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Antibodies play a critical protective role in the host response to blood-stage malaria infection. The role of cytokines in shaping the antibody response to blood-stage malaria is unclear. Interferon lambda (IFNλ), a type III interferon, is a cytokine produced early during blood-stage malaria infection that has an unknown physiological role during malaria infection. We demonstrate that B cell-intrinsic IFNλ signals suppress the acute antibody response, acute plasmablast response, and impede acute parasite clearance during a primary blood-stage malaria infection. Our findings demonstrate a previously unappreciated role for B cell intrinsic IFNλ-signaling in the initiation of the humoral immune response in the host response to experimental malaria.

Malarial disease caused by Plasmodium parasites challenges the mammalian immune system with a delicate balancing act. Robust inflammatory responses are required to control parasite replication within red blood cells, which if unchecked, can lead to severe anemia and fatality. However, the same inflammatory response that controls parasite replication is also associated with immunopathology and severe disease, as is exemplified by cerebral malaria. A robust literature has identified critical roles for innate, cellular, and humoral immune responses orchestrated by IFN-γ and TH1 type responses in controlling blood stage malarial disease. In contrast, TGF-β and IL-10 have been identified as important anti–inflammatory immunomodulators that help to limit inflammation and pathology during malaria. TGF-β is a pleiotropic cytokine, with the ability to exert a wide variety of context-dependent immunomodulatory roles. The specific mechanisms that allow TGF-β to protect against malarial pathology remain essentially unexplored and offer a promising avenue to dissect the most critical elements of immunomodulation in avoiding severe malaria. Here we discuss potential immunomodulatory roles for TGF-β during malaria in light of recent advances in our understanding of the role of Tregs during blood-stage malaria.

The pathology of malaria is caused by infection of red blood cells with unicellular Plasmodium parasites. During blood-stage development, the parasite replicates within a membrane-bound parasitophorous vacuole. A central nexus for host–parasite interactions, this unique parasite shelter functions in nutrient acquisition, subcompartmentalization and the export of virulence factors, making its functional molecules attractive targets for the development of novel intervention strategies to combat the devastating impact of malaria. In this Review, we explore the origin, development, molecular composition and functions of the parasitophorous vacuole of Plasmodium blood stages. We also discuss the relevance of the malaria parasite’s intravacuolar lifestyle for successful erythrocyte infection and provide perspectives for future research directions in parasitophorous vacuole biology. During intraerythrocytic development, malaria parasites replicate within a membrane-bound parasitophorous vacuole. In this Review, Matz, Beck and Blackman explore the origin, development, molecular composition and functions of the parasitophorous vacuole during blood-stage development. They also discuss the relevance of the malaria parasite’s intravacuolar lifestyle for successful erythrocyte infection and provide perspectives for future research directions.

Introduction: As the quest for an effective blood stage malaria vaccine continues, there is increasing reliance on the use of controlled human malaria infections (CHMI) in non-endemic settings to test vaccine efficacy at the earliest possible time. This is seen as a way to accelerate vaccine research and quickly eliminate candidates with poor efficacy.Areas covered: The data from these studies need to be carefully examined and interpreted in light of the very different roles that antibody and cellular immunity play in protection and within the context of the distinct clinical sensitivities of volunteers living in malaria-non-endemic countries compared to those living in endemic countries. With current strategies, it is likely that vaccines with protective immunological ‘signatures’ will be missed and potentially good candidates discarded.Expert commentary: Efficacy data from early phase vaccine trials in non-endemic countries should not be used to decide whether or not to proceed to vaccine trials...

We consider a mathematical model for malaria involving, susceptible red blood cells (RBCs), latent infected red blood cells (RBCs), active IRBCs, intracellular parasites, extracellular parasites and effector cells. We extend the model to include effect of treatment on the prognosis of malaria. One of the questions addressed in our study is: what range of the parameter, [Formula: see text] which denotes the number of intracellular parasites released from a naturally dying activated infected red blood cell can lead to malaria pathogenesis? Sensitivity analysis revealed that poor parametric estimation can lead to wrong disease prognosis, and consequently to over or under-prescription of treatment drugs. In malaria endemic areas where the parasite is developing resistance to the drugs, this can limit options of treatment drugs. We recommend that the administration of malaria treatment drugs should be done under supervision as is the case for TB to ensure complete adherence to treatment and reduce the emergence of malaria drug resistant strains. Secondly, we recommend that individuals with malaria or showing symptoms of the disease should be tested for other chronic infections which could complicate the treatment of malaria.

The blood stage of the malaria parasite life cycle is responsible for all the clinical symptoms of malaria. During the blood stage, Plasmodium merozoites invade and multiply within host red blood cells (RBCs). Here, we review the progress made, challenges faced, and new strategies available for the development of blood stage malaria vaccines. We discuss our current understanding of immune responses against blood stages and the status of clinical development of various blood stage malaria vaccine candidates. We then discuss possible paths forward to develop effective blood stage malaria vaccines. This includes a discussion of protective immune mechanisms that can be elicited to target blood stage parasites, novel delivery systems, immunoassays and animal models to optimize vaccine candidates in preclinical studies, and use of challenge models to get an early readout of vaccine efficacy.

There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part.

Malaria is one of the most dangerous diseases that threatens people’s lives around the world. In this paper, we study a reaction-diffusion model for the within-host dynamics of malaria infection with an antibody immune response. The model is given by a system of partial differential equations (PDEs) to describe the blood-stage of malaria life cycle. It addresses the interactions between uninfected red blood cells, antibodies, and three types of infected red blood cells, namely ring-infected red blood cells, trophozoite-infected red blood cells and schizont-infected red blood cells. Moreover, the model contains a parameter to measure the efficacy of isoleucine starvation and its effect on the growth of malaria parasites. We show the basic properties of the model. We compute all equilibria and derive the thresholds from the conditions of existence of malaria equilibrium points. We prove the global stability of all equilibrium points based on choosing suitable Lyapunov functionals. We use the characteristic equations to verify the local instability of equilibrium points. We finally execute numerical simulations to validate the theoretical results and highlight some important observations. The results indicate that isoleucine starvation can have a critical impact on the stability of equilibrium points. When the efficacy of isoleucine starvation is high, it switches the system from the infection state to the malaria-free state. The presence of an antibody immune response does not lead to the elimination of malaria infection, but it suppresses the growth of malaria parasites and increases the amount of healthy red blood cells.

An efficacious malaria vaccine is necessary to advance the current control measures towards malaria elimination. To-date, only RTS,S/AS01, a leading pre-erythrocytic stage vaccine completed phase 3 trials, but with an efficacy of 28-36% in children, and 18-26% in infants, that waned over time. Blood-stage malaria vaccines protect against disease, and are considered effective targets for the logical design of next generation vaccines to improve the RTS,S field efficacy. Therefore, novel blood-stage vaccine candidate discovery efforts are critical, albeit with several challenges including, high polymorphisms in vaccine antigens, poor understanding of targets of naturally protective immunity, and difficulties in the expression of high AT-rich plasmodial proteins. Areas covered: PubMed ( www.ncbi.nlm.nih.gov/pubmed ) was searched to review the progress and future prospects of malaria vaccine research and development. We focused on post-genome vaccine candidate discovery, malaria vaccine development, sequence diversity, pre-clinical and clinical trials. Expert commentary: Post-genome high-throughput technologies using wheat germ cell-free protein synthesis technology and immuno-profiling with sera from malaria patients with clearly defined outcomes are highlighted to overcome current challenges of malaria vaccine candidate discovery.

The existence of asymptomatically parasitemic individuals in malaria-endemic areas has long been recognised to signify naturally acquired immunity to malaria disease, resulting from control of the parasite’s asexual blood-stage. This has for many years been viewed as a ‘proof-of-concept’ encouraging the development of blood-stage vaccines (BSVs). Results of clinical trials of candidate subunit BSVs have mostly, however, not lived up to early expectations and the field is currently experiencing a challenging period.

This study analysed the dynamics of blood stage malaria with immune response and under administration of Coartem as a combination therapy. The techniques of mathematical modelling were used in coming up and analysing the deterministic model. Sensitivity analysis and statistical approaches were used to compare model simulated treatment results with the use of Coartem and other antimalarial drugs. We sought to theoretically assess if Coartem can bring improvement in the treatment of malaria as compared to the other drugs. Our analysis and numerical results suggest that Coartem compares well with other antimalarial drug that have been on the market. However, the shortfall of our model is that it could not give good comparative results between Coartem treatment and other combination treatment schemes with similar mode of action. Our study predicted effects of different drug treatment protocols in malaria using a theoretical mathematical model, which gives an insight into potential effective treatment schemes.

The Malaria Immunology Database (MalarImDB, www.malarimdb.org) is a novel literature-based database of host mediators in blood-stage malaria. We designed this open-access online tool because intensive malaria research has resulted in a dazzling complexity of host mediators with pathogenic or protective functions. MalarImDB allows comparisons between expression levels in humans, expression levels in murine models, and functional data from experimental treatments in mice. The database is equipped with multiple search engines to retrieve information from many published studies. The search output is visualized schematically in tables, thereby revealing similarities and disparities. Thus, the primary aim of this database is to present a clear overview of the currently available data about malaria and to simplify literature searches.

SummarySeveral years ago the Walter Reed Army Institute of Research (WRAIR) initiated an independent analysis of the candidate malaria blood stage vaccine SPf66. WRAIR contracted for the synthesis and formulation of SPf66 in United States Food and Drug Administration (FDA) inspected laboratories within the U.S., and in 1992, filed an Investigational New Drug (IND) application with the FDA. Preclinical studies indicated that the vaccine could be synthesized to meet its release specifications, and when adjuvanted with alum, was essentially equivalent to Colombian produced SPf66 in regards to immunogenicity in preclinical studies of rodents and primates, and in human volunteers in Phase I studies. The goal of these efforts was ultimately to conduct a Phase IIb field trial to determine the safety and efficacy of SPf66 produced under current Good Manufacturing Practices (cGMP). Such a trial is currently underway in a malaria endemic refugee camp along the Thai–Burmese border. Here we briefly describe the study and present the formal analytic plan that was submitted to regulatory authorities in the United States for analysis of the study results. We believe such independent confirmatory studies are an essential part of the vaccine development process and are required to provide important data regarding the safety and efficacy of candidate vaccines in diverse geographical regions, and as a means to assess their role in the context of broader malaria control programmes.

Item does not contain fulltext The development of a vaccine against malaria has public health priority. In a controlled setting, preliminary data on the efficacy of Plasmodium falciparum vaccine candidates can be obtained by exposing immunized human volunteers to the bites of laboratory-reared P. falciparum-infected mosquitoes. Using empirical data, we show that these trials, with small numbers of volunteers, are sufficiently powered to detect protective biological effects induced by preerythrocytic and/or blood-stage candidate vaccines if parasitemia is measured daily by quantitative polymerase chain reaction. Sporozoite challenge trials are thus a powerful tool for early selection of candidates that warrant efficacy of trials in the field. 01 augustus 2012

Malaria fever is highly periodic and is associated with the parasite replication cycles in red blood cells. The existence of periodicity in malaria infection demonstrates that parasite replication in different red blood cells is synchronized. In this article, rigorous mathematical analysis of an age-structured human malaria model of infected red blood cells (Rouzine and McKenzie, Proc Natl Acad Sci USA 100:3473-3478, 2003) is provided and the synchronization of Plasmodium falciparum erythrocytic stages is investigated. By using the replication rate as the bifurcation parameter, the existence of Hopf bifurcation in the age-structured malaria infection model is obtained. Numerical simulations indicate that synchronization with regular periodic oscillations (of period 48 h) occurs when the replication rate increases. Therefore, Kwiatkowski and Nowak's observation (Proc Natl Acad Sci USA 88:5111-5113, 1991) that synchronization could be generated at modest replication rates is confirmed.

Malaria, a disease caused by the protozoan parasite Plasmodium, remains a serious healthcare problem in developing countries worldwide. While the host-parasite relationship in humans has been difficult to determine, the pliability of murine malaria models has enabled valuable contributions to the understanding of the pathogenesis of disease. Although no single model reflects precisely malaria infection of the human, different models collectively provide important information on the mechanisms of protective immunity and immunopathogenesis. This review summarizes progress towards understanding the broad spectrum of immune responsiveness to the blood stages of the malaria parasite during experimental infections in mice and highlights how examination of murine malarias sheds light on the factors involved in the modulation of vaccine-potentiated immunity.

Malaria is a global health problem and the need for a vaccine that could prevent millions of deaths annually cannot be further justified. A number of strategies have been adopted in the pursuit of making a successful malaria vaccine including the use of blood stage antigens which would primarily target the merozoite and prevent its replication through the asexual blood cycle of the parasite. In this regard, merozoite surface proteins have gained a lot of attention by the malaria vaccine fraternity for development as subunit vaccines. In spite of concentrated efforts spanning a long number of years, we are not close on producing a successful blood stage vaccine, especially one based on merozoite surface proteins (MSP). However, a recent systematic review with meta-analysis of 33 different studies has reported that antibodies against MSP proteins (MSP-1(19) and MSP-3) exhibit the strongest association with lower incidence of malaria and protection. Also the efficacy of an MSP based vaccine, Combination B, in significantly reducing parasite density among infected children in Papua New Guinea supports the development of MSP based malaria vaccines. In light of these developments, in this commentary, we address different aspects and concerns about MSP based vaccines-the need to develop MSP based blood stage malaria vaccines, our successes and failures from the current and past MSP vaccine trails, the lessons learnt from these studies, the future directions and challenges that still face us.

Plasmodium falciparum malaria is a major global health problem, responsible for up to 1 million deaths each year. Major efforts have been made to develop an effective vaccine against this disease, to reduce the associated morbidity and mortality. There has already been considerable progress, with the first vaccine against the pre-erythrocytic stages of P. falciparum now en route to licensure. There remains, however, a strong scientific rationale for the development of a highly effective additional vaccine component against the blood stages of the parasite, which could be deployed in conjunction with partially effective control measures against the pre-erythrocytic stages. Here, recent progress in the clinical development of blood-stage vaccines is reviewed, including methods of antigen selection, the limitations of in-vitro assays for selecting vaccines for clinical development, and the results of recently published clinical trials. This review seeks to summarize recent developments in our understanding of immunity to blood-stage parasites, as well as the relevant key advances made in vaccine technologies over the last decade. The future challenges that face this field of vaccine research are also described.

Item does not contain fulltext Development and optimization of first generation malaria vaccine candidates has been facilitated by the existence of a well-established Plasmodium falciparum clinical challenge model in which infectious sporozoites are administered to human subjects via mosquito bite. While ideal for testing pre-erythrocytic stage vaccines, some researchers believe that the sporozoite challenge model is less appropriate for testing blood stage vaccines. Here we report a consultation, co-sponsored by PATH MVI, USAID, EMVI and WHO, where scientists from all institutions globally that have conducted such clinical challenges in recent years and representatives from regulatory agencies and funding agencies met to discuss clinical malaria challenge models. Participants discussed strengthening and harmonizing the sporozoite challenge model and considered the pros and cons of further developing a blood stage challenge possibly better suited for evaluating the efficacy of blood stage vaccines. This report summarizes major findings and recommendations, including an update on the Plasmodium vivax clinical challenge model, the prospects for performing experimental challenge trials in malaria endemic countries and an update on clinical safety data. While the focus of the meeting was on the optimization of clinical challenge models for evaluation of blood stage candidate malaria vaccines, many of the considerations are relevant for the application of challenge trials to other purposes.

There are 300-500 million cases of malaria each year and of the more than one million people that die each year from malaria, most are children under 5 years of age. The cloning of malaria antigens in 1983 offered great hope of developing a viable subunit vaccine. While some subunit vaccines have shown great promise in model systems, an efficacious human vaccine is still not available. Immunological studies have shown that numerous factors such as parasite's antigenic variation and polymorphism, immunological non-responsiveness to individual vaccine antigens, parasite-induced apoptosis of immune effector and memory cells, immune deviation as a result of maternal immunity and alterations of dendritic cell function can impede the development of vaccines. These findings indicate that alternative novel approaches are required to tackle the disease and induce protection against malaria.

The development of malaria blood-stage vaccines is gathering momentum: there are several new funding initiatives, one multiantigen formulation is currently being tested and at least one other blood-stage vaccine is expected to begin trials in 2001. However, there is no consensus over the best way to select which form of an antigen to take into clinical testing. There is thus a danger that less-effective vaccines might be tested in the field in the order of their availability, rather than merit. Here, we argue that first proving efficacy in the New World monkey challenge model would accelerate development.

Protection against malaria from a vaccine requires modulation of the immune response to malaria antigens. This modulation by pathogen-derived molecules is explored in this study. Human immune cells synergistically express signaling proteins when stimulated by certain combinations of pathogen-derived molecules. Some of these expression profiles indicate a Th1-mediated immune response, which may be the immune response needed for the next-generation malaria of vaccines, in terms of effectiveness.

Although a clearer understanding of the underlying mechanisms involved in protection and immunopathology during blood-stage malaria has emerged, the mechanisms involved in regulating the adaptive immune response especially those required to maintain a balance between beneficial and deleterious responses remain unclear. Recent evidence suggests the importance of CD11c⁺ dendritic cells (DC) and CD4⁺Foxp3⁺ regulatory T cells in regulating immune responses during infection and autoimmune disease, but information concerning the contribution of these cells to regulating immunity to malaria is limited. Here, we review recent findings from our laboratory and others in experimental models of malaria in mice and in Plasmodium-infected humans on the roles of DC and natural regulatory T cells in regulating adaptive immunity to blood-stage malaria.

The development of a malaria vaccine seems to be a definite possibility despite the fact that even individuals with a life time of endemic exposure do not develop sterile immunity. An effective malaria vaccine would be invaluable in preventing malaria-associated deaths in endemic areas, especially amongst children less than 5 years of age and pregnant women. This review discusses our current understanding of immunity against the asexual blood stage of malaria - the stage that is responsible for the symptoms of the disease - and approaches to the design of an asexual blood stage vaccine.

The authors discuss results from an early trial of a vaccine based on Plasmodium MSP-3 protein reported by Pierre Druilhe and colleagues.

In summary, the host has no shortage of potential cytotoxic molecules for the intraerythrocyte stage, but for most of these it remains to be established whether they really play a significant role in resistance to infection

In this report we will review some of the attempts carried out by the different research groups around the world, focusing toward the end on the work conducted at the Instituto de Immunologia, Hospital San Juan de Dios, Bogota, Colombia

Background Sample size has increasingly become a prerequisite for grant approval. Study size calculations for multicentre trials are more complicated because these sites present different assumptions on incidence of disease expected in the control group; this then changes the mechanism of sample size determination. This paper suggested an alternative approach to estimating study size in multicentre vaccine efficacy trials. Methods The approach suggested in this paper was to determine the expected number of events for a given sample size under set of different assumptions. The power was then calculated given the expected number of events under the set of assumptions so as to assess the sensitivity of the sample size. The approach was then illustrated assuming a malaria vaccine efficacy trial planned in four centres. Results The approach showed that by assuming 30% cumulative incidence of malaria in three of the centres and 10% cumulative incidence in the other centre, a sample size of 460 children in each centre (total 1,840) corresponding to a total of 339 events gives 90% power to detect vaccine efficacy of 30% at 5% level of significance, allowing for 15% loss to follow-up. However, if the incidence is lower than anticipated or a centre drops out altogether the power will be low. But this would not have much effect if it were a low incidence centre. Rather, it might have major effect if it were a high incidence centre. Discussion Decision on recruitment depends on whether separate estimates of efficacy in each transmission level are reasonable. If not, equal numbers can be recruited, which then gives safety data for each site and overall efficacy. Recruiting all or most subjects in the highest transmission site can minimize sample size but may be better to spread the risk due to uncertainty about incidence due to year to year variation and also the possibility of a site dropping due to political or other unforeseen problems. Conclusion The approach demonstrated the potential of estimating the expected number of events required to give a specified power for multicentre efficacy trails of blood stage malaria antigens.