The association between the number of salivary gland sporozoites and the duration of the pre-patent period in humans (A,B,C) and mice (D,E,F).

<p>In panels A,B,D,E unvaccinated/untreated control infections are denoted by a solid line (and darker shade of colour) whilst humans given a pre-erythrocytic vaccine (PEV) candidate or mice given an anti-circumsporozoite protein antibody (PEV) are shown by a dashed line (lighter shade of colour). Panels (A) and (D) show the number of sporozoites in the salivary glands following blood-feeding used in the different experimental infections. Panels (B) and (E) show the survival curves predicted by the model for the time between sporozoite inoculation and patent parasitaemia. Grey, green, blue and red lines shows predictions for a vertebrate host with 5 bites from mosquitoes with 1–10, 11–100, 101–1000 and >1000 salivary gland sporozoites after blood-feeding, respectively (grey line is omitted from B as no human volunteers received bites solely from mosquitoes with 1–10 residual-sporozoites). Panels (C) and (F) show the ability of the best fit model to predict the time to patency for humans and mice. Each point gives the prediction for an individual volunteer according to the residual-sporozoite score of biting mosquitoes and whether they received a PEV (orange dots) or were untreated (blue dots).</p

The frequency and impact on the time to patency in humans of mosquito bites with ≤10 residual-sporozoites.

<p>Grey bars show how many volunteers received bites from mosquitoes with ≤10 salivary gland sporozoites. Black dots (and line) show model predictions for the mean time to patency for volunteers with different number of (≤10) bites. As the impact of the lightly infected bites will depend on the number of residual-sporozoites in the bites the volunteer received, in this example all volunteer receive 5 bites from mosquitoes with 101–1000 residual-sporozoites in addition to the extra mosquito bites with ≤10 residual-sporozoites.</p

The association between the number of salivary gland sporozoites and the probability of infection in humans (A,B,C) and mice (D,E,F).

<p>In panels A,B,D,E naïve infections are denoted by a darker shade of colour whilst hosts given an anti-circumsporozoite protein vaccine or antibody (Pre-Erythrocytic Vaccine -PEV) are a lighter shade. Unvaccinated control humans are excluded from the analysis in (A-C) as all received very high levels of parasite challenge and all developed infection (so there is no variability to test the association with residual-sporozoite load). Panels (A) and (D) show the number of sporozoites in the salivary glands following blood-feeding used in the different experimental infections (be it 0 (orange), 1–10 (purple), 11–100 (green), 101–1000 (blue) or >1000 (red). Panels (B) and (E) show model predictions of the probability that a single bite from a mosquito with a given number of salivary gland sporozoites following blood-feeding will induce patent infection (black lines show 95% confidence interval estimates on model predictions). Panels (C) and (F) show model predictions for overall probability of infection for each individual human and mouse and as estimated using the best fit model. Each point gives the prediction for an individual volunteer according to the number of bites they receive, the residual-sporozoite score of those individual bites (taken from panel (B) and (E) and whether they received a PEV (orange dots) or were untreated (blue dots).</p

Probability of Transmission of Malaria from Mosquito to Human Is Regulated by Mosquito Parasite Density in Naïve and Vaccinated Hosts.

Over a century since Ronald Ross discovered that malaria is caused by the bite of an infectious mosquito it is still unclear how the number of parasites injected influences disease transmission. Currently it is assumed that all mosquitoes with salivary gland sporozoites are equally infectious irrespective of the number of parasites they harbour, though this has never been rigorously tested. Here we analyse >1000 experimental infections of humans and mice and demonstrate a dose-dependency for probability of infection and the length of the host pre-patent period. Mosquitoes with a higher numbers of sporozoites in their salivary glands following blood-feeding are more likely to have caused infection (and have done so quicker) than mosquitoes with fewer parasites. A similar dose response for the probability of infection was seen for humans given a pre-erythrocytic vaccine candidate targeting circumsporozoite protein (CSP), and in mice with and without transfusion of anti-CSP antibodies. These interventions prevented infection more efficiently from bites made by mosquitoes with fewer parasites. The importance of parasite number has widespread implications across malariology, ranging from our basic understanding of the parasite, how vaccines are evaluated and the way in which transmission should be measured in the field. It also provides direct evidence for why the only registered malaria vaccine RTS,S was partially effective in recent clinical trials.TSC was supported by the UK Medical Research Council (MRC)/UK Department for International Development (DFID) under the MRC/DFID Concordat agreement (www.mrc.ac.uk). AMB received support from the PATH Malaria Vaccine Initiative (www.malariavaccine.org) and the MRC (MR/N00227X/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A novel multiple-stage antimalarial agent that inhibits protein synthesis.

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery

Corrigendum:A novel multiple-stage antimalarial agent that inhibits protein synthesis

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase

As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase.

As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment