Laboratory investigation of immune responses to acellular pertussis vaccines when used for boosting adolescents after primary immunisation with whole cell pertussis vaccines: a comparison with data from clinical study.

The lack of unequivocal immunological correlates of human protection and an absence of a validated animal model for acellular pertussis vaccines, compounded by limited opportunity to undertake efficacy studies in humans and laboratory evaluation side by side, has made it difficult to compare vaccines and formulations. In the present study, the effect on the booster response to pertussis in adolescents primed in infancy with whole cell pertussis vaccine, of three low dose acellular pertussis/diphtheria/tetanus toxoid (TdPa) formulations with or without inactivated poliomyelitis vaccine (IPV) components, was investigated. To assess the relationship between laboratory vaccine evaluation and clinical trial performance, parallel evaluation of the same TdPa vaccines were carried out in a mouse booster model with whole cell pertussis vaccine priming. Prior to boosting, the clinical subjects had low cell mediated immune responses (CMI) responses to pertussis vaccine components. After boosting, all TdPa formulations stimulated CMI responses to the pertussis vaccine components assessed. The booster responses to the pertussis antigens remained skewed towards Th1 type even though acellular pertussis vaccines were used. In general the antibody and CMI responses to pertussis antigens in the mouse model followed the trend seen in the human subjects. Protection against aerosol challenge with virulent Bordetella pertussis was related to the magnitude of the antibody and CMI responses in the mouse model. As in the human subjects, the responses remained skewed towards Th1 type.

Enhanced resistance to erythromycin is conferred by the enterococcal msrC determinant in Staphylococcus aureus.

OBJECTIVES: The msrC gene, found on the chromosome of Enterococcus faecium, shares a high degree of similarity with the staphylococcal erythromycin resistance determinant msr(A). The enterococcal determinant was cloned into Staphylococcus aureus to determine whether msrC could confer antibiotic resistance in staphylococci. METHODS: A shuttle vector comprising pBluescript and pSK265 was used to introduce multiple copies of msrC into S. aureus RN4220. The integration vector pCL84 was employed to insert a single copy of msrC into the S. aureus chromosome. MICs were determined by the broth microdilution method. RESULTS: Expression of msrC from both chromosomal and plasmid loci in erythromycin-susceptible S. aureus RN4220 (MIC 0.25 mg/L) gave rise to enhanced protection against erythromycin, with an MIC of 32-64 mg/L for S. aureus RN4220 containing msrC in multiple copies and an MIC of 16-64 mg/L with msrC inserted as a single copy in the S. aureus chromosome. CONCLUSIONS: MsrC mediates high-level resistance to erythromycin in S. aureus.

Msr(A) and related macrolide/streptogramin resistance determinants: incomplete transporters?

The gene msr(A) confers inducible resistance to 14-membered-ring macrolides and type B streptogramins (MS(B) resistance) in staphylococci. The encoded hydrophilic protein (Msr(A)) is 488 amino acids and contains two ATP-binding motifs characteristic of the ABC transporters. The classical organisation of ABC transporters requires interaction between the two cytoplasmically located ATP-binding domains with two hydrophobic domains positioned in the membrane. Msr(A) appears to mediate drug efflux and yet contains no hydrophobic membrane spanning domains. In addition, Msr(A) functions in previously sensitive heterologous hosts such as Staphylococcus aureus in the absence of other plasmid encoded products. Current research on Msr(A) and related determinants in Gram-positive cocci and in antibiotic producing organisms is reviewed. Alternative hypotheses for the mechanism of action of Msr(A) (i.e. active transport vs. ribosomal protection) are discussed. Evidence indicating Msr(A) may have a role in virulence in addition to conferring antibiotic resistance is also considered.