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

Virus-like particles (VLPs) are non-infectious self-assembling nanoparticles, useful in medicine and nanotechnology. Their repetitive molecularly-defined architecture is attractive for engineering multivalency, notably for vaccination. However, decorating VLPs with target-antigens by genetic fusion or chemical modification is time-consuming and often leads to capsid misassembly or antigen misfolding, hindering generation of protective immunity. Here we establish a platform for irreversibly decorating VLPs simply by mixing with protein antigen. SpyCatcher is a genetically-encoded protein designed to spontaneously form a covalent bond to its peptide-partner SpyTag. We expressed in E. coli VLPs from the bacteriophage AP205 genetically fused to SpyCatcher. We demonstrated quantitative covalent coupling to SpyCatcher-VLPs after mixing with SpyTag-linked to malaria antigens, including CIDR and Pfs25. In addition, we showed coupling to the VLPs for peptides relevant to cancer from epidermal growth factor receptor and telomerase. Injecting SpyCatcher-VLPs decorated with a malarial antigen efficiently induced antibody responses after only a single immunization. This simple, efficient and modular decoration of nanoparticles should accelerate vaccine development, as well as other applications of nanoparticle devices.

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Plug-and-Display: decoration of Virus-Like Particles via isopeptide bonds for modular immunization.

Current applications of nanoparticles in infectious diseases.

For over 100 years, vaccines have been one of the most effective medical interventions for reducing infectious disease, and are estimated to save millions of lives globally each year. Nevertheless, many diseases are not yet preventable by vaccination. This large unmet medical need demands further research and the development of novel vaccines with high efficacy and safety. Compared to the 19th and early 20th century vaccines that were made of killed, inactivated, or live-attenuated pathogens, modern vaccines containing isolated, highly purified antigenic protein subunits are safer but tend to induce lower levels of protective immunity. One strategy to overcome the latter is to design antigen nanoparticles: assemblies of polypeptides that present multiple copies of subunit antigens in well-ordered arrays with defined orientations that can potentially mimic the repetitiveness, geometry, size, and shape of the natural host-pathogen surface interactions. Such nanoparticles offer a collective strength of multiple binding sites (avidity) and can provide improved antigen stability and immunogenicity. Several exciting advances have emerged lately, including preclinical evidence that this strategy may be applicable for the development of innovative new vaccines, for example, protecting against influenza, human immunodeficiency virus, and respiratory syncytial virus. Here, we provide a concise review of a critical selection of data that demonstrate the potential of this field. In addition, we highlight how the use of self-assembling protein nanoparticles can be effectively combined with the emerging discipline of structural vaccinology for maximum impact in the rational design of vaccine antigens.

Self-assembling protein nanoparticles in the design of vaccines

Plasmodium sporozoites deposited in the skin following a mosquito bite must migrate and invade blood vessels to complete their development in the liver. Once in the bloodstream, sporozoites arrest in the liver sinusoids, but the molecular determinants that mediate this specific homing are not yet genetically defined. Here we investigate the involvement of the thrombospondin-related sporozoite protein (TRSP) in this process using knockout Plasmodium berghei parasites and in vivo bioluminescence imaging in mice. Resorting to a homing assay, trsp knockout sporozoites were found to arrest in the liver similar to control parasites. Moreover, we found no defects in the establishment of infection in mice following inoculation of trsp knockout sporozoites via intravenous and cutaneous injection or mosquito bite. Accordingly, mutant sporozoites were also able to successfully invade hepatocytes in vitro. Altogether, these results suggest TRSP may have a redundant role in the completion of the pre-erythrocytic phase of the malaria parasite. Nonetheless, identifying molecules with paramount roles in this phase could aid in the search for new antigens needed for the design of a protective vaccine against malaria.

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TRSP is dispensable for the Plasmodium pre-erythrocytic phase

The effect of air pollution on human physiological function in China: a longitudinal study

Air pollution and fasting blood glucose: A longitudinal study in China.

Brachial-ankle pulse wave velocity (baPWV) is an independent predictor of cardiovascular events and mortality. However, there is no related data on the association of baPWVwith coal workers’ pneumoconiosis (CWP). We explored the baPWV in subjects withCWP and the associated risk factors. Thiscase-control study included 1,007 male CWP cases without a history of stroke and coronary heart disease and 1,007 matched controls from the Kailuan cohort study. All of the participants underwent assessment for baPWV and traditional cardiovascular risk factors. The cumulative silica dust exposure (work history linked to a job-exposure matrix) was estimated for the CWP cases. Compared with the controls, the CWP cases had higher baPWV (1762.0 ± 355 cm/s vs. 1718.6 ± 354 cm/s, P = 0.006) and a higher risk of increased baPWV (defined as more than the median baPWV of the population distribution; odds ratio 1.43, 95% confidence interval 1.11–1.83) after adjusting for traditional cardiovascular risk factors. Age ≥60 years, body mass index, heart rate, and hypertension were all significantly associated with increased baPWV in the CWP cases. Compared to non-CWP subjects without hypertension, the odds ratios for increased baPWV gradually increased (P for trend, 0.001) across the CWP subjects without hypertension (odds ratio 1.20, 95%confidence interval 0.90–1.61), subjects with hypertension alone (odds ratio 2.54, 95% confidence interval 1.95–3.30), and CWP subjects with hypertension (odds ratio 3.34, 95% confidence interval 2.56–4.37). We detected a significant positive exposure-response relationship between silica dust-exposure quartiles and increased baPWV in CWP cases (P for trend < 0.001). For patients with CWP, increased baPWV was associated with traditional cardiovascular risk factors and long-term silica dust exposure.

/pdf/cross-section-analysis-of-coal-workers-pneumoconiosis-and-4fqp0t1baa.pdf

Taicheng Yao

Papers

The effect of air pollution on human physiological function in China: a longitudinal study

Air pollution and fasting blood glucose: A longitudinal study in China.

Cross-section analysis of coal workers' pneumoconiosis and higher brachial-ankle pulse wave velocity within Kailuan study.