The history of pneumococcal conjugate vaccine development: dose selection

Abstract

Pneumococcal conjugate vaccines (PCVs) differ in polysaccharide (PS) dose, carrier protein and conjugation method. PCV development proceeded initially upon principles successfully proven in Haemophilus influenzae type b (Hib) conjugate vaccine development. However, the need to successfully incorporate multiple serotypes while minimizing the total PS dose and total carrier protein load saw some early vaccine candidates fail. Dose–range studies of individual serotypes indicated that much lower PS doses were needed compared with Hib conjugate vaccines, although subsequent studies confirmed that lower Hib PS doses were possible. Furthermore, the immune response to individual serotype doses was carrier protein dependent. A ‘one-size fits most’ approach has characterized PS dose selection, but peculiarities of individual serotypes are increasingly apparent, raising the question whether re-formulation of PCVs to maximize individual serotype performance is needed.

Keywords::

• dose–range
• immune response
• interference
• pneumococcal conjugate vaccine
• Streptococcus pneumoniae
• vaccine

Financial & competing interests disclosure

PREVENAR/PREVNAR are trademarks of the Pfizer group. SYNFLORIX is a trademark of the GlaxoSmithKline Group of Companies. JT Poolman and GPJM van den Dobbelsteen are employees of Crucell. 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.

The author thanks J Wolter (independent medical writer on behalf of Crucell) for writing the first draft of the manuscript and C Laferriere for critical reading.

Key issues

• • The development of Pneumococcal conjugate vaccines (PCVs) proceeded initially upon principles successfully proven in Hib conjugate vaccine development. However, dose–range studies of individual serotypes showed that much lower polysaccharide (PS) doses were needed compared with Haemophilus influenzae type b (Hib) conjugate vaccines, and that immunogenicity was also influenced by the carrier protein. Current PCVs contain between 1 and 4 μg PS per serotype, which is up to 10-times lower than the PS dose used in most Hib conjugate vaccines, although lower Hib PS doses were subsequently shown to be possible.

• • Currently licensed PCVs vary in the number of serotypes they contain, the carrier proteins used and in the methods of conjugation employed. In clinical practice, these differences have not translated into marked differences in global effectiveness. However, individual PCVs differ in their potential for causing interference to the immune response to co-administered vaccines and in the immunogenicity and effectiveness of some serotypes.

• • Individual serotypes show unique properties in terms of phenotype, virulence and the clinical diseases they cause. These properties in turn influence the immunogenicity of serotype-specific PS included in vaccines.

• • Use of a global ELISA antibody threshold as a measure of the efficacy of individual serotypes has proven to be an oversimplification. Experience has shown that the level of antibody needed to protect against disease is not the same for individual serotypes and is also likely to be different for different clinical syndromes. Opsonophagocytic assay now is widely recognized as a critical secondary read-out.

• • A ‘one-size fits most’ approach has characterized PS dose selection, but unique characteristics of individual serotypes are increasingly apparent, raising the question whether reformulation of PCVs to maximize individual serotype performance is needed.

Notes