A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti-malarial drugs are discovered and developed have led to a dramatic increase in the number and diversity of new molecules presently in pre-clinical and early clinical development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Sub-region, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting molecules, or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well-tolerated to be used in vulnerable populations: in pregnancy, especially the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria.

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New developments in anti-malarial target candidate and product profiles

Immunity to malaria has been linked to the availability and function of helper CD4+ T cells, cytotoxic CD8+ T cells and γδ T cells that can respond to both the asymptomatic liver stage and the symptomatic blood stage of Plasmodium sp. infection. These T cell responses are also thought to be modulated by regulatory T cells. However, the precise mechanisms governing the development and function of Plasmodium-specific T cells and their capacity to form tissue-resident and long-lived memory populations are less well understood. The field has arrived at a point where the push for vaccines that exploit T cell-mediated immunity to malaria has made it imperative to define and reconcile the mechanisms that regulate the development and functions of Plasmodium-specific T cells. Here, we review our current understanding of the mechanisms by which T cell subsets orchestrate host resistance to Plasmodium infection on the basis of observational and mechanistic studies in humans, non-human primates and rodent models. We also examine the potential of new experimental strategies and human infection systems to inform a new generation of approaches to harness T cell responses against malaria. John Harty and colleagues explain how different subsets of CD4+ T cells, CD8+ T cells and γδ T cells respond to the Plasmodium parasites that cause malaria. They discuss the major challenges that need to be overcome in order to harness T cell responses for malaria vaccines and therapies.

/pdf/t-cell-mediated-immunity-to-malaria-37d1y9rcw9.pdf

T cell-mediated immunity to malaria

Controlled human malaria infection (CHMI) accelerates development of anti-malarial interventions. So far, CHMI is done by exposure of volunteers to bites of five mosquitoes carrying Plasmodium falciparum sporozoites (PfSPZ), a technique available in only a few centres worldwide. Mosquito-mediated CHMI is logistically complex, exact PfSPZ dosage is impossible and live mosquito-based interventions are not suitable for further clinical development. An open-labelled, randomized, dose-finding study in 18–45 year old, healthy, malaria-naive volunteers was performed to assess if intravenous (IV) injection of 50 to 3,200 aseptic, purified, cryopreserved PfSPZ is safe and achieves infection kinetics comparable to published data of mosquito-mediated CHMI. An independent study site verified the fully infectious dose using direct venous inoculation of PfSPZ. Parasite kinetics were assessed by thick blood smear microscopy and quantitative real time PCR. IV inoculation with 50, 200, 800, or 3,200 PfSPZ led to parasitaemia in 1/3, 1/3, 7/9, and 9/9 volunteers, respectively. The geometric mean pre-patent period (GMPPP) was 11.2 days (range 10.5–12.5) in the 3,200 PfSPZ IV group. Subsequently, six volunteers received 3,200 PfSPZ by direct venous inoculation at an independent investigational site. All six developed parasitaemia (GMPPP: 11.4 days, range: 10.4–12.3). Inoculation of PfSPZ was safe. Infection rate and pre-patent period depended on dose, and injection of 3,200 PfSPZ led to a GMPPP similar to CHMI with five PfSPZ-infected mosquitoes. The infectious dose of PfSPZ predicted dosage of radiation-attenuated PfSPZ required for successful vaccination. IV inoculation of PfSPZ is safe, well tolerated and highly reproducible. It shall further accelerate development of anti-malarial interventions through standardization and facilitation of CHMI. Beyond this, rational dose selection for whole PfSPZ-based immunization and complex study designs are now possible. ClinicalTrials.gov NCT01624961
 and NCT01771848
 .

/pdf/direct-venous-inoculation-of-plasmodium-falciparum-wpdj0hl4l5.pdf

Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. Background. Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point. Methods. Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data. Results. FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine- or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR. Conclusions. FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates. Clinical Trials Registration. NCT02044198.

Demonstration of the blood-stage plasmodium falciparum controlled human malaria infection model to assess efficacy of the p. falciparum apical membrane antigen 1 Vaccine, FMP2.1/AS01

Controlled human infection model (CHIM) studies have pivotal importance in vaccine development, being useful for proof of concept, pathogenesis, down-selection and immunogenicity studies.  To date, however, they have seldom been carried out in low and middle income countries (LMIC), which is where the greatest burden of vaccine preventable illness is found.  This workshop discussed the benefits and barriers to CHIM studies in Malawi.  Benefits include improved vaccine effectiveness and host country capacity development in clinical, laboratory and governance domains.  Barriers include acceptability, safety and regulatory issues. The report suggests a framework by which ethical, laboratory, scientific and governance issues may be addressed by investigators considering or planning CHIM in LMIC.

A framework for Controlled Human Infection Model (CHIM) studies in Malawi: Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi.

Controlled human malaria infection (CHMI) by mosquito bite has been used to assess new anti-malaria interventions in > 1,500 volunteers since development of methods for infecting mosquitoes by feeding on Plasmodium falciparum (Pf) gametocyte cultures. Such CHMIs have never been used in Africa. Aseptic, purified, cryopreserved Pf sporozoites, PfSPZ Challenge, were used to infect Dutch volunteers by intradermal injection. We conducted a double-blind, placebo-controlled trial to assess safety and infectivity of PfSPZ Challenge in adult male Tanzanians. Volunteers were injected intradermally with 10,000 (N = 12) or 25,000 (N = 12) PfSPZ or normal saline (N = 6). PfSPZ Challenge was well tolerated and safe. Eleven of 12 and 10 of 11 subjects, who received 10,000 and 25,000 PfSPZ, developed parasitemia. In 10,000 versus 25,000 PfSPZ groups geometric mean days from injection to Pf positivity by thick blood film was 15.4 versus 13.5 (P = 0.023). Alpha-thalassemia heterozygosity had no apparent effect on infectivity. PfSPZ Challenge was safe, well tolerated, and infectious.

SHEKALAGHE AND OTHERS INJECTION OF TANZANIANS WITH P. FALCIPARUM SPOROZOITES Controlled Human Malaria Infection of Tanzanians by Intradermal Injection of Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites

Controlled human malaria infection (CHMI) is a powerful tool to evaluate malaria vaccine and prophylactic drug efficacy. Until recently CHMI was only carried out by the bite of infected mosquitoes. A parenteral method of CHMI would standardize Plasmodium falciparum sporozoite (PfSPZ) administration, eliminate the need for expensive challenge facility infrastructure, and allow for use of many P. falciparum strains. Recently, intradermal (ID) injection of aseptic, purified, cryopreserved PfSPZ was shown to induce P. falciparum malaria; however, 100% infection rates were not achieved by ID injection. To optimize ID PfSPZ dosing so as to achieve 100% infection, 30 adults aged 18-45 years were randomized to one of six groups composed of five volunteers each. The parameters of dose (1 × 10(4) versus 5 × 10(4) PfSPZ total dose per volunteer), number of injections (two versus eight), and aliquot volume per ID injection (10 μL versus 50 μL) were studied. Three groups attained 100% infection: 1 × 10(4) PfSPZ in 50 μL/2 doses, 1 × 10(4) PfSPZ in 10 μL/2 doses, and 5 × 10(4) PfSPZ in 10 μL/8 doses. The group that received 5 × 10(4) PfSPZ total dose in eight 10 μL injections had a 100% infection rate and the shortest prepatent period (mean of 12.7 days), approaching the prepatent period for the current CHMI standard of five infected mosquitoes.

Optimizing Intradermal Administration of Cryopreserved Plasmodium falciparum Sporozoites in Controlled Human Malaria Infection

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SHEKALAGHE AND OTHERS INJECTION OF TANZANIANS WITH P. FALCIPARUM SPOROZOITES Controlled Human Malaria Infection of Tanzanians by Intradermal Injection of Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites

Optimizing Intradermal Administration of Cryopreserved Plasmodium falciparum Sporozoites in Controlled Human Malaria Infection