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Nature Communications Jun 2024Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen...
Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called "R78C", combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial.
Topics: Malaria Vaccines; Animals; Plasmodium falciparum; Protozoan Proteins; Female; Malaria, Falciparum; Antigens, Protozoan; Rats; Antibodies, Protozoan; Antibodies, Monoclonal; Humans; Epitopes; Carrier Proteins
PubMed: 38849365
DOI: 10.1038/s41467-024-48721-3 -
PLoS Computational Biology Jun 2024Immunization through repeated direct venous inoculation of Plasmodium falciparum (Pf) sporozoites (PfSPZ) under chloroquine chemoprophylaxis, using the PfSPZ...
Immunization through repeated direct venous inoculation of Plasmodium falciparum (Pf) sporozoites (PfSPZ) under chloroquine chemoprophylaxis, using the PfSPZ Chemoprophylaxis Vaccine (PfSPZ-CVac), induces high-level protection against controlled human malaria infection (CHMI). Humoral and cellular immunity contribute to vaccine efficacy but only limited information about the implicated Pf-specific antigens is available. Here, we examined Pf-specific antibody profiles, measured by protein arrays representing the full Pf proteome, of 40 placebo- and PfSPZ-immunized malaria-naïve volunteers from an earlier published PfSPZ-CVac dose-escalation trial. For this purpose, we both utilized and adapted supervised machine learning methods to identify predictive antibody profiles at two different time points: after immunization and before CHMI. We developed an adapted multitask support vector machine (SVM) approach and compared it to standard methods, i.e. single-task SVM, regularized logistic regression and random forests. Our results show, that the multitask SVM approach improved the classification performance to discriminate the protection status based on the underlying antibody-profiles while combining time- and dose-dependent data in the prediction model. Additionally, we developed the new fEature diStance exPlainabilitY (ESPY) method to quantify the impact of single antigens on the non-linear multitask SVM model and make it more interpretable. In conclusion, our multitask SVM model outperforms the studied standard approaches in regard of classification performance. Moreover, with our new explanation method ESPY, we were able to interpret the impact of Pf-specific antigen antibody responses that predict sterile protective immunity against CHMI after immunization. The identified Pf-specific antigens may contribute to a better understanding of immunity against human malaria and may foster vaccine development.
Topics: Malaria Vaccines; Humans; Plasmodium falciparum; Malaria, Falciparum; Antibodies, Protozoan; Machine Learning; Vaccine Efficacy; Support Vector Machine; Computational Biology
PubMed: 38848436
DOI: 10.1371/journal.pcbi.1012131 -
Antimicrobial Agents and Chemotherapy Jun 2024The human malaria- monkey model has served the malaria research community since its inception in 1966 at the Gorgas Memorial Laboratory (GML) in Panama. Spanning over... (Review)
Review
The human malaria- monkey model has served the malaria research community since its inception in 1966 at the Gorgas Memorial Laboratory (GML) in Panama. Spanning over five decades, this model has been instrumental in evaluating the efficacy and pharmacokinetics of a wide array of candidate antimalarial drugs, whether used singly or in combination. The animal model could be infected with drug-resistant and susceptible and strains that follow a characteristic and reproducible course of infection, remarkably like human untreated and treated infections. Over the years, the model has enabled the evaluation of several synthetic and semisynthetic endoperoxides, for instance, artelinic acid, artesunate, artemether, arteether, and artemisone. These compounds have been evaluated alone and in combination with long-acting partner drugs, commonly referred to as artemisinin-based combination therapies, which are recommended as first-line treatment against uncomplicated malaria. Further, the model has also supported the evaluation of the primaquine analog tafenoquine against blood stages of , contributing to its progression to clinical trials and eventual approval. Besides, the / model at GML has also played a pivotal role in exploring the biology, immunology, and pathogenesis of malaria and in the characterization of drug-resistant and strains. This minireview offers a historical overview of the most significant contributions made by the Panamanian owl monkey () to malaria chemotherapy research.
PubMed: 38837364
DOI: 10.1128/aac.00338-24 -
Parasites, Hosts and Diseases May 2024Malaria is a global disease affecting a large portion of the world's population. Although vaccines have recently become available, their efficacies are suboptimal. We...
Malaria is a global disease affecting a large portion of the world's population. Although vaccines have recently become available, their efficacies are suboptimal. We generated virus-like particles (VLPs) that expressed either apical membrane antigen 1 (AMA1) or microneme-associated antigen (MIC) of Plasmodium berghei and compared their efficacy in BALB/c mice. We found that immune sera acquired from AMA1 VLP- or MIC VLP-immunized mice specifically interacted with the antigen of choice and the whole P. berghei lysate antigen, indicating that the antibodies were highly parasite-specific. Both VLP vaccines significantly enhanced germinal center B cell frequencies in the inguinal lymph nodes of mice compared with the control, but only the mice that received MIC VLPs showed significantly enhanced CD4+ T cell responses in the blood following P. berghei challenge infection. AMA1 and MIC VLPs significantly suppressed TNF-α and interleukin-10 production but had a negligible effect on interferon-γ. Both VLPs prevented excessive parasitemia buildup in immunized mice, although parasite burden reduction induced by MIC VLPs was slightly more effective than that induced by AMA1. Both VLPs were equally effective at preventing body weight loss. Our findings demonstrated that the MIC VLP was an effective inducer of protection against murine experimental malaria and should be the focus of further development.
Topics: Animals; Plasmodium berghei; Mice, Inbred BALB C; Vaccines, Virus-Like Particle; Malaria Vaccines; Malaria; Membrane Proteins; Mice; Protozoan Proteins; Antigens, Protozoan; Female; Antibodies, Protozoan; Parasitemia; CD4-Positive T-Lymphocytes; B-Lymphocytes
PubMed: 38835260
DOI: 10.3347/PHD.24017 -
Health Science Reports Jun 2024Between 2000 and 2015, significant gains were recorded in reducing the global burden of malaria due to enhanced global collaboration and increased funding. However,...
INTRODUCTION
Between 2000 and 2015, significant gains were recorded in reducing the global burden of malaria due to enhanced global collaboration and increased funding. However, progress has stagnated post-2015, and the COVID-19 pandemic seems to have reversed some of these gains, necessitating a critical reevaluation of interventions. This paper aims to analyze the setbacks and offer recommendations for advancement in malaria control and prevention in sub-Saharan Africa.
METHODS
We conducted searches on Google Scholar, PubMed, and relevant organization websites to identify relevant studies on malaria control and prevention and associated challenges in sub-Saharan Africa from 2015 to the present. Additionally, studies on individual sub-Saharan African countries were reviewed to ensure comprehensiveness. Data from selected studies were extracted and analyzed using a narrative synthesis approach to offer a concise overview of the evidence.
FINDINGS
We observe that the halt in progress of malaria control in sub-Saharan Africa has deep roots in socioeconomic, political, and environmental factors. These challenges are exacerbated by the population explosion in the region, low coverage of interventions due to funding deficits and incessant crises, and the degradation of the efficacy of existing malaria commodities.
CONCLUSION
Sub-Saharan Africa is at a crossroads in its fight against malaria. Promising new frontiers such as malaria vaccines, preventive monoclonal antibodies, new-generation insecticide-treated nets, and potentially artificial intelligence-driven technologies offer hope in advancing malaria control and prevention in the region. Through commitment and collaboration, leveraging these opportunities can help surmount challenges and ultimately eliminate malaria in sub-Saharan Africa.
PubMed: 38831778
DOI: 10.1002/hsr2.2122 -
Wellcome Open Research 2023Falciparum malaria remains a global health problem. Two vaccines, based on the circumsporozoite antigen, are available. RTS, S/AS01 was recommended for use in 2021...
Safety and immunogenicity of varied doses of R21/Matrix-M™ vaccine at three years follow-up: A phase 1b age de-escalation, dose-escalation trial in adults, children, and infants in Kilifi-Kenya.
BACKGROUND
Falciparum malaria remains a global health problem. Two vaccines, based on the circumsporozoite antigen, are available. RTS, S/AS01 was recommended for use in 2021 following the advice of the World Health Organisation (WHO) Strategic Advisory Group of Experts (SAGE) on Immunization and WHO Malaria Policy Advisory Group (MPAG). It has since been pre-qualified in 2022 by the WHO. R21 is similar to RTS, S/AS01, and recently licensed in Nigeria, Ghana and Burkina Faso following Phase 3 trial results.
METHODS
We conducted a Phase 1b age de-escalation, dose escalation bridging study after a change in the manufacturing process for R21. We recruited healthy adults and children and used a three dose primary vaccination series with a booster dose at 1-2 years. Variable doses of R21 and adjuvant (Matrix-M ™) were administered at 10µgR21/50 µg Matrix-M™, 5µgR21/25µg Matrix-M™ and 5µgR21/50µg Matrix-M™ to 20 adults, 20 children, and 51 infants.
RESULTS
Self-limiting adverse events were reported relating to the injection site and mild systemic symptoms. Two serious adverse events were reported, neither linked to vaccination. High levels of IgG antibodies to the circumsporozoite antigen were induced, and geometric mean titres in infants, the target group, were 1.1 (0.9 to 1.3) EU/mL at day 0, 10175 (7724 to 13404) EU/mL at day 84 and (following a booster dose at day 421) 6792 (5310 to 8687) EU/mL at day 456.
CONCLUSION
R21/Matrix-M™ is safe, and immunogenic when given at varied doses with the peak immune response seen in infants 28 days after a three dose primary vaccination series given four weeks apart. Antibody responses were restored 28 days after a 4 dose given one year post a three dose primary series in the young children and infants.
REGISTRATION
Clinicaltrials.gov (NCT03580824; 9 of July 2018; Pan African Clinical Trials Registry (PACTR202105682956280; 17 May 2021).
PubMed: 38813551
DOI: 10.12688/wellcomeopenres.19795.1 -
Targeting Prohibitin 2-Hu-Hsp70A1A complex as a unique approach towards malaria vaccine development.IScience Jun 2024Malaria parasite invasion to host erythrocytes is mediated by multiple interactions between merozoite ligands and erythrocyte receptors that contribute toward the...
Malaria parasite invasion to host erythrocytes is mediated by multiple interactions between merozoite ligands and erythrocyte receptors that contribute toward the development of disease pathology. Here, we report a novel antigen prohibitin "PHB2" and identify its cognate partner "Hsp70A1A" in host erythrocyte that plays a crucial role in mediating host-parasite interaction during merozoite invasion. Using small interfering RNA (siRNA)- and glucosamine-6-phosphate riboswitch (glmS) ribozyme-mediated approach, we show that loss of Hsp70A1A in red blood cells (RBCs) or PHB2 in infected red blood cells (iRBCs), respectively, inhibit PHB2-Hsp70A1A interaction leading to invasion inhibition. Antibodies targeting PHB2 and monoclonal antibody therapeutics against Hsp70A1A efficiently block parasite invasion. Recombinant PHB2 binds to RBCs which is inhibited by anti-PHB2 antibody and monoclonal antibody against Hsp70A1A. The validation of PHB2 to serve as antigen is further supported by detection of anti-PHB2 antibody in patient sera. Overall, this study proposes PHB2 as vaccine candidate and highlights the use of monoclonal antibody therapeutics for future malaria treatment.
PubMed: 38812541
DOI: 10.1016/j.isci.2024.109918 -
Journal, Genetic Engineering &... Jun 2024Malaria has remained a major health concern for decades among people living in tropical and sub-tropical countries. Plasmodium falciparum is one of the critical species...
BACKGROUND
Malaria has remained a major health concern for decades among people living in tropical and sub-tropical countries. Plasmodium falciparum is one of the critical species that cause severe malaria and is responsible for major mortality. Moreover, the parasite has generated resistance against all WHO recommended drugs and therapies. Therefore, there is an urgent need for preventive measures in the form of reliable vaccines to achieve the target of a malaria-free world. Surface proteins are the preferable choice for subunit vaccine development because they are rapidly detected and engaged by host immune cells and vaccination-induced antibodies. Additionally, abundant surface or membrane proteins may contribute to the opsonization of pathogens by vaccine-induced antibodies.
RESULTS
In our study, we have listed all those surface proteins from the literature that could be functionally important and essential for infection and immune evasion of the malaria parasite. Eight Plasmodium surface and membrane proteins from the pre-erythrocyte and erythrocyte stages were shortlisted. Thirty-seven epitopes (B-cell, CTL, and HTL epitopes) from these proteins were predicted using immune-informatic tools and joined with suitable peptide linkers to design a vaccine construct. A TLR-4 agonist peptide adjuvant was added at the N-terminus of the multi-epitope series, followed by the PADRE sequence and EAAAK linker. The TLR-4 receptor was docked with the construct's anticipated model structure. The complex of vaccine and TLR-4, with the lowest energy -1514, was found to be stable under simulated physiological settings.
CONCLUSION
This study has provided a novel multi-epitope construct that may be exploited further for the development of an efficient vaccine for malaria.
PubMed: 38797552
DOI: 10.1016/j.jgeb.2024.100377 -
Vaccines May 2024Malaria is caused by eukaryotic protozoan parasites of the genus . There are 249 million new cases and 608,000 deaths annually, and new interventions are desperately...
Malaria is caused by eukaryotic protozoan parasites of the genus . There are 249 million new cases and 608,000 deaths annually, and new interventions are desperately needed. Malaria vaccines can be divided into three categories: liver stage, blood stage, or transmission-blocking vaccines. Transmission-blocking vaccines prevent the transmission of disease by the mosquito vector from one human to another. Pfs230 is one of the leading transmission-blocking vaccine antigens for malaria. Here, we describe the development of a 24-copy self-assembling nanoparticle vaccine comprising domain 1 of Pfs230 genetically fused to ferritin. The single-component Pfs230D1-ferritin construct forms a stable and homogenous 24-copy nanoparticle with good production yields. The nanoparticle is highly immunogenic, as two low-dose vaccinations of New Zealand White rabbits elicited a potent and durable antibody response with high transmission-reducing activity when formulated in two distinct adjuvants suitable for translation to human use. This single-component 24-copy Pfs230D1-ferritin nanoparticle vaccine has the potential to improve production pipelines and the cost of manufacturing a potent and durable transmission-blocking vaccine for malaria control.
PubMed: 38793797
DOI: 10.3390/vaccines12050546 -
Vaccines Apr 2024The WHO reported an estimated 249 million malaria cases and 608,000 malaria deaths in 85 countries in 2022. A total of 94% of malaria deaths occurred in Africa, 80% of... (Review)
Review
The WHO reported an estimated 249 million malaria cases and 608,000 malaria deaths in 85 countries in 2022. A total of 94% of malaria deaths occurred in Africa, 80% of which were children under 5. In other words, one child dies every minute from malaria. The RTS,S/AS01 malaria vaccine, which uses the circumsporozoite protein (CSP) to target sporozoite infection of the liver, achieved modest efficacy. The Malaria Vaccine Implementation Program (MVIP), coordinated by the WHO and completed at the end of 2023, found that immunization reduced mortality by only 13%. To further reduce malaria death, the development of a more effective malaria vaccine is a high priority. Three malaria vaccine targets being considered are the sporozoite liver infection (pre-erythrocytic stage), the merozoite red blood cell infection (asexual erythrocytic stage), and the gamete/zygote mosquito infection (sexual/transmission stage). These targets involve specific ligand-receptor interactions. However, most current malaria vaccine candidates that target two major parasite population bottlenecks, liver infection, and mosquito midgut infection, do not focus on such parasite ligands. Here, we evaluate the potential of newly identified parasite ligands with a phage peptide-display technique as novel malaria vaccine antigens.
PubMed: 38793735
DOI: 10.3390/vaccines12050484