Telas de proteção em habitações para prevenção de doenças transmitidas por mosquitos: sinopse baseada em evidências

Contexto e objetivo: A transmissão de doenças por mosquitos afeta a população e a economia de todo o mundo. Há um número considerável de doenças que podem ser transmitidas por mosquitos, com destaque para a malária e a dengue, endêmica em regiões tropicais. Evidentemente, medidas preventivas são imprescindíveis para a redução da transmissão. Avaliar as evidências de efetividade das telas de proteção com e sem inseticida para prevenção de doenças transmitidas por mosquitos. Métodos: Trata-se de sinopse baseada em evidências. Procedeu-se à busca por estudos que associavam o uso de telas de proteção contra mosquitos à redução do contágio de doenças transmitidas por mosquitos em três bases de dados: PubMed (1966-2024), Portal BVS (1982-2024) e Epistemonikos (2024) e também no metabuscador de evidências TRIP DATABASE (2024). O desfecho de análise envolveu a efetividade das telas de proteção na redução de doenças transmitidas por mosquitos. Resultados: Foram encontradas 307 citações. Seis estudos (1 revisão sistemática e 5 ensaios clínicos) foram incluídos. Discussão: A maioria dos estudos envolveu a colocação de telas de proteção com inseticida, havendo evidência de alta certeza para redução de mortalidade por malária e redução na entrada de mosquitos nas habitações, mesmo com redes sem inseticida. Conclusões: Embora não haja robustez na evidência da efetividade das telas de proteção sem inseticidas contra mosquitos transmissores de doenças, o que demanda a necessidade de realização de novos estudos prospectivos, parece lícita e benéfica a utilização de telas de proteção em regiões endêmicas para doenças transmitidas por esses vetores.

Gene expression analysis of Anopheles Meigen, 1818 (Diptera: Culicidae) innate immunity after Plasmodium Marchiafava & Celli, 1885 (Apicomplexa) infection: Toward developing new malaria control strategies.

Despite the critical role of the Anopheles innate immune system in defending against Plasmodium infection, there is still limited information about the key immune mechanisms in Anopheles. This review assesses recent findings on the expression characteristics of immune-related genes in Anopheles following exposure to Plasmodium. A literature review, unrestricted by publication date, was conducted to evaluate immune-related gene expression in different organs of Anopheles after Plasmodium infection. Mosquito immune responses in the midgut are essential for reducing parasite populations. Additionally, innate immune responses in the salivary glands and hemocytes circulating in the hemocoel play key roles in defense against the parasite. Transcriptomic analysis of the mosquito's innate immune response to Plasmodium infection provides valuable insights into key immune mechanisms in mosquito defense. A deeper understanding of immune mechanisms in different organs of Anopheles following Plasmodium infection will aid in discovering critical targets for designing novel control strategies.

Obesity, diabetes, Plasmodium infection, and severe malaria in adults: A systematic review and meta-analysis.

BACKGROUND: This study aimed to investigate existing evidence regarding the associations of obesity and diabetes with Plasmodium infection and severe malaria in adults. METHODS: We comprehensively searched relevant studies using EMBASE, MEDLINE, Global Health, and CINAHL. The primary exposures were obesity and diabetes. The primary outcomes were Plasmodium infection and severe malaria. We performed meta-analyses to pool unadjusted and adjusted odds ratios (ORs) using a random-effects model. RESULTS: We found 9 studies that met our inclusion criteria; all these studies were eligible for meta-analyses. None of the 9 studies investigated the potential link between obesity and Plasmodium infection. The meta-analysis results showed that there was no statistically significant relationship between obesity and severe malaria (two studies), diabetes and Plasmodium infection (five studies), or diabetes and severe malaria (three studies). CONCLUSION: Our study findings showed that obesity was not associated with severe malaria, and diabetes was not associated with neither Plasmodium infection nor severe malaria. Additional epidemiological studies should be conducted to elucidate the relationships between obesity, diabetes, and Plasmodium infection.

Microfluidic device: A versatile biosensor platform to multiplex aptamer-based detection of malaria biomarkers.

Plasmodium falciparum malaria remains a dominant infectious disease that affects Africa than the rest of the world, considering its associated cases and death rates. It's a febrile illness that produces several reliable biomarkers, for example, P. falciparum lactate dehydrogenase (PfLDH), P. falciparum Plasmodium glutamate dehydrogenase (PfGDH), and P. falciparum histidine-rich proteins (HRP-II) in blood circulatory system that can easily be employed as targets in rapid diagnostic tests (RDTs). In recent times, several DNA aptamers have been developed via SELEX technology to detect some specific malaria biomarkers (PfLDH, PvLDH, HRP-II, PfGDH) in a biosensor mode with good binding affinity properties to overcome the trend of cross-reactivity, limited sensitivity and stability problems that have been observed with immunodiagnostics. In this review, we summarized existing diagnostic methods and relevant biomarkers to suggest promising approaches to develop sensitive and species-specific multiplexed diagnostic devices enabling effective detection of malaria in complex biological matrices and surveillance in the endemic region.

Adaptation of lot quality assurance sampling to monitor seasonal malaria chemoprevention delivery performance.

Malaria Consortium supports delivery of seasonal malaria chemoprevention (SMC) to children ages 3-59 months using sulfadoxine-pyrimethamine plus amodiaquine. Lot quality assurance sampling (LQAS) was adapted as a cost-efficient method for end-of-cycle SMC monitoring surveys across supported countries and an implementation challenges reporting system was established in Nigeria. We present a case study of its application in Nasarawa State. LQAS facilitated timely local performance assessment across 16 indicators. Development of new reporting tools has played a key role in stimulating national-level discussions on improvements to SMC supervisory processes and implementer training and provided a framework for engagement with local stakeholders.

Range dynamics of Anopheles mosquitoes in Africa suggest a significant increase in the malaria transmission risk.

Despite a more than 100-year effort to combat malaria, it remains one of the most malignant infectious diseases globally, especially in Africa. Malaria is transmitted by several Anopheles mosquitoes. However, until now few studies have investigated future range dynamics of major An. mosquitoes in Africa through a unified scheme. Through a unified scheme, we developed 21 species distribution models to predict the range dynamics of 21 major An. species in Africa under future scenarios and also examined their overall range dynamic patterns mainly through suitability overlap index and range overlap index. Although future range dynamics varied substantially among the 21 An. species, we predicted large future range expansions for all 21 An. species, and increases in suitability overlap index were detected in more than 90% of the African continent for all future scenarios. Additionally, we predicted high range overlap index in West Africa, East Africa, South Sudan, Angola, and the Democratic Republic of the Congo under future scenarios. Although the relative impacts of land use, topography and climate variables on the range dynamics depended on species and spatial scale, climate played the strongest roles in the range dynamics of most species. Africa might face an increasing risk of malaria transmissions in the future, and better strategies are required to address this problem. Mitigating climate change and human disturbance of natural ecosystems might be essential to reduce the proliferation of An. species and the risk of malaria transmissions in Africa in the future. Our strategies against their impacts should be species-specific.

Exploring the hidden mental health consequences of malaria beyond the fever.

Malaria morbidity has various presentations and the focus now shifts to uncommon signs and symptoms of malaria infection such as cognitive impairment to address the morbidity when the mortality declines. About 50% of children admitted to hospitals due to malaria experience neurological complications due to factors like low blood sugar, inflammation, elevated pressure, decreased oxygen levels, and excitotoxicity. Malaria during pregnancy negatively also impacts children's cognitive, behavioral, and executive function leading to neurodevelopmental delay due to increased susceptibility which can significantly affect maternal and child health, leading to higher rates of underestimated factors like anxiety, depression, and PTSD. Despite having the world's second-largest tribal population, India's indigenous and tribal communities and their mental health are less explored and less understood. Western psychological tools and neurocognitive assessment tools are not universally applicable, thus necessitating the development of tailored tools to investigate psychological or neurocognitive impairment. This paper has illuminated the hidden mental health consequences of malaria infection, emphasizing the prevalence, nature, and implications of psychological distress among affected individuals. The findings underscore the importance of recognizing and addressing these psychological consequences in the holistic management and prevention of malaria and its mental health consequences.

An observational analysis of the impact of indoor residual spraying in two distinct contexts of Burkina Faso.

BACKGROUND: Indoor residual spraying (IRS) is a cornerstone malaria control intervention in Burkina Faso. From 2018 to 2021, non-pyrethroid IRS was implemented annually in two regions of Burkina Faso with distinct malaria transmission patterns, concurrently with annual seasonal malaria chemoprevention (SMC), and a mass insecticide-treated net (ITN) distribution in 2019. METHODS: A retrospective quasi-experimental approach was used to evaluate the impact of the 2018, 2020, and 2021 IRS campaigns on routinely reported confirmed malaria case incidence at health facilities. The 2019 campaign was excluded due to lack of data reporting during a health sector strike. Controlled interrupted time series models were fit to detect changes in level and trend in malaria case incidence rates following each IRS campaign when compared to the baseline period 24-months before IRS. IRS districts Solenzo (Sudano-Sahelien climate), and Kampti (tropical climate) were compared with neighbouring control districts and the analyses were stratified by region. Modelled health facility catchment population estimates based on travel time to health facilities and weighted by non-malaria outpatient visits were used as an offset. The study period encompassed July 2016 through June 2022, excluding July 2018 to June 2019. RESULTS: District-level population and structure coverage achieved by IRS campaigns was greater than 85% in 2018, 2020, and 2021 in Solenzo and Kampti. In Solenzo a significant difference in malaria case incidence rates was detected after the 2018 campaign (IRR = 0.683; 95% CI 0.564-0.827) when compared to the control district. The effect was not detected following the 2020 or 2021 IRS campaigns. In Kampti, estimated malaria incidence rates were between 36 and 38% lower than in the control district following all three IRS campaigns compared to the baseline period. CONCLUSIONS: Implementation of IRS in Kampti, a tropical region of Burkina Faso, appeared to have a consistent significant beneficial impact on malaria case rates. An initial positive impact in Solenzo after the first IRS campaign was not sustained in the successive evaluated IRS campaigns. This study points to a differential effect of IRS in different malaria transmission settings and in combination with ITN and SMC implementation.

Health facility-based prevalence of typhoid fever, typhus and malaria among individuals suspected of acute febrile illnesses in Southwest Region, Ethiopia.

Background: Acute febrile illnesses such as typhoid fever, typhus, and malaria are still major causes of hospital admission in many parts of Ethiopia. However, there are substantial gaps in the monitoring systems, which result in a lack of knowledge about the geographic distribution and role of common pathogens, particularly in rural areas. Thus, this study was aimed at assessing the seroprevalence of typhoid fever, typhus, and malaria among suspected acute febrile patients at the MTU Teaching Hospital and Mizan-Aman Health Center, Southwest region of Ethiopia. Method: A health facility-based cross-sectional study was carried out from July to October 2022. Blood samples were collected from a total of 384 individuals. Widal and Weilfelix direct card agglutination and tube agglutination test methods were used for the Salmonella enterica serotype Typhi (S. typhi) and Rickettsia infections. The diagnosis of malaria was made using thick and thin blood smears. Questionnaires given by interviewers were used to gather information on risk factors and other sociodemographic factors. The data was analyzed using STATA/SE 14.0. Result: A total of 371 patients were tested for S. Typhi and Rickettsia infections using direct card agglutination and tube agglutination methods. Using the screening test, 20.5% (76/371) patients were reactive either for O or H antigens or both, of which 55.3% (42/76) were reactive by the titration test at the cutoff value ≥ 1:80. About 17.5% (65/371) were reactive to OX19 antigen by card agglutination test, and of which 58.5% (38/65) were reactive by the titration test at the cutoff value ≥ 1:80. The overall seroprevalence of S. Typhi and Rickettsia infections using combined direct card and tube agglutination techniques was 11.3% (42/371) and 10.2% (38/371), respectively. Out of 384 suspected malaria patients, 43 (11.2%) were found positive either for P. falciparum, 27 (7.03%), or P. vivax, 16 (4.2%). Conclusion: In this study, typhoid fever, typhus, and malaria were found among symptomatic acute febrile patients. To increase disease awareness, it is necessary to provide sustainable health education about risk factor behaviors, disease transmission, and prevention strategies. In addition, improving laboratory diagnosis services and early treatment may also lower the likelihood of potentially fatal consequences.

Haematological Profile in Patients With Acute Falciparum Malaria: A Hospital-Based Study.

Introduction Malaria is the most common parasitic disease affecting humans. Haematological alterations in malaria are expected, and these changes play a significant role in fatal complications. The present study aims to assess the clinical and haematological profile in patients with acute falciparum malaria and the significance of various haematological and coagulation alterations with the clinical severity of malaria. Methods The prospective cross-sectional study included 68 acute falciparum malaria cases. Thick and thin blood film microscopy and a rapid diagnostic kit were used to diagnose malaria. The cases were subjected to various haematological and biochemical investigations. Bone marrow aspiration samples were also collected. Using appropriate statistical methods, the findings were compared between severe and uncomplicated malaria cases. A p-value below 0.05 was considered significant. Results The participants' ages ranged from 14 to 78. Most participants (n = 51, 75%) were male and belonged to the lower income group (33, 48.5%). Significant variations in mean parasite count between severe and uncomplicated malaria cases (p-value < 0.01) were observed. The severe and uncomplicated groups showed significant differences in haemoglobin (gm/dL), haematocrit, red blood cell count, reticulocyte, serum iron, and ESR levels (p-value < 0.05). The severe malaria group had considerably reduced mean platelet counts (p-value < 0.01). Only five instances (7.3%) had an appropriate erythropoietic response after day 28. Erythroid hyperplasia with dyserythropoietic alterations was most common in patients with severe anaemia and low-grade parasitaemia. Conclusion Acute falciparum malaria is often associated with haematological alterations. Anaemia and thrombocytopenia were the most expected alterations associated with disease prognosis and mortality.

New directions for malaria vector control using geography and geospatial analysis.

As we strive towards the ambitious goal of malaria elimination, we must embrace integrated strategies and interventions. Like many diseases, malaria is heterogeneously distributed. This inherent spatial component means that geography and geospatial data is likely to have an important role in malaria control strategies. For instance, focussing interventions in areas where malaria risk is highest is likely to provide more cost-effective malaria control programmes. Equally, many malaria vector control strategies, particularly interventions like larval source management, would benefit from accurate maps of malaria vector habitats - sources of water that are used for malarial mosquito oviposition and larval development. In many landscapes, particularly in rural areas, the formation and persistence of these habitats is controlled by geographical factors, notably those related to hydrology. This is especially true for malaria vector species like Anopheles funestsus that show a preference for more permanent, often naturally occurring water sources like small rivers and spring-fed ponds. Previous work has embraced geographical concepts, techniques, and geospatial data for studying malaria risk and vector habitats. But there is much to be learnt if we are to fully exploit what the broader geographical discipline can offer in terms of operational malaria control, particularly in the face of a changing climate. This chapter outlines potential new directions related to several geographical concepts, data sources and analytical approaches, including terrain analysis, satellite imagery, drone technology and field-based observations. These directions are discussed within the context of designing new protocols and procedures that could be readily deployed within malaria control programmes, particularly those within sub-Saharan Africa, with a particular focus on experiences in the Kilombero Valley and the Zanzibar Archipelago, United Republic of Tanzania.

PfEMP1 and var genes - Still of key importance in Plasmodium falciparum malaria pathogenesis and immunity.

The most severe form of malaria, caused by infection with Plasmodium falciparum parasites, continues to be an important cause of human suffering and poverty. The P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of clonally variant antigens, which mediates the adhesion of infected erythrocytes to the vascular endothelium in various tissues and organs, is a central component of the pathogenesis of the disease and a key target of the acquired immune response to malaria. Much new knowledge has accumulated since we published a systematic overview of the PfEMP1 family almost ten years ago. In this chapter, we therefore aim to summarize research progress since 2015 on the structure, function, regulation etc. of this key protein family of arguably the most important human parasite. Recent insights regarding PfEMP1-specific immune responses and PfEMP1-specific vaccination against malaria, as well as an outlook for the coming years are also covered.

NDV targets the invasion pathway in malaria parasite through cell surface sialic acid interaction.

Merozoites utilize sialic acids on the red blood cell (RBC) cell surface to rapidly adhere to and invade the RBCs. Newcastle disease virus (NDV) displays a strong affinity toward membrane-bound sialic acids. Incubation of NDV with the malaria parasites dose-dependently reduces its cellular viability. The antiplasmodial activity of NDV is specific, as incubation with Japanese encephalitis virus, duck enteritis virus, infectious bronchitis virus, and influenza virus did not affect the parasite propagation. Interestingly, NDV is reducing more than 80% invasion when RBCs are pretreated with the virus. Removal of the RBC surface proteins or the NDV coat proteins results in disruption of the virus binding to RBC. It suggests the involvement of specific protein: ligand interaction in virus binding. We established that the virus engages with the parasitized RBCs (PRBCs) through its hemagglutinin neuraminidase (HN) protein by recognizing sialic acid-containing glycoproteins on the cell surface. Blocking of the HN protein with free sialic acid or anti-HN antibodies abolished the virus binding as well as its ability to reduce parasite growth. Interestingly, the purified HN from the virus alone could inhibit the parasite's growth in a dose-dependent manner. NDV binds strongly to knobless murine parasite strain Plasmodium yoelii and restricted the parasite growth in mice. Furthermore, the virus was found to preferentially target the PRBCs compared to normal erythrocytes. Immunolocalization studies reveal that NDV is localized on the plasma membrane as well as weakly inside the PRBC. NDV causes neither any infection nor aggregation of the human RBCs. Our findings suggest that NDV is a potential candidate for developing targeted drug delivery platforms for the Plasmodium-infected RBCs.

Semi-field evaluation of aquatic predators for the control of Anopheles funestus in rural south-eastern Tanzania.

BACKGROUND: Biological control is a promising alternative or complementary approach for controlling vector populations in response to the spread of insecticide resistance in malaria vectors. This study evaluated the efficacy of three selected potential predators on the density and fitness parameters of Anopheles funestus larvae in rural Tanzania. METHODS: Common predator families Aeshnidae (dragonflies), Coenagrionidae (damselflies), and Notonectidae (backswimmers) and An. funestus group larvae were collected from natural aquatic habitats in rural south-eastern Tanzania. Predators were starved for 12-h while An. funestus larvae were given fish food before starting the experiment. Anopheles funestus larvae were placed into artificial habitats containing predators, exposing them to potential predation. The number of surviving An. funestus larvae were counted every 24-h. An emergence traps were placed at the top of artificial habitats to capture emerging mosquitoes. Emerged mosquitoes were monitored until they died. Female wings were measured and used as a proxy for body size. Generalized linear mixed models (GLMM) with binomial variates at 95% CI and Cox proportional hazard models were used to assess the proportion of dead mosquitoes and the daily survival determined. RESULTS: There were significant differences in the number of emerged mosquitoes between the treatment and control groups (P < 0.001). Thus, all predator species played a significant role in reducing the density of An. funestus mosquitoes (P < 0.001). Furthermore, these predators had notable effects on the fitness parameters and survival of emerged mosquitoes (P < 0.001). Among the three predators studied, Coenagrionidae (damselflies) were most efficient followed by Notonectidae (backswimmers), with Aeshnidae (dragonflies) being the least efficient. CONCLUSION: Selected aquatic predators have the potential to reduce the survival and density of An. funestus larvae. They might eventually be included within an integrated malaria vector control strategy, ultimately leading to a reduction in malaria transmission.

Patient socio-demographics and clinical factors associated with malaria mortality: a case control study in the northern region of Ghana.

BACKGROUND: Ghana is a malaria-endemic country with the entire population at risk. The Northern region of the country recorded the highest malaria case fatality rate (CFR) for two consecutive years: 1.11% in 2013 and 1.07% in 2014. Even though the National Malaria Elimination Programme (NMEP) has achieved a reduction in malaria mortality, the existence of high case fatality in the Northern region was alarming. This study, therefore, aimed to determine the factors associated with malaria mortality in the northern region of Ghana to institute control measures. METHODS: An unmatched case control study was conducted from July 2015 to August 2015. The study population consisted of patients admitted to health facilities for severe malaria in the Northern region of Ghana. A case was defined as a patient diagnosed with severe malaria at an eligible health facility who died as a result of malaria. A control was a patient diagnosed with severe malaria admitted to an eligible health facility who did not die. Health facilities that recorded CFRs of 1.0% and above were randomly sampled for this study, after which, 10 cases and 20 controls were recruited from each health facility. Information on cases and controls was then abstracted from hospital records using an electronically deployed abstraction tool. Continuous variables were expressed as means and medians, and categorical variables as frequencies and proportions. Multivariable logistic regression was used to assess the strength of the association between malaria mortality and factors predictive of malaria mortality. A p-value of < 0.05 was considered statistically significant. RESULTS: In all, a total of 95 cases and 190 controls participated in this study. The median ages of cases and controls were 4.1 years (IQR = 21.6) and 5.7 years (IQR = 18.2), respectively. Fifty-four (56.8%) cases were females, while 93 (49.0%) of the controls were females. Factors associated with malaria mortality included: duration of hospital stay less than 24 h [aOR: 12.0, 95% CI (5.9-24.6)], severe pallor [aOR: 2.3, 95% CI (1.1-4.6)], children under 5 years [aOR: 2.8, 95% CI (1.4-5.6)], oral Artesunate/Amodiaquine administration [aOR: 0.4, 95% CI (0.2-0.9)] and sepsis as an additional diagnosis [aOR: 4.1, 95% CI (1.8-9.5)]. CONCLUSION: Predictors of malaria mortality in the Northern region include children under 5 years, severe pallor, sepsis as an additional diagnosis, and use of oral anti-malarial. Patients with severe pallor and sepsis as co-morbidities should receive proactive management. The NMEP and its partners should implement measures to strengthen the referral system, anaemia prevention and management, and retrain health workers on malaria case management. Malaria control interventions targeted at under five children in the region should be reviewed and enhanced.

Embedded-deep-learning-based sample-to-answer device for on-site malaria diagnosis.

Improvements in digital microscopy are critical for the development of a malaria diagnosis method that is accurate at the cellular level and exhibits satisfactory clinical performance. Digital microscopy can be enhanced by improving deep learning algorithms and achieving consistent staining results. In this study, a novel miLab™ device incorporating the solid hydrogel staining method was proposed for consistent blood film preparation, eliminating the use of complex equipment and liquid reagent maintenance. The miLab™ ensures consistent, high-quality, and reproducible blood films across various hematocrits by leveraging deformable staining patches. Embedded-deep-learning-enabled miLab™ was utilized to detect and classify malarial parasites from autofocused images of stained blood cells using an internal optical system. The results of this method were consistent with manual microscopy images. This method not only minimizes human error but also facilitates remote assistance and review by experts through digital image transmission. This method can set a new paradigm for on-site malaria diagnosis. The miLab™ algorithm for malaria detection achieved a total accuracy of 98.86% for infected red blood cell (RBC) classification. Clinical validation performed in Malawi demonstrated an overall percent agreement of 92.21%. Based on these results, miLab™ can become a reliable and efficient tool for decentralized malaria diagnosis.

Plasmodium falciparum transmission based on merozoite surface protein 1 (msp1) and 2 (msp2) gene diversity and antibody responses in Ibadan, Nigeria.

Background: Nigeria is a major contributor to the global malaria burden. The genetic diversity of malaria parasite populations as well as antibody responses of individuals in affected areas against antigens of the parasite can reveal the transmission intensity, a key information required to control the disease. This work was carried out to determine the allelic frequency of highly polymorphic Plasmodium falciparum genes and antibody responses against schizont crude antigens in an area of Ibadan, Nigeria. Materials and methods: Blood was collected from 147 individuals with symptoms suspected to be malaria. Malaria infection was determined using a rapid diagnostic test (RDT), and msp1 and msp2 were genotyped by a nested PCR method. In addition, levels of IgG directed against P. falciparum FCR3S1.2 schizont extract was measured in ELISA. Results: Approximately 25% (36/147) were positive for a P. falciparum infection in RDT, but only 32 of the positive samples were successfully genotyped. MAD20 was the most prevalent and K1 the least prevalent of the msp1 alleles. For msp2, FC27 was more prevalent than 3D7. The mean multiplicities of infection (MOI) were 1.9 and 1.7 for msp1 and msp2, respectively. IgG levels correlated positively with age, however there was no difference in median antibody levels between RDT-positive and RDT-negative individuals. Conclusion: Low MOI has before been correlated with low/intermediate transmission intensity, however, in this study, similar levels of P. falciparum-specific antibodies between infected and non-infected individuals point more towards a high level of exposure and a need for further measures to control the spread of malaria in this area.

Experimental vaccination by single dose sporozoite injection of blood-stage attenuated malaria parasites.

Malaria vaccination approaches using live Plasmodium parasites are currently explored, with either attenuated mosquito-derived sporozoites or attenuated blood-stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood-stage multiplication rate. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. Furthermore, we tested the P. berghei mutants for avirulence and resolving blood-stage infections, while preserving sporozoite formation and liver infection. Targeting 51 genes yielded 18 P. berghei gene-deletion mutants with several mutants causing mild infections. Infections with the two most attenuated mutants either by blood stages or by sporozoites were cleared by the immune response. Immunization of mice led to protection from disease after challenge with wild-type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow-growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and will aid in developing new as well as safeguarding existing attenuated parasite vaccines.

Incorporation of an Isohexide Subunit into the Endochin-like Quinolone Scaffold.

In order to improve the drug-likeness qualities, the antimalarial endochin-like quinolone (ELQ) scaffold has been modified by replacing the 4-(trifluoromethoxy)phenyl portion with an isoidide unit that is further adjustable by varying the distal O-substituents. As expected, the water solubilities of the new analogs are greatly improved, and the melting points are lower. However, the antimalarial potency of the new analogs is reduced to EC50 > 1 millimolar, a result ascribable to the hydrophilic nature of the new substitution.