Disparate kinetics in immune response of two different Haemophilus influenzae type b conjugate vaccines: Immunogenicity and safety observations from a randomized controlled phase IV study in healthy infants and toddlers using a 2+1 schedule

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.

KEYWORDS:

• 2+1 schedule
• antibody avidity
• Haemophilus influenzae type b
• hexavalent vaccine
• immunogenicity
• immune response kinetics
• infants
• non-inferiority
• safety

Acknowledgments

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.

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.

Data availability statement

Anonymized individual patient data and study documents can be requested for further research from http://www.clinicalstudydatarequest.com.

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.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2342630.

Additional information

Funding

This clinical study and the development of the manuscript was funded by GSK.