IMRAS-A clinical trial of mosquito-bite immunization with live, radiation-attenuated P. falciparum sporozoites: Impact of immunization parameters on protective efficacy and generation of a repository of immunologic reagents.

Background: Immunization with radiation-attenuated sporozoites (RAS) by mosquito bite provides >90% sterile protection against Plasmodium falciparum (Pf) malaria in humans. RAS invade hepatocytes but do not replicate. CD8+ T cells recognizing parasite-derived peptides on the surface of infected hepatocytes are likely the primary protective mechanism.

Medical Abortion in Midwifery Scope of Practice: A Qualitative Exploration of the Attitudes of Registered Midwives in British Columbia.

Introduction: Across Canada and internationally, access to abortion remains challenging, particularly for those living in rural and remote communities. International research and policy call for the training of advanced practice clinicians, including midwives, to provide abortion services to fill the ever-increasing access gap. Research in other jurisdictions has examined the attitudes of midwives toward this potential expansion of scope of practice, but such studies have not been undertaken in British Columbia.

Abortion-related care and the role of the midwife: a global perspective.

Introduction: The International Confederation of Midwives (ICM) represents 132 midwifery associations in 113 countries. The ICM disseminates the Essential Competencies for Basic Midwifery Practice (EC) that describes the global scope of midwifery practice. The basic (core) and expanded (additional or optional) role of midwives in providing abortion-related care services was first described in 2010.

Controlled Human Malaria Infection at the Walter Reed Army Institute of Research: The Past, Present, and Future From an Entomological Perspective.

Thirty years ago, the Entomology Branch at the Walter Reed Army Institute of Research (WRAIR) performed the first controlled human malaria infection, in which lab-reared mosquitoes were infected with lab-cultured malaria parasites and allowed to feed on human volunteers. The development of this model was a turning point for pre-erythrocytic malaria vaccine research and, through decades of refinement, has supported 30 years of efficacy testing of a suite of antimalarial vaccines and drugs. In this article, we present a historical overview of the research that enabled the first challenge to occur and the modifications made to the challenge over time, a summary of the 104 challenges performed by WRAIR from the first into 2015, and a prospective look at what the next generation of challenges might entail.

Using infective mosquitoes to challenge monkeys with Plasmodium knowlesi in malaria vaccine studies.

Background: When rhesus monkeys (Macaca mulatta) are used to test malaria vaccines, animals are often challenged by the intravenous injection of sporozoites. However, natural exposure to malaria comes via mosquito bite, and antibodies can neutralize sporozoites as they traverse the skin. Thus, intravenous injection may not fairly assess humoral immunity from anti-sporozoite malaria vaccines.

First-in-human evaluation of genetically attenuated Plasmodium falciparum sporozoites administered by bite of Anopheles mosquitoes to adult volunteers.

Background: Immunization with genetically engineered, attenuated malaria parasites (GAP) that arrest during liver infection confers sterile protection in mouse malaria models. A first generation Plasmodium falciparum GAP (Pf p52(-)/p36(-) GAP) was previously generated by deletion of two pre-erythrocytic stage-expressed genes (P52 and P36) in the NF54 strain.

Methods: A first-in-human, proof-of-concept, safety and immunogenicity clinical trial in six human volunteers was conducted.

Mosquito bisection as a variable in estimates of PCR-derived malaria sporozoite rates.

Background: Highly sensitive polymerase chain reaction (PCR) methods offer an alternative to the light microscopy examination of mosquito salivary glands for the determination of malaria sporozoite rates in wild caught female Anopheles. Removal of mosquito abdomens is assumed to eliminate false positives caused by malaria oocyst DNA in the midgut. This assumption has not been tested with current gold standard PCR assays, and for the variety of conditions that specimens could encounter in the laboratory and field.

Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-gamma/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection.

Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed "LSA-NRC." We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system.

Preerythrocytic, live-attenuated Plasmodium falciparum vaccine candidates by design.

Falciparum malaria is initiated when Anopheles mosquitoes transmit the Plasmodium sporozoite stage during a blood meal. Irradiated sporozoites confer sterile protection against subsequent malaria infection in animal models and humans. This level of protection is unmatched by current recombinant malaria vaccines.

Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection.

Background: To further increase the efficacy of malaria vaccine RTS,S/AS02A, we tested the RTS,S antigen formulated using the AS01B Adjuvant System (GlaxoSmithKline Biologicals).

Methods: In a double-blind, randomized trial, 102 healthy volunteers were evenly allocated to receive RTS,S/AS01B or RTS,S/AS02A vaccine at months 0, 1, and 2 of the study, followed by malaria challenge. Protected vaccine recipients were rechallenged 5 months later.

Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-1) administered in adjuvant system AS01B or AS02A.

Background: This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems.

Methodology/principal Findings: After a preliminary safety evaluation of low dose AMA-1/AS01B (10 microg/0.5 mL) in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 microg/0.

Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research.

Background: Immunization with RTS,S/AS02 consistently protects some vaccinees against malaria infection in experimental challenges and in field trials. A brief immunization schedule against falciparum malaria would be compatible with the Expanded Programme on Immunization, or in combination with other prevention measures, interrupt epidemic malaria or protect individuals upon sudden travel to an endemic area.

Methods: We conducted an open label, Phase 2a trial of two different full dose schedules of RTS,S/AS02 in 40 healthy malaria-naïve adults.

A phase I/IIa safety, immunogenicity, and efficacy bridging randomized study of a two-dose regimen of liquid and lyophilized formulations of the candidate malaria vaccine RTS,S/AS02A in malaria-naïve adults.

We conducted an open-label safety and immunogenicity bridging study that compared liquid and lyophilized formulations of the candidate malaria vaccine RTS,S formulated in AS02A in 34 healthy, malaria-naïve adults at WRAIR. Volunteers received two doses of either formulation on a 0, 1-month schedule. Both vaccines were well tolerated and similarly immunogenic.

Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites.

During 1989-1999, 11 volunteers were immunized by the bites of 1001-2927 irradiated mosquitoes harboring infectious sporozoites of Plasmodium falciparum (Pf) strain NF54 or clone 3D7/NF54. Ten volunteers were first challenged by the bites of Pf-infected mosquitoes 2-9 weeks after the last immunization, and all were protected. A volunteer challenged 10 weeks after the last immunization was not protected.

Causal prophylactic efficacy of atovaquone-proguanil (Malarone) in a human challenge model.

Plasmodia infect the liver for about 7 days before subsequently infecting the blood. Present prophylaxis against Plasmodium falciparum malaria employs agents that primarily kill blood stages and must be continued for 28 days after the last exposure. Atovaquone-proguanil (Malarone) is a new antimalarial agent that is licensed in 35 countries as treatment against blood-stage infection, but its components (atovaquone and proguanil) have separately been shown to be active also against liver stages.

Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria.

After initial successful evaluation of the circumsporozoite-based vaccine RTS,S/SBAS2, developed by SmithKline Beecham Biologicals with the Walter Reed Army Institute of Research, protective efficacy of several regimens against Plasmodium falciparum challenge was determined. A controlled phase 1/2a study evaluated 1 or 2 standard doses of RTS,S/SBAS2 in 2 groups whose members received open-label therapy and 3 immunizations in blinded groups who received standard, one-half, or one-fifth doses. RTS,S/SBAS2 was safe and immunogenic in all groups.

Long-term efficacy and immune responses following immunization with the RTS,S malaria vaccine.

The malaria sporozoite vaccine candidate RTS,S, formulated with an oil-in-water emulsion plus the immunostimulants monophosphoryl lipid A and the saponin derivative QS21 (vaccine 3), recently showed superior efficacy over two other experimental formulations. Immunized volunteers were followed to determine the duration of protective immune responses. Antibody levels decreased to between one-third and one-half of peak values 6 months after the last dose of vaccine.

Notes on the routine intravenous use of isometamidium in the control of bovine trypanosomiasis on the Kenya coast.

Various chemotherapeutic regimes were used to control trypanosomiasis in 3,000 Boran cattle on an estate on the Kenya coast. Recently the therapeutic use of isometamidium by the intravenous route was adopted to treat individual trypanosome-infected cattle. This was in order to overcome tissue reactions encountered after intramuscular injection and also to control a "thin cow" syndrome attributed to chronic trypanosomiasis.

Chemical evolution and the evolution of the earth's crust.

It is hypothesized that there is a close relationship between the geologic evolution of the global plates of the Earth's crust and the chemical evolution of life on the Earth. Characteristics of the axes of plate spreading are discussed in relation to postulated environments conductive to the synthesis of chemical compounds thought to be important biological precursors. Likely locations for in situ measurements to test the hypothesis are identified.

Auxin Does Not Alter the Permeability of Pea Segments to Tritium-labeled Water.

The possibility of an auxin effect on the permeability of pea (Pisum sativum L. ev. Alaska) segments to tritium-labeled water has been investigated by three separate laboratories, and the combined results are presented.

Activation of Avena coleoptile cell wall glycosidases by hydrogen ions and auxin.

Several cell wall-bound glycosidases present in Avena sativa coleoptiles were assayed by following the hydrolysis of p-nitrophenyl-glycosides. Particular emphasis was placed on characterizing some parameters affecting the activity of beta-galactosidase. The pH optimum of this enzyme is 4.

Prebiotic synthesis of propiolaldehyde and nicotinamide.

We have identified propiololdehyde as a product of the action of an electric discharge on mixtures of methane and water or methane, nitrogen, and water. The aldehyde reacts with cyanoacetaldehyde and ammonia (other "prebiological molecules") to yield nicotinonitrile. This substance can be hydrolyzed to nicotinamide and nicotinic acid.