Towards a Vaccine against Plasmodium vivax Malaria

The authors discuss a new study that suggests thatPlasmodium vivax Duffy-binding protein could be a candidate antigen for developing aP. vivax vaccine

Development of fluorescent Plasmodium falciparum for in vitro growth inhibition assays

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum </it><it>in vitro </it>growth inhibition assays are widely used to evaluate and quantify the functional activity of acquired and vaccine-induced antibodies and the anti-malarial activity of known drugs and novel compounds. However, several constraints have limited the use of these assays in large-scale population studies, vaccine trials and compound screening for drug discovery and development.</p> <p>Methods</p> <p>The D10 <it>P. falciparum </it>line was transfected to express green fluorescent protein (GFP). <it>In vitro </it>growth inhibition assays were performed over one or two cycles of <it>P. falciparum </it>asexual replication using inhibitory polyclonal antibodies raised in rabbits, an inhibitory monoclonal antibody, human serum samples, and anti-malarials. Parasitaemia was evaluated by microscopy and flow cytometry.</p> <p>Results</p> <p>Transfected parasites expressed GFP throughout all asexual stages and were clearly detectable by flow cytometry and fluorescence microscopy. Measurement of parasite growth inhibition was the same when determined by detection of GFP fluorescence or staining with ethidium bromide. There was no difference in the inhibitory activity of samples when tested against the transfected parasites compared to the parental line. The level of fluorescence of GFP-expressing parasites increased throughout the course of asexual development. Among ring-stages, GFP-fluorescent parasites were readily separated from uninfected erythrocytes by flow cytometry, whereas this was less clear using ethidium bromide staining. Inhibition by serum and antibody samples was consistently higher when tested over two cycles of growth compared to one, and when using a 1 in 10 sample dilution compared to 1 in 20, but there was no difference detected when using a different starting parasitaemia to set-up growth assays. Flow cytometry based measurements of parasitaemia proved more reproducible than microscopy counts.</p> <p>Conclusions</p> <p>Flow cytometry based assays using GFP-fluorescent parasites proved sensitive and highly reproducible for quantifying the growth-inhibitory activity of antibodies and anti-malarials, with superior reproducibility to light microscopy, and are suitable for high-throughput applications.</p

Different Life Cycle Stages of Plasmodium falciparum Induce Contrasting Responses in Dendritic Cells

Dendritic cells are key linkers of innate and adaptive immunity. Efficient dendritic cell activation is central to the acquisition of immunity and the efficacy of vaccines. Understanding how dendritic cells are affected by Plasmodium falciparum blood-stage parasites will help to understand how immunity is acquired and maintained, and how vaccine responses may be impacted by malaria infection or exposure. This study investigates the response of dendritic cells to two different life stages of the malaria parasite, parasitized red blood cells and merozoites, using a murine model. We demonstrate that the dendritic cell responses to merozoites are robust whereas dendritic cell activation, particularly CD40 and pro-inflammatory cytokine expression, is compromised in the presence of freshly isolated parasitized red blood cells. The mechanism of dendritic cell suppression by parasitized red blood cells is host red cell membrane-independent. Furthermore, we show that cryopreserved parasitized red blood cells have a substantially reduced capacity for dendritic cell activation

Application of the Malaria Management Model to the Analysis of Costs and Benefits of DDT versus Non-DDT Malaria Control

Introduction: DDT is considered to be the most cost-effective insecticide for combating malaria. However, it is also the mostenvironmentally persistent and can pose risks to human health when sprayed indoors. Therefore, the use of DDT for vectorcontrol remains controversial.Methods: In this paper we develop a computer-based simulation model to assess some of the costs and benefits of thecontinued use of DDT for Indoor Residual Spraying (IRS) versus its rapid phase out. We apply the prototype model to theaggregated sub Saharan African region. For putting the question about the continued use of DDT for IRS versus its rapidphase out into perspective we calculate the same costs and benefits for alternative combinations of integrated vectormanagement interventions.Results: Our simulation results confirm that the current mix of integrated vector management interventions with DDT as themain insecticide is cheaper than the same mix with alternative insecticides when only direct costs are considered. However,combinations with a stronger focus on insecticide-treated bed nets and environmental management show higher levels ofcost-effectiveness than interventions with a focus on IRS. Thus, this focus would also allow phasing out DDT in a costeffectivemanner. Although a rapid phase out of DDT for IRS is the most expensive of the tested intervention combinationsit can have important economic benefits in addition to health and environmental impacts that are difficult to assess inmonetary terms. Those economic benefits captured by the model include the avoided risk of losses in agricultural exports.Conclusions: The prototype simulation model illustrates how a computer-based scenario analysis tool can inform debateson malaria control policies in general and on the continued use of DDT for IRS versus its rapid phase out in specific.Simulation models create systematic mechanisms for analyzing alternative interventions and making informed trade offs

Dendritic Cell Responses and Function in Malaria

Malaria remains a serious threat to global health. Sustained malaria control and, eventually, eradication will only be achieved with a broadly effective malaria vaccine. Yet a fundamental lack of knowledge about how antimalarial immunity is acquired has hindered vaccine development efforts to date. Understanding how malaria-causing parasites modulate the host immune system, specifically dendritic cells (DCs), key initiators of adaptive and vaccine antigen-based immune responses, is vital for effective vaccine design. This review comprehensively summarizes how exposure to Plasmodium spp. impacts human DC function in vivo and in vitro. We have highlighted the heterogeneity of the data observed in these studies, compared and critiqued the models used to generate our current understanding of DC function in malaria, and examined the mechanisms by which Plasmodium spp. mediate these effects. This review highlights potential research directions which could lead to improved efficacy of existing vaccines, and outlines novel targets for next-generation vaccine strategies to target malaria

Multiple morbidities in pregnancy: Time for research, innovation, and action

Progress indicators in maternal health in many low- and middle-income countries (LMICs) continue to fall below international standards despite Millennium Development Goal commitments and Sustainable Development Goal (SDG) aspirations [1]. While maternal mortality has fallen by 44% globally since 1990, many countries will struggle to meet the SDG target of fewer than 70 maternal deaths per 100,000 live births by 2030 [2]. Despite substantial efforts, globally over 300,000 women still die each year during pregnancy, childbirth, or the postpartum period, mostly from preventable causes. The burden of morbidity and mortality is inequitable, with vulnerable and marginalized populations at greatest risk. Although this burden disproportionately occurs in LMICs, it also affects increasing numbers of women in some high-income countries [3]. Improved counts of so-called indirect causes highlight the importance of nonobstetric morbidity during pregnancy, contributing around one-third of maternal deaths in LMICs [4]. Indirect causes include the effects of infections, noncommunicable diseases (NCDs), and mental health disorders. These highly prevalent conditions overlap and co-occur such that many women experience multimorbidity during and around pregnancy

Determinants of knowledge of critical danger signs, safe childbirth and immediate newborn care practices among auxiliary midwives: a cross sectional survey in Myanmar

Objectives The re-emergence of community-based health workers such as the auxiliary midwives (AMWs) in Myanmar, who are local female volunteers, has been an important strategy to address global health workforce shortages. The Myanmar government recommends one AMW for every village. The aim of this study is to investigate the current knowledge of critical danger signs and practices for safe childbirth and immediate newborn care of AMWs to inform potential task shifting of additional healthcare responsibilities. Methods A cross-sectional survey was conducted from July 2015 to June 2016 in three hard-to-reach areas in Myanmar. Face-to-face interviews were conducted using a pretested questionnaire. Results Among 262 AMWs participating in the study, only 8% of AMWs were able to identify at least 80% of 20 critical danger signs. Factors associated with greater knowledge of critical danger signs included older age over 35 years (adjusted OR (AOR) 2.19, 95% CI 0.99 to 4.83), having received refresher training within the last year (AOR 2.20, 95% CI 1.21 to 4.01) and receiving adequate supervision (AOR 5.04, 95% CI 2.74 to 9.29). Those who employed all six safe childbirth and immediate newborn care practices were more likely to report greater knowledge of danger signs (AOR 2.81, 95% CI 1.50 to 5.26), adequate work supervision (AOR 3.18 95% CI 1.62 to 6.24) and less education (AOR 0.44, 95% CI 0.23 to 0.88). Conclusion The low level of knowledge of critical danger signs and reported practices for safe childbirth identified suggest that an evaluation of the current AMW training and supervision programme needs to be revisited to ensure that existing practices, including recognition of danger signs, meet quality care standards before new interventions are introduced or new responsibilities given to AMWs

The Relationship between Anti-merozoite Antibodies and Incidence of Plasmodium falciparum Malaria: A Systematic Review and Meta-analysis

A systematic review and meta-analysis examining the association between anti-merozoite antibody responses and incidence of Plasmodium falciparum malaria by Freya Fowkes and colleagues aids identification of antigens that confer protection from malaria

Low Levels of Human Antibodies to Gametocyte-Infected Erythrocytes Contrasts the PfEMP1-Dominant Response to Asexual Stages in P. falciparum Malaria.

Vaccines that target Plasmodium falciparum gametocytes have the potential to reduce malaria transmission and are thus attractive targets for malaria control. However, very little is known about human immune responses to gametocytes present in human hosts. We evaluated naturally-acquired antibodies to gametocyte-infected erythrocytes (gametocyte-IEs) of different developmental stages compared to other asexual parasite stages among naturally-exposed Kenyan residents. We found that acquired antibodies strongly recognized the surface of mature asexual-IEs, but there was limited reactivity to the surface of gametocyte-IEs of different stages. We used genetically-modified P. falciparum with suppressed expression of PfEMP1, the major surface antigen of asexual-stage IEs, to demonstrate that PfEMP1 is a dominant target of antibodies to asexual-IEs, in contrast to gametocyte-IEs. Antibody reactivity to gametocyte-IEs was similar to asexual-IEs lacking PfEMP1. Significant antibody reactivity to the surface of gametocytes was observed when outside of the host erythrocyte, including recognition of the major gametocyte antigen, Pfs230. This indicates that there is a deficiency of acquired antibodies to gametocyte-IEs despite the acquisition of antibodies to gametocyte antigens and asexual IEs. Our findings suggest that the acquisition of substantial immunity to the surface of gametocyte-IEs is limited, which may facilitate immune evasion to enable malaria transmission even in the face of substantial host immunity to malaria. Further studies are needed to understand the basis for the limited acquisition of antibodies to gametocytes and whether vaccine strategies can generate substantial immunity