Interpreting results from trials of pneumococcal conjugate vaccines: a statistical test for detecting vaccine-induced increases in carriage of nonvaccine serotypes.

Conjugate vaccines against Streptococcus pneumoniae (pneumococcus) protect against nasopharyngeal carriage of serotypes included in the vaccine. However, in several clinical trials, vaccinees have shown increased carriage of nonvaccine serotypes of pneumococcus. These increases may be due to serotype replacement, if vaccine-induced protection against carriage of vaccine serotypes increases susceptibility to carriage of nonvaccine serotypes. Alternatively, observed increases may be an artifact of "unmasking," in which nonvaccine serotypes are more readily detected among vaccinees than among controls because vaccine serotypes are not present. In this paper, a statistical test for distinguishing serotype replacement from unmasking is described. The test attempts to reject a null model of unmasking alone; serotype replacement is inferred if the observed increase in detectable nonvaccine serotype carriage among vaccinees is significantly greater than that expected under the null model. Significance is assessed using the Bayesian "posterior predictive p value" as modified by Robins et al. (J Am Stat Assoc 2000;95:1143-56). Analysis of data from a South African trial suggests that replacement may have occurred in the study, but results do not reach the conventional level of significance in rejecting the null hypothesis of unmasking (p = 0.074). The author performs sensitivity analyses for the prior and for unmeasured confounding by differences in susceptibility to pneumococcus carriage. The implications of the findings and the assumptions and limitations of this technique are then discussed.