Treatment for First Cytomegalovirus Infection Post-Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir.

BACKGROUND: Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated efficacy of maribavir with fewer treatment-limiting toxicities than valganciclovir. METHODS: In this multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT were stratified and randomized 1:1 to maribavir 400 mg twice daily or valganciclovir (dose-adjusted for renal clearance) for 8 weeks with 12 weeks of follow-up. The primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of noninferiority margin of 7.0%). The key secondary endpoint was a composite of the primary endpoint with no findings of CMV tissue-invasive disease at week 8 through week 16. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Among patients treated (273 maribavir; 274 valganciclovir), the primary endpoint of noninferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference: -7.7%; 95% confidence interval [CI]: -14.98, -.36; lower limit of 95% CI of treatment difference exceeded -7.0%). At week 16, 52.7% and 48.5% of patients treated (maribavir and valganciclovir, respectively) maintained CMV viremia clearance without tissue-invasive disease (adjusted difference: 4.4%; 95% CI: -3.91, 12.76). With maribavir (vs valganciclovir), fewer patients experienced neutropenia (16.1% and 52.9%) or discontinued due to TEAEs (27.8% and 41.2%). Discontinuations were mostly due to neutropenia (maribavir, 4.0%; valganciclovir, 17.5%). CONCLUSIONS: Although noninferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified noninferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Clinical Trials Registration. NCT02927067 [AURORA].

Bacillus Calmette-Guérin vaccination of human newborns induces T cells with complex cytokine and phenotypic profiles.

The immune response to vaccination with bacillus Calmette-Guérin (BCG), the only tuberculosis vaccine available, has not been fully characterized. We used multiparameter flow cytometry to examine specific T cell cytokine production and phenotypic profiles in blood from 10-wk-old infants routinely vaccinated with BCG at birth. Ex vivo stimulation of whole blood with BCG for 12 h induced expression of predominantly IFN-gamma, IL-2, and TNF-alpha in CD4+ T cells in seven distinct cytokine combinations. IL-4 and IL-10 expression was detected in CD4+ T cells at low frequencies and only in cells that did not coexpress type 1 cytokines. Specific CD8+ T cells were less frequent than CD4+ T cells and produced mainly IFN-gamma and/or IL-2 and less TNF-alpha, IL-4, and IL-10. Importantly, many mycobacteria-specific CD4+ and CD8+ T cells did not produce IFN-gamma. The predominant phenotype of BCG-specific type 1 T cells was that of effector cells, i.e., CD45RA-CCR7-CD27+, which may reflect persistence of Mycobacterium bovis BCG in infants until 10 wk of age. Among five phenotypic patterns of CD4+ T cells, central memory cells were more likely to be IL-2+ and effector cells were more likely to be IFN-gamma+. We concluded that neonatal vaccination with BCG induces T cells with a complex pattern of cytokine expression and phenotypes. Measuring IFN-gamma production alone underestimates the magnitude and complexity of the host cytokine response to BCG vaccination and may not be an optimal readout in studies of BCG and novel tuberculosis vaccination.

The effect of bacille Calmette-Guérin vaccine strain and route of administration on induced immune responses in vaccinated infants.

Vaccination with Mycobacterium bovis bacille Calmette-Guerin (BCG) has variable efficacy in preventing tuberculosis. Both BCG strain and route of administration have been implicated in determining efficacy; however, these variables are not considered in current clinical recommendations for vaccine choice. We evaluated antigen-specific immunity after percutaneous or intradermal administration of Japanese BCG or intradermal administration of Danish BCG. Ten weeks after vaccination of neonates, percutaneous Japanese BCG had induced significantly higher frequencies of BCG-specific interferon- gamma -producing CD4(+) and CD8(+) T cells in BCG-stimulated whole blood than did intradermal Danish BCG. Similarly, percutaneous vaccination with Japanese BCG resulted in significantly greater secretion of the T helper 1-type cytokines interferon- gamma, tumor necrosis factor- alpha , and interleukin-2; significantly lower secretion of the T helper 2-type cytokine interleukin-4; and greater CD4(+) and CD8(+) T cell proliferation. Thus, BCG strain and route of neonatal vaccination confer different levels of immune activation, which may affect the efficacy of the vaccine.