Development of a highly effective vaccine or antibodies for prevention and ultimately elimination of malaria is urgently needed. Here, we report the isolation of a number of human monoclonal antibodies (mAbs) directed against the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) from several subjects immunized with an attenuated whole sporozoite (SPZ) vaccine (Sanaria® PfSPZ Vaccine). Passive transfer of one of these antibodies, mAb CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. Stoichiometry and affinity of mAb CIS43 for PfCSP indicate two sequential multivalent binding events to six sites: the first 7-fold higher affinity binding event is to a unique “junctional” epitope positioned between the N-terminus and the central repeat domain of PfCSP. Moreover, mAb CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Crystal structures of the CIS43 fragment antigen binding (Fab) in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope’s conformational flexibility, and defined NPN as the structural repeat motif. The demonstration that mAb CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next generation rational vaccine design.

Interhemispheric inhibition is thought to mediate cortical rivalry between the two hemispheres through callosal input. The long-lasting form of this inhibition is believed to operate via γ-aminobutyric acid type B (GABA(B)) receptors, but the process is poorly understood at the cellular level. We found that the firing of layer 5 pyramidal neurons in rat somatosensory cortex due to contralateral sensory stimulation was inhibited for hundreds of milliseconds when paired with ipsilateral stimulation. The inhibition acted directly on apical dendrites via layer 1 interneurons but was silent in the absence of pyramidal cell firing, relying on metabotropic inhibition of active dendritic currents recruited during neuronal activity. The results not only reveal the microcircuitry underlying interhemispheric inhibition but also demonstrate the importance of active dendritic properties for cortical output.

Abstract. Evaluations of the African childhood malaria burden do not fully quantify the contributions of cerebral malaria (CM), CM-associated neurological sequelae, malarial anemia, respiratory distress, hypoglycemia, and pregnancy-related complications. We estimated the impact of these malaria manifestations on members of the African population Ͻ 5 years old. Calculations were based on an extensive literature review that used National Library of Medicine search engines, other bibliographic sources, and demographic data. In sub-Saharan Africa, CM annually affects 575,000 children Ͻ 5 years of age and 110,000 (ϳ19% case fatality rate [CFR]) die. Childhood survivors of CM experience developmental and behavioral impairments: each year, 9,000-19,000 children (Ͼ 2% of survivors of CM) Ͻ 5 years of age in Africa experience neurological complications lasting Ͼ 6 months. Severe malarial anemia heavily burdens hospitals with rising admission and CFRs and with treatments that are complicated by limited and sometimes contaminated blood supplies. Severe malarial anemia occurs 1.42-5.66 million times annually and kills 190,000-974,000 (Ͼ 13% CFR) children Ͻ 5 years of age annually. Respiratory distress, hypoglycemia, and overlapping clinical manifestations cause 1.12-1.99 million cases and Ͼ 225,000 (Ͼ 18% CFR) additional deaths among African children with malaria. Maternal, placental, or fetal malaria infection during pregnancy adversely affects development and survival of fetuses and newborns through low birth weight (LBW), maternal anemia, and possibly abortion and stillbirth. Between 167,000 and 967,000 cases of malaria-associated LBW occur yearly; malaria-induced LBW kills 62,000-363,000 (Ͼ 38% CFR) newborns each year. All the gaps in the burden comprise 0.4-1.7 million deaths annually, Ͼ 50% of which are due to severe malarial anemia. These malaria-induced medical problems constitute major clinical, public health, and research challenges in that they may contribute to more than double the mortality than is generally acknowledged.

Abstract.Sensitive field-deployable diagnostic tests can assist malaria programs in achieving elimination. The performance of a new Alere™ Malaria Ag P.f Ultra Sensitive rapid diagnostic test (uRDT) was compared with the currently available SD Bioline Malaria Ag P.f RDT in blood specimens from asymptomatic individuals in Nagongera, Uganda, and in a Karen Village, Myanmar, representative of high- and low-transmission areas, respectively, as well as in pretreatment specimens from study participants from four Plasmodium falciparum-induced blood-stage malaria (IBSM) studies. A quantitative reverse transcription PCR (qRT-PCR) and a highly sensitive enzyme-linked immunosorbent assay (ELISA) test for histidine-rich protein II (HRP2) were used as reference assays. The uRDT showed a greater than 10-fold lower limit of detection for HRP2 compared with the RDT. The sensitivity of the uRDT was 84% and 44% against qRT-PCR in Uganda and Myanmar, respectively, and that of the RDT was 62% and 0% for the same two sites. The specificities of the uRDT were 92% and 99.8% against qRT-PCR for Uganda and Myanmar, respectively, and 99% and 99.8% against the HRP2 reference ELISA. The RDT had specificities of 95% and 100% against qRT-PCR for Uganda and Myanmar, respectively, and 96% and 100% against the HRP2 reference ELISA. The uRDT detected new infections in IBSM study participants 1.5 days sooner than the RDT. The uRDT has the same workflow as currently available RDTs, but improved performance characteristics to identify asymptomatic malaria infections. The uRDT may be a useful tool for malaria elimination strategies.

Malaria is an ancient disease that continues to cause enormous human morbidity and mortality. The life cycle of the causative parasite involves multiple tissues in two distinct host organisms, mosquitoes and humans. However, all the clinical symptoms of malaria are a consequence of infection of human erythrocytes. An understanding of the basic mechanisms that govern parasite invasion, remodeling, growth, and reinvasion of erythrocytes and the complex events leading to tissue pathology may yield new diagnostics and treatments for malaria. This approach is revealing a more complete picture of the most serious syndrome associated with this infection-cerebral malaria. We focus on the most recent understanding of the molecular basis of infection, summarize our finding from an ongoing pediatric cerebral malaria autopsy study in Malawi, and integrate these insights to malarial pathology.