Cumulative Fraction of Response for Once- and Twice-Daily Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis.

Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under the drug concentration-time curve over 24 h divided by MIC (AUC0-24/MIC), with a PDT of 252. Second, in the hollow-fiber system model of tuberculosis, plasma-equivalent PDTs were identified as an AUC0-24/MIC of 195 in log-phase bacteria and 201 in pH 5.8 cultures. Third, delamanid plasma AUC0-24/MIC and sputum bacterial decline data from two early bactericidal activity trials identified a clinical PDT of AUC0-24/MIC of 171. Finally, the CFRs for the currently approved 100-mg BID dose were determined to be above 95% in two MDR-TB clinical trials. The CFR for the 200-mg QD dose, evaluated in a trial in which delamanid was administered as 100 mg BID for 8 weeks plus 200 mg QD for 18 weeks, was 89.3% based on the mouse PDT and >90% on the other PDTs. QTcF (QTc interval corrected for heart rate by Fridericia's formula) prolongation was approximately 50% lower for the 200 mg QD dose than the 100 mg BID dose. In conclusion, while CFRs of 100 mg BID and 200 mg QD delamanid were close to or above 90% in patients with MDR-TB, more-convenient once-daily dosing of delamanid is feasible and likely to have less effect on QTcF prolongation.

A baculovirus dual expression system-based malaria vaccine induces strong protection against Plasmodium berghei sporozoite challenge in mice.

We have previously shown that a recombinant baculovirus that displays Plasmodium berghei circumsporozoite protein (PbCSP), a homolog of the leading human malaria vaccine candidate, on the viral envelope protected 60% of mice against P. berghei infection. Here, we describe a second-generation baculovirus vaccine based on the "baculovirus dual expression system," which drives PbCSP expression by a dual promoter that consists of tandemly arranged baculovirus-derived polyhedrin and mammal-derived cytomegalovirus promoters. The baculovirus-based PbCSP vaccine not only displayed PbCSP on the viral envelope but also expressed PbCSP upon transduction of mammalian cells. Immunization with the baculovirus-based PbCSP vaccine elicited high PbCSP-specific antibody titers (predominantly immunoglobulin G1 [IgG1] and IgG2a) and PbCSP-specific CD8(+) T-cell responses without extraneous immunological adjuvants in mice, indicating that there was induction of both Th1 and Th2 responses (a mixed Th1/Th2 response). Importantly, upon intramuscular inoculation, the baculovirus-based PbCSP vaccine conferred complete protection against sporozoite challenge. Thus, the baculovirus-based PbCSP vaccine induced strong protective immune responses against preerythrocytic parasites. These results introduce a novel concept for the baculovirus dual expression system that functions as both a subunit vaccine and a DNA vaccine and offer a promising new alternative to current human vaccine delivery platforms.