, avidity maturation and immune response kinetics.Citation1 During clinical development, a higher geometric mean concentration (GMC) of anti-PRP antibody was seen after the primary vaccination with DTaP5-HB-IPV-Hib compared to DTPa-HBV-IPV/Hib. However, following the booster dose in toddlers, the opposite was seen with a lower booster effect after DTaP5-HB-IPV-Hib versus DTPa-HBV-IPV/Hib.Citation13–15 The reasons for these different response kinetics with both vaccines and their clinical implications are currently unclear. In addition, little is known about antibody quality,Citation16,Citation17 although it has been shown that Hib-OMP induces lower-avidity antibodies than Hib-TT with potentially decreased efficiency for reducing carriage.Citation17,Citation18
Nowadays, these hexavalent vaccines are often co-administered with meningococcal vaccines, which include the same carrier proteins. Meningitis B (MenB) vaccine (Bexsero, GSK) contains three proteins as well as outer membrane vesicles of N. meningitidis.Citation19 In the meningitis C (MenC, NeisVac C, Pfizer) and meningitis A, C, W-135 and Y (MenACWY, Nimenrix, Pfizer) vaccines, the polysaccharide is conjugated to tetanus toxoid.Citation20,Citation21
Here we present the results of a randomized study, intending to compare the immunogenicity and safety of DTPa-HBV-IPV/Hib versus DTaP5-HB-IPV-Hib, both administered in a 2 + 1 schedule, in terms of anti-PRP antibody GMCs and proportion of participants with anti-PRP antibody concentrations equal to or higher than a threshold of 5 µg/mL 1 month after the booster dose. In a post-hoc analysis, the potential effect of concomitant vaccinations was also studied.
Methods
Ethics
The study was performed in compliance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP), the ethical principles of the Declaration of Helsinki as well as all applicable laws and regulations. The study was reviewed and approved by the relevant independent ethics committees or institutional review boards at each study center. All infants’ parents or their legally authorized representative(s) provided informed consent prior to any study-related procedures.
Study setup
This study was designed as a phase IV, single-blind, randomized, controlled, multi-country, non-inferiority study in healthy infants and toddlers 6 to 12 weeks of age at the time of first vaccination and born after at least 37 weeks of gestation (NCT04535037). Main exclusion criteria were known history of diphtheria, tetanus, pertussis, hepatitis B virus, poliomyelitis, or Hib diseases since birth, any confirmed or suspected immunosuppressive or immunodeficient condition, and major congenital defects. Full inclusion and exclusion criteria are listed in the supplemental material.
The participants were randomly assigned (1:1 ratio) to receive either DTPa-HBV-IPV/Hib (Ih group; Infanrix hexa, GSK) or DTaP5-HB-IPV-Hib (Va group; Vaxelis, MCM Vaccine BV); both using a 2 + 1 schedule with primary doses at 2 and 4 months, and booster dose at 12 months. Both vaccines were co-administered with a 13-valent pneumococcal conjugate vaccine (PCV-13, Prevenar 13, Pfizer), as part of the national recommendations. Other vaccines given in accordance with the national immunization schedule as routine vaccination practice (e.g., rotavirus, meningococcal vaccines) were allowed during the study period ().
Figure 1. Time schedule of study vaccination, study visits, and concomitant vaccinations.
Sample anaysis
Blood samples were collected 1 month after the second dose of primary vaccination, before the administration of the booster dose, and 1 month after the booster dose (study visits 3, 4, and 5, ). Total immunoglobulin (Ig) anti-PRP antibodies were measured in serum using a validated enzyme-linked immunosorbent assay (ELISA). 96-well microplates coated with the purified antigen were incubated with dilutions of serum samples, controls, and standard. Microplates were washed and goat anti-human Ig polyclonal antibodies, conjugated to horseradish peroxidase (HRP) were added. Enzyme activity was revealed spectrophotometrically using tetramethylbenzidine. Concentrations were calculated from the calibrated reference standard curve using a four parameters logistic fitting algorithm and expressed in µg/mL. Assay cutoff (lower limit of precision and linearity) was 0.066 µg/mL. Seroprotection was defined as antibody concentration ≥0.15 µg/mL (indicative of short-term protection) and 1 µg/mL (indicative of long-term protection).
The avidity index of the anti-PRP antibody depends on the ability of a chaotropic agent to detach the complex between the antigen and the antibodies of a sample. The method is based on the anti-PRP ELISA with one additional step introduced. After addition and incubation of the sample, an extra incubation (15 minutes) with a chaotropic agent (NH4SCN 0.25 M) is added in order to disrupt the antigen–antibody complex. The remaining antibodies, demonstrating a higher binding force to the antigen, are quantified by continuing the current assay. The avidity index (calculated as remaining antibody titer/initial antibody titer and expressed in %) therefore provides a means to report the high avidity fraction present in a sample.
Study endpoints
The primary endpoints were confirmatory and evaluated hierarchically to control for the risk of erroneous conclusions.
The first primary endpoint was to demonstrate that the Hib response in the Ih group was non-inferior to the Va group, 1 month post-booster vaccination in terms of GMC (lower limit of the 2-sided 95% confidence interval [CI] of the GMC ratio Ih/Va >0.5). The second primary endpoint for non-inferiority was in terms of the percentage of participants with anti-PRP antibody concentrations ≥5 µg/mL (first primary endpoint met and lower limit of the 2-sided 95% CI on group difference Ih-Va in the percentage >-10%).
The third and fourth primary endpoints were to demonstrate that the Hib response in the Ih group was superior to the Va group 1 month post-booster vaccination in terms of GMC (the two previous endpoints met and lower limit of the 2-sided 95% CI of the GMC ratio Ih/Va >1.0) and in terms of the percentage of participants with anti-PRP antibody concentrations ≥5 µg/mL (the three previous endpoints met and lower limit of the 2-sided 95% CI on group difference Ih-Va in the percentage >0%).
Secondary endpoints were to describe the immunogenicity of the Hib components in terms of percentage of participants above the thresholds for short- and long-term seroprotection (≥0.15 µg/mL and ≥1 µg/mL) as well as in terms of the GMCs post-primary, pre-, and post-booster. This analysis was repeated by country separately as a complementary analysis. The tertiary exploratory objective was to assess the quality of the anti-PRP response post-booster vaccination using the avidity index of anti-PRP antibodies.
Safety evaluation consisted of recording unsolicited adverse events (AEs) occurring within 31 days following any vaccine dose. A brief physical examination, including assessment of body temperature, was taken before each vaccination. Serious adverse events (SAEs) were recorded from first study dose up to study end (1 month post-booster).
Results
Demographics
Twenty-one centers in Germany, Italy, and Spain participated in the study. The first participant was enrolled in February 2021, and the last participant completed the study in July 2022. A total of 500 participants were enrolled; 470 participants (94.0%) completed the study ().
Figure 2. Participant disposition.
The demographics were generally well balanced between both groups; 52.0% of the participants were male, with somewhat more male participants (57.8%) in the Ih group than in the Va group (46.2%). At study start, the infants had a median age of 9.0 weeks and were born after a median gestational age of 39.0 weeks. In both groups, most of the participants were of White Caucasian/European heritage (94.2%) (). In total, 379 (75.8%) of the participants’ mothers received diphtheria/tetanus/pertussis vaccine during pregnancy, 109 (21.8%) mothers did not, and for 12 (2.4%) participants, the mother’s vaccination status was unknown.
Table 1. Participant demographics (exposed set).
Immunogenicity
At 1 month post-booster, the adjusted ratio of anti-PRP antibody GMCs in the Ih group versus the Va group was 0.917 (95% CI 0.710–1.185). The first primary objective in relation to GMCs was met as the lower limit of the group GMC ratio 95% CI was at 0.710 and thus above 0.5. The percentage of participants reaching anti-PRP antibody concentrations ≥5 µg/mL at 1 month post-booster was 75.4% in the Ih group versus 81.7% in the Va group (95% CI for the difference between groups: −14.1%–1.5%). The second primary objective in relation to percentage of participants with anti-PRP antibody concentrations ≥5 μg/mL was not met as the lower limit of the 2-sided 95% CI on group difference in the percentage was -14.10% and thus not higher than -10%. shows the reverse cumulative curves (RCC) of the post-booster anti-PRP antibody concentrations in both groups. In the participants showing the 20% highest and 20% lowest anti-PRP antibody concentrations, little difference is observed between both groups. In-between, there is a slight separation in favor of the Va group.
Figure 3. Reverse cumulative curves of the post-booster anti-PRP antibody concentrations.
Due to the hierarchical procedure and because the second criterion for non-inferiority was not met, the condition for evaluation of the third and fourth primary objectives on superiority was not met.
At post-primary visits, anti-PRP antibody concentrations in the Ih group showed 79.8% of the participants had short-term protection (≥0.15 µg/ml), and 30.5% had long-term protection (≥1 µg/mL) while the Va group showed 100% of the participants had short-term protection and 92.2% had long-term protection (). The pre-booster data showed a decrease in antibody concentrations in both groups when compared to the post-primary concentrations: in the Ih group 61.2% had short-term protection and in the Va group 94.4% had short-term protection. At the post-booster visit, an increase in antibody concentrations was observed in both groups: in the Ih group 99.5% of participants had short-term protection and 97.2% had long-term protection, while in the Va group 99.5% of participants had short-term protection and 94.5% had long-term protection.
Table 2. Number and percentage of participants with anti-PRP antibody concentrations equal to or above correlates of clinical protection and GMCs post-primary, pre-booster, and post-booster vaccination (per protocol set).
At 1 month post-primary, the anti-PRP antibody GMC in the Ih group was 0.5 µg/mL, which decreased to 0.2 µg/mL pre-booster, and increased post-booster to 12.0 µg/mL. In the Va group, the GMCs were 11.3, 1.9, and 12.9 µg/mL at post-primary, pre-, and post-booster ().
Concomitant vaccination
Country differences with regard to anti-PRP antibody concentrations were observed (). In Germany and Spain, high post-primary anti-PRP antibody GMCs were observed in the Va group and point estimates of post-booster levels were only slightly higher than post-primary, whereas in the Ih group, a 15- to 30-fold increase in anti-PRP antibody GMC was noted post-booster compared to post-primary. However, the values reached in Germany were overall lower than those observed in Spain. In Italy, although the number of participants was low, even higher anti-PRP post-primary and post-booster values were observed in the Va group as compared to Germany and Spain. In light of these differences observed in the descriptive analysis by country, post-hoc analyzes were performed according to concomitant vaccines.
Table 3. GMCs of anti-PRP antibodies post-primary, pre-booster, and post-booster by country. (per protocol set).
In Germany and Spain, MenB vaccine was predominantly administered at the infant age of 3 and 5 months, i.e., in between both primary study vaccination visits and at the time of post-primary blood sampling (). In Spain, an additional vaccination with MenB was also administered at the infant age of 13 months, i.e., at the time of study post-booster blood sampling. In two study sites in Spain, MenB was administered at infant age of 2 and 4 months, i.e., concomitantly with both primary study vaccination visits. In Italy, MenB vaccine was administered at infant age of 5 and 8 months, i.e., the first dose at the post-primary blood sampling visit.
When looking at infants in Germany who received MenB at age of 3 and 5 months versus those who did not, the post-primary point estimate of anti-PRP antibody GMC in the Va group was only slightly higher in infants who received MenB (8.0 µg/mL versus 6.5 µg/mL), but CIs were wide (). Post-booster, the point estimate of anti-PRP antibody GMC in the Va group was lower in the infants who received MenB (6.7 µg/mL versus 9.1 µg/mL).
Table 4. GMCs of anti-PRP antibodies post-primary, pre-booster, and post-booster by country and by concomitant MenB or MenC/MenACWY vaccination (per protocol set).
In Spain, the number of participants who did not receive MenB was too low to draw any conclusions. However, when comparing the concomitant versus the shifted administration that was used in two centers, it was observed that the shifted MenB administration at infant age of 3 and 5 months had a higher post-primary point estimate of anti-PRP antibody GMCs compared to concomitant vaccination at infant age 2 and 4 months (14.6 µg/mL versus 9.8 µg/mL) in the Va group ().
Table 5. Post-primary GMCs of anti-PRP antibodies in Spain, by timing of MenB vaccine administration, relative to study vaccination. (per protocol set).
MenC and MenACWY vaccines were mostly administered at the post-booster blood sampling visit in Germany (). In Spain, most MenC vaccination were administered at infant age of 4 months, i.e., concomitantly with the second primary vaccination visit. A minority of infants received MenACWY or MenC post-primary, which was administered at or close to infant age of 13 months, i.e., post-booster blood sampling visit. In Italy, no MenC or MenACWY vaccines were concomitantly administered.
In Spain when comparing the participants with MenC/MenACWY vaccination for the post-primary assessment versus those without, no effect was observed in the Ih group (anti-PRP antibody GMC point estimates 0.52 µg/mL versus 0.50 µg/mL, ). For the post-booster analysis, too few participants did not receive MenC/MenACWY vaccine to draw conclusions.
Two rotavirus vaccines were used during the study: Rotarix (GSK), administered in a 2-dose schedule between 6 and 24 weeks of age, and RotaTeq (Merck Sharp & Dohme), administered in a 3-dose schedule between 6 and 32 weeks of age. The choice of rotavirus vaccine, as well as the timing of administration relative to the DTPa-HBV-IPV/Hib and DTaP5-HB-IPV-Hib doses was highly variable between participants, with no differences between both study groups.
Avidity
The point estimate of the avidity index was higher in the Ih group versus the Va group post-booster (25.7% [95% CI 23.9–27.7] versus 23.2% [95% CI 21.6–24.9]) although the CIs overlap. The RCC of the avidity index () show a separation of the curves with a higher avidity index noted in the Ih group compared to the Va group.
Figure 4. Reverse cumulative curves of the post-booster avidity index of anti-PRP antibodies.
Safety
A total of 178 (71.5%) participants in the Ih group and 199 (79.3%) participants in the Va group experienced at least one symptom of unsolicited AE within the 31-days follow-up period after each vaccination. The highest incidence of AE by preferred term was pyrexia (103 [41.4%] participants in the Ih group and 132 [52.6%] participants in the Va group), followed by irritability (31 [12.4%] participants in the Ih group and 37 [14.7%] participants in the Va group), and upper respiratory tract infection (18 [7.2%] participants in the Ih group and 20 [8.0%] participants in the Va group). When considering the two most frequent AEs by dose, pyrexia occurred slightly more frequently after the second primary dose versus the first primary dose or the booster dose in both groups, and consistently somewhat more frequent in the Va group versus the Ih group (Supplemental table S1). Irritability was reported slightly less frequently after the booster dose versus the primary doses in both groups.
Most of the unsolicited AEs were mild or moderate in severity (, respectively, 144 [57.8%] and 30 [12.0%] participants in the Ih group, and 156 [62.2%] and 38 [15.1%] participants in the Va group). There was a similar number of participants in both groups with severe symptoms (4 [1.6%] in the Ih group and 5 [2.0%] in the Va group). The most frequently reported AE in both treatment groups, pyrexia, was generally reported as mild (96 [38.6%] participants in the Ih group and 112 [44.6%] in the Va group). By dose and despite low numbers, severity of pyrexia was consistently somewhat lower in the Ih group versus the Va group. Severity of irritability by dose was similar in both groups (Supplemental table S2).
A total of 113 (45.4%) participants in the Ih group and 142 (56.6%) participants in the Va group experienced at least one unsolicited AE considered by the investigator to be related to the study intervention. Most of these were mild in severity. The most frequently reported vaccination-related AE was pyrexia (Ih group: 88 [35.3%], Va group: 118 [47.0%]), followed by irritability (Ih group: 29 [11.6%], Va group 33 [13.1%]), restlessness (Ih group: 8 [3.2%], Va group: 13 [5.2%]), injection site erythema (Ih group: 6 [2.4%], Va group: 8 [3.2%]), injection site pain (Ih group: 6 [2.4%], Va group: 8 [3.2%]) and injection site swelling (Ih group: 7 [2.8%], Va group: 8 [3.2%]).
A total of 14 (5.6%) participants in the Ih group and 10 (4.0%) participants in the Va group experienced at least one serious AE during the study. Of these, one (seizure in a participant in the Ih group) was considered vaccination-related by the investigator.
Discussion
The first primary endpoint of this study (non-inferiority of DTPa-HBV-IPV/Hib versus DTaP5-HB-IPV-Hib in terms of anti-PRP antibody GMC) was met. However, the percentage of participants reaching antibody levels above 5 µg/mL did not meet the second primary endpoint. Due to the hierarchical study design, this meant the third and fourth primary endpoints regarding superiority were also not met.
Previous phase III studies comparing DTaP5-HB-IPV-Hib and DTPa-HBV-IPV/Hib using different administration schedules have consistently shown the former induces a higher post-primary Hib antibody response, while the latter induces a stronger boosting effect.Citation13–15 In these studies, DTPa-HBV-IPV/Hib induced a numerically higher antibody concentration or titer post-booster although the number of participants reaching short- or long-term protection was similar between both vaccines. The observation in the current study that the non-inferiority is not met post-booster at the threshold of 5 µg/mL is not in line with these previous studies. A small separation of the anti-PRP concentration RCC curves is observed in the high-middle range in favor of the Va group. However, overall the RCC curves demonstrate a similar response in the post-booster antibody concentrations and the difference between both groups is not expected to be clinically relevant.
In the current study, post-primary and post-booster anti-PRP concentrations in the Va group are higher than previously published, while the concentrations in the Ih group are in line with the previously mentioned phase III studies.Citation13–15 To study these unexpected anti-PRP responses, and to investigate the country differences observed, a post-hoc analysis was performed on the potential additional boosting effect of concomitantly administered vaccines with similar conjugate proteins (outer membrane proteins in MenB and DTaP5-HB-IPV-Hib; tetanus toxoid in MenC/MenACWY and DTPa-HBV-IPV/Hib).
In the two countries that recruited the majority of the participants (Germany and Spain), the main overall observations of 1) a higher primary vaccination response in the Va group, but a stronger boosting in the Ih group resulting in similar post-booster responses with both vaccines, and 2) post-booster responses in the Va group that resulted in only slightly higher GMCs compared to post-primary, are confirmed at a country level. We could find no clear explanation on why the post-booster responses reached with both vaccines in Germany are overall lower than those observed in Spain. In Germany, the number of participants is relatively low, resulting in wide CIs, while in Spain, an insufficient number of participants did not receive MenB vaccination to study its effect. Although the number of participants was low in Italy, we observed an even higher post-primary and post-booster anti-PRP response in the Va group as compared to Germany and Spain. However, since in Italy the second MenB dose was given at the infant age of 8 months, the additional boosting effect in the Va group could be due to boosting of the anti-PRP response through the carrier protein administration contained in MenB which is further enhanced by the administration at a more advanced age of the infant.
The observation in Spain that the point estimates are higher following the shifted MenB administration at infant age of 3 and 5 months as compared to concomitant vaccination at infant age 2 and 4 months, might also indicate a potential boosting effect of the additional MenB proteins. If the membrane vesicles instead of the proteins in the MenB vaccine were to provide an enhancing effect, the concomitant vaccination would have stimulated anti-PRP immune response, which was not observed.
Since repeated dose injections may enhance the immune responses relative to traditional bolus immunizations,Citation22 the additional presentation of the N. meningitidis proteins in the MenB vaccine administered at 1 month interval to study vaccines may have acted as additional booster to Hib response in the Va group, driven by the meningococcal serogroup B carrier protein. Similar findings were also reported by Rajan et al.Citation23 They found higher post-primary responses following DTaP5-HB-IPV-Hib vaccination when MenB vaccine was also co-administered at the first and third hexavalent vaccine administrations at infant age of 2 and 4 months. The observed country differences are difficult to explain.
The immune response to the DTPa-HBV-IPV/Hib vaccination was generally in line with previously published results.Citation13–15 and surprisingly, a similar boosting effect of the tetanus toxoid conjugated carrier protein containing vaccines MenC/MenACWY on DTPa-HBV-IPV/Hib vaccination was not observed, although such immune enhancement has been previously described.Citation24,Citation25 The reason for the absence of a boosting effect of the concomitant vaccinations in the Ih group is unclear but might be due to an immune bystander interference effect of the co-administration with the pneumococcal conjugate vaccine PCV-13. It has been previously shown that CRM197 conjugate vaccines, such as PCV-13 which contains a relatively high dose of 32 µg CRM197, can induce a lower response to the PRP-TT component of diphtheria-tetanus-acellular pertussis vaccines.Citation25,Citation26 Thus, the combination of a stimulatory effect of MenB vaccination in the Va group and a negative immune bystander effect of the pneumococcal vaccination in the Ih group may have influenced the overall results of the current study.
The concomitant administration of oral rotavirus vaccine was similar in both study groups with regard to timing as well as the vaccine that was used. No impact on any of the hexavalent combination vaccine components is expected .Citation27–29
In terms of immunogenicity, the two vaccines demonstrated different kinetics of the immune response when comparing post-primary with post-booster titers (more than 20-fold for the Ih group versus less than 1.2-fold for the Va group). This could indicate a differential ability of the two vaccines, in particular of the carrier proteins of the conjugate, to induce T-helper responses.Citation30 The Hib-OMP conjugate (Va group) seems to preferentially induce antibody-producing B cells, while the Hib-TT conjugate (Ih group) seems stronger in inducing memory B cells. The clinical implications of this difference in titers and boostability are not known. Although a lower immune response of DTPa-HBV-IPV/Hib post priming compared to DTaP5-HB-IPV-Hib has been observed, the lower post-priming immunogenicity and waning of the antibodies during the first year of life up to boosting does not seem to be clinically relevant when looking at real-life data, since successful Hib disease control is achieved in countries where routine vaccination programs include Hib vaccination.Citation1,Citation2 DTPa-HBV-IPV/Hib was the only hexavalent vaccine on the market for many years providing excellent Hib disease controlCitation3 and a high vaccine effectiveness in a 2 + 1 schedule continues to be observed.Citation31–33
In addition, the high boostability of DTPa-HBV-IPV/Hib vaccination indicates adequate priming and development of the immune memory. Lee et al.Citation9 observe in their study that despite significant antibody responses, “children who experience Hib disease despite vaccination appear to have a defect in immunological priming, leading to a qualitative difference in Hib-specific memory B cells. Low anti-PRP antibody avidity decreases the functional activity of anti-PRP antibody in the sera of these children experiencing vaccine failure, leading to disease susceptibility.” Because of the important role that antibody avidity plays in the vaccine efficacy,Citation9 our observation that DTPa-HBV-IPV/Hib induces slightly higher antibody avidity pre- and post-booster compared to DTaP5-HB-IPV-Hib might be clinically relevant, especially since this also matches with literature that Hib-OMP induces lower-avidity antibodies than Hib-TT.Citation17,Citation18
Both vaccines were well tolerated. For the main AE of fever, although none of the differences appear significant, the point estimates show consistently slightly lower incidence following DTPa-HBV-IPV/Hib as compared to DTaP5-HB-IPV-Hib, both overall and by severity. This is consistent with the results of the only other comparative study using a 2 + 1 design,Citation14 showing an increased incidence of pyrexia both overall and by severity following DTaP5-HB-IPV-Hib compared to DTPa-HBV-IPV/Hib. Yet, in the current study there was no further rise of the fever levels post-booster.
The current study was not designed to assess the effects of concomitant vaccinations, and the variation in vaccination schedules and vaccines among the countries is a limitation. Strengths of the study include the number of participants, as well as a good balance of participant characteristics between both treatment groups. The observations in the Ih group are in line with previously reported studies.
In conclusion, we showed that DTPa-HBV-IPV/Hib and DTaP5-HB-IPV-Hib vaccines are well tolerated, and we showed non-inferiority of post-booster Hib response after DTPa-HBV-IPV/Hib vaccination versus DTaP5-HB-IPV-Hib in terms of GMC. Our study is consistent with the apparent different kinetics of primary and booster responses of the two vaccines in a 2 + 1 schedule, although the post-primary and post-booster responses after DTaP5-HB-IPV-Hib vaccination were higher than in the pivotal phase III studies, possibly due to the impact of concomitant vaccinations. The administration of MenB vaccine at 1 month interval to study vaccines may have acted as an additional booster to Hib response in the Va group, while the pneumococcal vaccine may have blunted the Hib response in the Ih group. Although vaccine effectiveness of both vaccines is high using a 2 + 1 schedule, the clinical implications of the different antibody responses, as well as the potentially important role of concomitant vaccinations in the immune response will need to be further studied.
Author contributions
All authors contributed to study design, data collection and/or data interpretation. All authors comply with the ICMJE authorship criteria and have approved the final submitted version.
Trademark statement
Infanrix hexa, Bexsero and Rotarix are trademarks owned by GlaxoSmithKline. Hexyon/Hexacima/Hexaxim are trademarks owned by Sanofi Pasteur. Vaxelis is a trademark owned by MCM Vaccine BV. Neisvac-C, Prevenar 13 and Nimenrix are trademarks owned by Pfizer. RotaTeq is a trademark owned by Merck Sharp & Dohme Corp.
20240109_MS_Hexa141_Supplemental material.docx
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The authors thank Akkodis Belgium for providing manuscript writing (Geert Behets) and coordination support on behalf of GSK.
Disclosure statement
NM, BC, NV, RWJ, MD and PVdS are employees of GSK. BC, RWJ, MD, PVdS own shares in the company and declare financial/non-financial relationships and activities.
FMT declares that his institution received payment from GSK for conducting this trial, from Ablynx, Abbot, Seqirus, Sanofi, MSD, Merck, Pfizer, Roche, Regeneron, Janssen, Medimmune, Novavax, Novartis, and GSK for other vaccine trials; FMT also reports receiving honoraria for lectures from Sanofi, MSD, Moderna, GSK, Biofabri, AstraZeneca, Novavax, Janssen, and Pfizer; payment of travel expenses and meeting fees from Pfizer, MSD, GSK, and Sanofi; and participation on data safety monitoring boards or advisory boards for Pfizer, GSK, Moderna, Sanofi, Astra Zeneca and Biofabri; FMT is also a member of WHO’s European Technical Advisory Group of Experts, coordinator of the Spanish Pediatric Clinical Trials Network, and coordinator of WHO collaborating center for vaccine safety of Santiago de Compostela. MH has received honoraria from GSK, Sanofi, MSD, Pfizer, Bavarian Nordic, AstraZeneca, OM-Pharma and Novartis Vaccines as an investigator in clinical trials, a member of advisory boards, and participant in speaker forums. SW declares that his private practice/WeMaMed received payment from GSK for conducting this trial, from Sanofi, MSD, Merck, Pfizer, Janssen and GSK for other vaccine trials. SW also reports receiving honoraria for lectures from Sanofi, GSK, Pfizer, Bavarian Nordic and MSD; payment of travel expenses and meeting fees from Sanofi, GSK, Pfizer, Bavarian Nordic and MSD; and participation on data safety monitoring boards or advisory boards for Sanofi, GSK and MSD. SB declares that that her institution received payment from GSK for conducting this trial, from Sanofi, Pfizer and GSK for other vaccine trials. SB is also a board member of the Italian Society of Pediatric Infectious Diseases.
Other authors have no competing interests to declare.
Data availability statement
Anonymized individual patient data and study documents can be requested for further research from http://www.clinicalstudydatarequest.com.
Supplementary material
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2342630.
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Funding
References
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