BackgroundGene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection.Methodology/Principal FindingsThe vaccine regimen was three monthly doses of two DNA plasmids (DNA) followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad). The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea), possibly related to immunization, was severe (Grade 3), preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27%) were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44–817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5–102) and were not associated with protection. Ex vivo IFN-γ ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13–408; AMA1 348, range 88–1270) and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p = 0.019). Flow cytometry identified predominant IFN-γ mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant.SignificanceThe DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%). Protection was associated with cell-mediated immunity to AMA1, with CSP probably contributing. Substituting a low seroprevalence vector for Ad5 and supplementing CSP/AMA1 with additional antigens may improve protection.Trial RegistrationClinicalTrials.govNCT00870987.

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Among recently redeployed combat veterans, clinically significant sleep disturbances and problems with sleep-disordered breathing are common but nonspecific findings across primary diagnoses of PTSD, TBI, major depression, and anxiety disorder, whereas more subtle differences in sleep architecture and arousals as measured by overnight PSG recordings were modestly, but significantly, effective at distinguishing among the diagnostic groups.

Over the past 10 years, our ability to recognize, treat, and identify the morbidity associated with the upper airway resistance syndrome (UARS) has improved vastly. The diagnosis of this syndrome is dependent on a high degree of clinical suspicion, and in the presence of an already known pulmonary disease such as asthma, the identification of UARS may be elusive. Treatment of this condition has received more recent attention in the literature, with oral appliance therapy as a viable treatment option in place of the usual positive-pressure ventilation devices.

The results of the study suggest that the FVP can serve as an alternative to respiratory bands in the differential diagnosis of sleep disordered breathing, and in the recognition of patients appropriate for bilevel continuous positive airway pressure devices.