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ABSTRACTIn pneumococcal conjugate vaccines (PCVs), polysaccharide antigens are often conjugated to protein carriers related to other common vaccines. It is therefore important to test PCV interaction with other pediatric vaccines when administered simultaneously. We assessed the immune response to an 11-valent PCV conjugated to diphtheria and tetanus carriers (PncD/T11), administered concomitantly, but in separate sites, with a combined vaccine containing epitopes related antigenically to the carriers: polyribosylribitol phosphate-tetanus tox oid (PRP-T), diphtheria toxoid (DT), and tetanus toxoid (TT). In addition, these combinations contained inactivated poliovirus vaccine (IPV) and either whole-cell pertussis (wP) or acellular pertussis (aP) components. After coadministration of PncD/T11 with the combined vaccine containing wP (DTwP/IPV/PRP-T), the responses to all polysaccharides in the PncD/T11 were satisfactory. In contrast, when coadministered with an aP-containing combination (DTaP/IPV/PRP-T), the response to all seven pneumococcal conjugates to TT was significantly reduced after primary and booster immunization. The pneumococcal conjugates to DT were not significantly reduced after the primary series, but were somewhat reduced after booster. It is likely that some suppression of the tetanus-mediated response occurred even when the PncD/T11 was coadministered with wP, but this suppression was masked by the adjuvant effect of wP. By replacing wP with aP, this adjuvant effect was removed, unmasking the suppression of the tetanus-mediated response. With the increasing use of multiple aP-containing vaccines in infancy, novel approaches to adjuvants and carrier protein technology are likely to be required.

Oxybutynin (Ditropan®), a direct antagonist of acetylcholine on muscarinic receptors, is administered in children for the treatment of vesical immaturity and is responsible for atropinic adverse effects, which are more frequent in paediatric than in adult patients. Oxybutynin is metabolized by oxidation to N-desethyloxybutynin, a stable and toxic metabolite, and previous results in vivo have suggested that cytochrome P450 2D6 (CYP2D6) may be involved in this pathway of metabolism. We used human liver microsomes genotyped as extensive metabolizers for CYP2D6 to determine the kinetic parameters of N-desethyloxybutynin formation Kmwas 16.5 ± 5.2 μM and Vmaxwas 76.8 ± 3.7 mmol/mg/h. Quinidine and anti-liver kidney microsome antibody type I had no inhibitory effects on N-desethyloxybutynin formation, demonstrating that CYP2D6 has no role in oxybutynin metabolism. The effects of specific inhibitors of other cytochromes P450 were also investigated. Recombinant human CYP 3A4 but not 2B6, 2D6, 2C8 and 2E1, displayed significant N-desethylation activity. Our results demonstrate that the CYP3A subfamily, and not CYP2D6, is involved in N-desethyloxybutynin formation.

This commentary discusses the barrier of vaccine price on sustainable immunization programs in developing countries and offers examples of new mechanisms driven by public–private partnerships to overcome issues of affordability. These mechanisms include Advance Market Commitments with vaccine manufacturers, which take a demand-pull approach to ensure increased production of available vaccines or development of new vaccines for neglected diseases. A second approach applies a supply-push mechanism, such as technology transfer to developing-country manufacturers. A public–private partnership that set long-term, maximum public-sector pricing to increase access of a Japanese encephalitis vaccine for the developing world is highlighted. Lessons learned from this experience can be applied to address common obstacles to new vaccine introduction in resource-limited countries, including issues of affordability, manufacturing capacity, equity in access, and quality assurance.