In the initial report, there was no difference

in the primary endpoints of IPD, pneumococcal disease or overall mortality, only in the secondary endpoint of all-cause pneumonia [14]. When follow-up was discontinued in December 2001, 83 incident cases of all-cause pneumonia, 62 incident cases of all-pneumococcal disease, 52 incident cases of IPD, and 711 deaths had occurred. As shown in Figure 1a, the trial revealed a 60% increased risk of all-cause pneumonia among vaccinated patients compared with placebo controls, primarily as a result of differences occurring within the first 6 months after immunization. The IPD cases in vaccinees were predominantly in vaccinated individuals with low CD4 cell counts, while the increase in all-cause pneumonia was found predominantly in those with CD4 counts of 200–350 cells/μL. Mortality was very high (53% www.selleckchem.com/products/AZD1152-HQPA.html of patients died during the study) and significantly lower in the intervention group [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.7–1.0]. In the first publication, the leading causes of death among participants were ‘unknown’ (23%), followed by wasting syndrome (20%), cryptococcal disease (17%) and tuberculosis (6%).

Nine vaccinated patients and 11 unvaccinated patients died from undiagnosed febrile respiratory illness. The authors concluded that the vaccine gave rise to a selective defect in the humoral response to re-challenge with pneumococcal antigens. The reduced mortality was regarded as a chance finding. Seven additional studies on PPV-23 and all-cause pneumonia Adenosine triphosphate were identified. Selleck Temsirolimus Three studies found no significant effect of PPV-23 immunization [19,37,38], four found a protective

effect [18,30,39,40], and the Uganda trial reported a harmful effect (Fig. 1b). The study by Teshale et al. [30] was considerably larger than the other studies. Its greater size allowed evaluation of vaccine effectiveness in smaller strata. Stratified for CD4 cell count at immunization, the unadjusted analyses showed a protective effect of PPV-23 in all strata but the 0–99 cells/μL stratum [incidence rate ratio (IRR)=1.3; 95% CI 1.1–1.5]. With correction for HIV RNA at time of immunization, the vaccine was found to be effective in all strata, although the effect was insignificant in patients with CD4 counts from 200 to 499 cells/μL. Stratification for HIV RNA at immunization revealed an independent association between high HIV RNA and low vaccine effectiveness. The vaccine was found to be effective in all but one stratum, which consisted of patients with HIV RNA above 105 copies/mL (IRR 1.0; 95% CI 0.9–1.1). Lastly, when data were stratified for time since immunization, a significant protective effect was demonstrated for the first 36 months. There was considerable heterogeneity in design, size and quality among the studies. Notably, the Lindenburg et al.