Glycoconjugate vaccines and immune interactions, and implications for vaccination schedules

Abstract

Conjugate vaccines using diphtheria toxoid variant (CRM₁₉₇), diphtheria toxoid and tetanus toxoid (TT) as carrier protein may induce immune interactions (interference or impairment as measured by lower antibody levels, or enhancement [higher antibody levels]) when coadministered with other vaccines. Immune enhancement occurs when two TT conjugates are coadministered. CRM₁₉₇ conjugate vaccines induce immune bystander interference when given with diphtheria-tetanus-acellular pertussis vaccines, which reduces responses to coadministered Haemophilus influenzae type b vaccine conjugated to TT. These bystander effects are greater as the amount of CRM₁₉₇ administered increases. When large amounts of either TT or CRM₁₉₇ are coadministered, dose-related carrier-induced epitopic suppression may occur, affecting immune responses to meningococcal or pneumococcal polysaccharides. These observations have implications for vaccine scheduling. The range of available alternative vaccines means that specific vaccine coadministrations can avoid or reduce CRM₁₉₇-induced interference. Potential interactions arising from new CRM₁₉₇ or TT conjugates will need to be thoroughly examined.

Keywords::

• carrier-induced epitopic suppression
• conjugate vaccines
• CRM₁₉₇
• enhancement
• Haemophilus influenzae type b
• hepatitis B
• interference
• meningococcal vaccine
• pneumococcal vaccine

Acknowledgements

The authors thank Joanne Wolter (independent medical writer on behalf of GSK) for writing the first draft of the manuscript and Ulrike Krause (GSK Biologicals) for assistance with preparation of the manuscript.

Financial & competing interests disclosure

Infanrix, Infanrix hexa and Synflorix are trademarks of the GlaxoSmithKline (GSK) group of companies. Pediacel and Hexavac are trademarks of Sanofi Pasteur. Meningitec, Prevenar/Prevnar and Prevnar13 are trademarks of the Pfizer group. Menjugate is a trademark of Novartis Vaccines. Ray Borrow has received assistance to attend scientific meetings from Wyeth, Novartis, Sanofi Pasteur and Baxter Bioscience and has served as an ad hoc consultant for Wyeth, GSK, Novartis, Sanofi Pasteur and Baxter Bioscience. Industry honoraria received for consulting, lecturing and writing are paid directly into Central Manchester and Manchester Children’s University Hospitals NHS Trust endowment fund. Ray Borrow has performed contract research on behalf of the Health Protection Agency (funded by Wyeth, Novartis Vaccines, Baxter Bioscience, GSK, Sanofi Pasteur, Alexion Pharmaceuticals Inc., Emergent Europe and Merck). Ron Dagan has had the following financial interests and/or arrangements with the corporate organizations listed below in the past 5 years: grant/research support: Berna/Crucell, Wyeth/Pfizer, MSD, Protea; scientific consultancy: Berna/Crucell, GSK, Novartis, Wyeth/Pfizer, Protea, MSD; speaker: Berna/Crucell, GSK, Wyeth/Pfizer; shareholder: Protea. Hans Hallander has participated in vaccine trials and surveillance programs financed by GSK, Sanofi Pasteur and MSD. The University Medicine of the Johannes Gutenberg University of Mainz, Germany, has received honoraria for the participation of Fred Zepp in scientific advisory boards of GSK, Novartis and Sanofi Pasteur, as well as research grants from pharmaceutical companies within the past 3 years. Jan Poolman was an employee of GSK Biologicals s.a. (GSK) at the time of writing. Jan Poolman is a designated inventor on a variety of patents owned by GSK. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was utilized in the production of this manuscript and was funded by GSK.