Pf7: an open dataset of genome variation in 20,000 worldwide samples.

We describe the MalariaGEN Pf7 data resource, the seventh release of genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.

Ex vivo piperaquine resistance developed rapidly in Plasmodium falciparum isolates in northern Cambodia compared to Thailand.

Background: The recent dramatic decline in dihydroartemisinin-piperaquine (DHA-PPQ) efficacy in northwestern Cambodia has raised concerns about the rapid spread of piperaquine resistance just as DHA-PPQ is being introduced as first-line therapy in neighbouring countries.

Methods: Ex vivo parasite susceptibilities were tracked to determine the rate of progression of DHA, PPQ and mefloquine (MQ) resistance from sentinel sites on the Thai-Cambodian and Thai-Myanmar borders from 2010 to 2015. Immediate ex vivo (IEV) histidine-rich protein 2 (HRP-2) assays were used on fresh patient Plasmodium falciparum isolates to determine drug susceptibility profiles.

Temporal Dynamics of CD8+ T Cell Effector Responses during Primary HIV Infection.

The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution.

Expansion of Inefficient HIV-Specific CD8 T Cells during Acute Infection.

Unlabelled: Attrition within the CD4(+)T cell compartment, high viremia, and a cytokine storm characterize the early days after HIV infection. When the first emerging HIV-specific CD8(+)T cell responses gain control over viral replication it is incomplete, and clearance of HIV infection is not achieved even in the rare cases of individuals who spontaneously control viral replication to nearly immeasurably low levels. Thus, despite their partial ability to control viremia, HIV-specific CD8(+)T cell responses are insufficient to clear HIV infection.

Genetic architecture of artemisinin-resistant Plasmodium falciparum.

We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance.

Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial.

Background: An estimated 100 million people have symptomatic dengue infection every year. This is the first report of a phase 3 vaccine efficacy trial of a candidate dengue vaccine. We aimed to assess the efficacy of the CYD dengue vaccine against symptomatic, virologically confirmed dengue in children.

Causal prophylactic efficacy of primaquine, tafenoquine, and atovaquone-proguanil against Plasmodium cynomolgi in a rhesus monkey model.

Since the 1940s, the large animal model to assess novel causal prophylactic antimalarial agents has been the Plasmodium cynomolgi sporozoite-infected Indian-origin rhesus monkey. In 2009 the model was reassessed with 3 clinical standards: primaquine (PQ), tafenoquine (TQ), and atovaquone-proguanil. Both control monkeys were parasitemic on day 8 post-sporozoite inoculation on day 0.

Blackwater fever in an uncomplicated Plasmodium falciparum patient treated with dihydroartemisinin-piperaquine.

The mechanism of massive intravascular haemolysis occurring during the treatment of malaria infection resulting in haemoglobinuria, commonly known as blackwater fever (BWF), remains unknown. BWF is most often seen in those with severe malaria treated with amino-alcohol drugs, including quinine, mefloquine and halofantrine. The potential for drugs containing artemisinins, chloroquine or piperaquine to cause oxidant haemolysis is believed to be much lower, particularly during treatment of uncomplicated malaria.

Optimizing the HRP-2 in vitro malaria drug susceptibility assay using a reference clone to improve comparisons of Plasmodium falciparum field isolates.

Background: Apparent emerging artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia requires development of practical tools to monitor for resistant parasites. Although in vitro anti-malarial susceptibility tests are widely used, uncertainties remain regarding interpretation of P. falciparum field isolate values.

Correlation of protection against Japanese encephalitis virus and JE vaccine (IXIARO(®)) induced neutralizing antibody titers.

Immune sera from volunteers vaccinated in a blinded Phase 3 clinical trial with JE-VAX(®) and a new Japanese encephalitis virus (JEV) vaccine (IC51 or IXIARO), were tested for the ability to protect mice against lethal JEV challenge. Sera from IXIARO vaccinated subjects were pooled into four batches based on neutralizing antibody measured by plaque reduction neutralization test (PRNT(50) titer): high (∼200), medium (∼40-50), low (∼20) and negative (<10). Pooled sera from JE-VAX(®) vaccinated subjects (PRNT(50) titer∼55) and pooled JEV antibody negative pre-vaccination sera were used as controls.

Plasmodium falciparum: effect of anti-malarial drugs on the production and secretion characteristics of histidine-rich protein II.

Plasmodium falciparum histidine-rich protein II (HRP2) is one of the best documented malaria proteins. However, little is known about the development of HRP2 concentrations under the influence of anti-malarial drugs. HRP2 levels were determined in cell medium mixture, cellular compartment, and in culture supernatant using a double-site sandwich ELISA specific for HRP2.

Histidine-rich protein II: a novel approach to malaria drug sensitivity testing.

The production of histidine-rich protein II (HRP2), a histidine- and alanine-rich protein produced by Plasmodium falciparum, is closely associated with the development and proliferation of the parasite and therefore is perfectly suited to reflect growth inhibition as a measure of drug susceptibility. It was the aim of the present study to develop a malaria drug sensitivity assay based on the measurement of HRP2 in a simple enzyme-linked immunosorbent assay (ELISA). The new test proved to be as reliable as traditional in vitro assays, while it was considerably easier to establish and perform.