Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.

SummaryIn a number of developing countries there is reportedly a high incidence of the availability of substandard drugs. T h e majority of these reports d o not contain quantitative data to support these claims, nor d o they describe the methodology employed for the quality assessment. Many assume counterfeiting as the reason for the poor quality and in some cases this is not justified. We collected 96 samples of chloroquine and selected antibacterials from Nigeria and Thailand in a controlled and methodical manner and analysed them using appropriately validated methods based on high-performance liquid chromatography capable of detecting drug-related impurities and quantifying active drug(s). The results indicate that 36.5% of the samples were substandard with respect to pharmacopoeia1 limits. Decomposition was the cause of poor quality in a number of the samples but overall, poor manufacturing appeared to be prevalent. The analyses generated little evidence to indicate fraudulent manufacturing. Treatment failure and drug-resistance are possible consequences of the use of substandard drugs.

We characterized vaccine-induced cellular responses to rabies virus in naive adult volunteers. Contrary to current paradigms, we observed potent and prolonged in vitro NK cell cytokine production and degranulation responses after restimulation of PBMCs with inactivated rabies virus in vaccinated, but not in unvaccinated, individuals. This “recall” NK cell response was absolutely dependent on Ag-specific IL-2 from CD45RO+ CD4+ T cells as well as IL-12 and IL-18 from accessory cells. Importantly, NK cells represented over 70% of all IFN-γ–secreting and degranulating cells in the first 12–18 h after virus rechallenge indicating they may be required for rapid control of infection after vaccination. Activation of NK cells may be a critical function of IL-2–secreting effector memory T cells. Although IL-2–dependent postvaccination NK cell activation has been reported previously, this is the first time the magnitude of this effect and its contribution to the overall vaccine-induced response has been appreciated and the mechanisms of NK activation postvaccination have been elucidated. Our data will allow standard protocols for evaluating vaccine-induced immunity to be adapted to assess NK cell effector responses.