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BMJ Global Health Apr 2024In October 2021, the WHO recommended the world's first malaria vaccine-RTS,S/AS01-to prevent malaria in children living in areas with moderate-to-high transmission in... (Review)
Review
In October 2021, the WHO recommended the world's first malaria vaccine-RTS,S/AS01-to prevent malaria in children living in areas with moderate-to-high transmission in sub-Saharan Africa (SSA). A second malaria vaccine, R21/Matrix-M, was recommended for use in October 2023 and added to the WHO list of prequalified vaccines in December 2023. This study analysis assessed the country status of implementation and delivery strategies for RTS,S/AS01 by searching websites for national malaria policies, guidelines and related documents. Direct contact with individuals working in malaria programmes was made to obtain documents not publicly available. 10 countries had documents with information relating to malaria vaccine implementation, 7 referencing RTS,S/AS01 and 3 (Burkina Faso, Kenya and Nigeria) referencing RTS,S/AS01 and R21/Matrix-M. Five other countries reported plans for malaria vaccine roll-out without specifying which vaccine. Ghana, Kenya and Malawi, which piloted RTS,S/AS01, have now integrated the vaccine into routine immunisation services. Cameroon and Burkina Faso are the first countries outside the pilot countries to incorporate the vaccine into national immunisation services. Uganda plans a phased RTS,S/AS01 introduction, while Guinea plans to first pilot RTS,S/AS01 in five districts. The RTS,S/AS01 schedule varied by country, with the first dose administered at 5 or 6 months in all countries but the fourth dose at either 18, 22 or 24 months. SSA countries have shown widespread interest in rolling out the malaria vaccine, the Global Alliance for Vaccines and Immunization having approved financial support for 20 of 30 countries which applied as of March 2024. Limited availability of RTS,S/AS01 means that some approved countries will not receive the required doses. Vaccine availability and equity must be addressed even as R21/Matrix-M becomes available.
Topics: Humans; Malaria Vaccines; Africa South of the Sahara; World Health Organization; Malaria; Immunization Programs; Health Policy
PubMed: 38688566
DOI: 10.1136/bmjgh-2023-014719 -
JCI Insight Apr 2024A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical... (Randomized Controlled Trial)
Randomized Controlled Trial
A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.
Topics: Malaria Vaccines; Immunity, Innate; Humans; Animals; Malaria, Falciparum; Plasmodium falciparum; Mice; Vaccines, Attenuated; Sporozoites; CD8-Positive T-Lymphocytes; Infant; Protozoan Proteins; Antibodies, Protozoan; Female; Parasitemia; Immunoglobulin G; Vaccine Efficacy
PubMed: 38687615
DOI: 10.1172/jci.insight.167408 -
In silico-based vaccine design against Naegleria fowleri causing primary amebic meningoencephalitis.Indian Journal of Pharmacology Mar 2024
Topics: Naegleria fowleri; Humans; Central Nervous System Protozoal Infections; Protozoan Vaccines; Computer Simulation; Meningoencephalitis; Amebiasis; Animals
PubMed: 38687320
DOI: 10.4103/ijp.ijp_482_23 -
Frontiers in Cellular and Infection... 2024
Topics: Antigens, Protozoan; Malaria; Humans; Plasmodium; Animals; Malaria Vaccines
PubMed: 38686096
DOI: 10.3389/fcimb.2024.1408366 -
NPJ Systems Biology and Applications Apr 2024Malaria vaccine development is hampered by extensive antigenic variation and complex life stages of Plasmodium species. Vaccine development has focused on a small number...
Malaria vaccine development is hampered by extensive antigenic variation and complex life stages of Plasmodium species. Vaccine development has focused on a small number of antigens, many of which were identified without utilizing systematic genome-level approaches. In this study, we implement a machine learning-based reverse vaccinology approach to predict potential new malaria vaccine candidate antigens. We assemble and analyze P. falciparum proteomic, structural, functional, immunological, genomic, and transcriptomic data, and use positive-unlabeled learning to predict potential antigens based on the properties of known antigens and remaining proteins. We prioritize candidate antigens based on model performance on reference antigens with different genetic diversity and quantify the protein properties that contribute most to identifying top candidates. Candidate antigens are characterized by gene essentiality, gene ontology, and gene expression in different life stages to inform future vaccine development. This approach provides a framework for identifying and prioritizing candidate vaccine antigens for a broad range of pathogens.
Topics: Plasmodium falciparum; Malaria Vaccines; Antigens, Protozoan; Malaria, Falciparum; Machine Learning; Humans; Proteomics; Vaccine Development; Protozoan Proteins; Computational Biology
PubMed: 38678051
DOI: 10.1038/s41540-024-00365-1 -
Molecules (Basel, Switzerland) Apr 2024Leishmaniasis, an infectious disease caused by pathogenic parasites, affects millions of people in developing countries, and its re-emergence in developed countries,...
Leishmaniasis, an infectious disease caused by pathogenic parasites, affects millions of people in developing countries, and its re-emergence in developed countries, particularly in Europe, poses a growing public health concern. The limitations of current treatments and the absence of effective vaccines necessitate the development of novel therapeutics. In this study, we focused on identifying small molecule inhibitors which prevents the interaction between peroxin 5 (PEX5) and peroxisomal targeting signal 1 (PTS1), pivotal for kinetoplastid parasite survival. The PEX5, containing a C-terminal tetratricopeptide repeat (TPR) domain, was expressed and purified, followed by the quantification of kinetic parameters of PEX5-PTS1 interactions. A fluorescence polarization-based high-throughput screening assay was developed and small molecules inhibiting the PEX5-PTS1 interaction were discovered through the screening of a library of 51,406 compounds. Based on the confirmatory assay, nine compounds showed half maximal inhibitory concentration (IC) values ranging from 3.89 to 24.50 µM. In silico docking using a homology model of PEX5 elucidated that the molecular interactions between PEX5 and the inhibitors share amino acids critical for PTS1 binding. Notably, compound P20 showed potent activity against the growth of promastigotes, promastigotes, and blood stream form, with IC values of 12.16, 19.21, and 3.06 μM, respectively. The findings underscore the potential of targeting PEX5-PTS1 interactions with small molecule inhibitors as a promising strategy for the discovery of new anti-parasitic compounds.
Topics: Leishmania donovani; High-Throughput Screening Assays; Peroxisome-Targeting Signal 1 Receptor; Molecular Docking Simulation; Protozoan Proteins; Fluorescence Polarization; Protein Binding; Small Molecule Libraries; Antiprotozoal Agents; Humans
PubMed: 38675653
DOI: 10.3390/molecules29081835 -
Life (Basel, Switzerland) Apr 2024The neglected Chagas disease (CD) is caused by the protozoan parasite . Despite CD dispersion throughout the world, it prevails in tropical areas affecting mainly poor... (Review)
Review
The neglected Chagas disease (CD) is caused by the protozoan parasite . Despite CD dispersion throughout the world, it prevails in tropical areas affecting mainly poor communities, causing devastating health, social and economic consequences. Clinically, CD is marked by a mildly symptomatic acute phase, and a chronic phase characterized by cardiac and/or digestive complications. Current treatment for CD relies on medications with strong side effects and reduced effectiveness. The complex interaction between the parasite and the host outlines the etiology and progression of CD. The unique characteristics and high adaptability of , its mechanisms of persistence, and evasion of the immune system seem to influence the course of the disease. Despite the efforts to uncover the pathology of CD, there are many gaps in understanding how it is established and reaches chronicity. Also, the lack of effective treatments and protective vaccines constitute challenges for public health. Here, we explain the background in which CD is established, from the peculiarities of molecular biology to the development of the host's immune response leading to the pathophysiology of CD. We also discuss the state of the art of treatments for CD and current challenges in basic and applied science.
PubMed: 38672758
DOI: 10.3390/life14040488 -
International Journal For Parasitology.... Apr 2024Leishmaniasis, a vector-borne disease, is caused by the infection of Leishmania spp., obligate intracellular protozoan parasites. Presently, human vaccines are...
Leishmaniasis, a vector-borne disease, is caused by the infection of Leishmania spp., obligate intracellular protozoan parasites. Presently, human vaccines are unavailable, and the primary treatment relies heavily on systemic drugs, often presenting with suboptimal formulations and substantial toxicity, making new drugs a high priority for LMIC countries burdened by the disease, but a low priority in the agenda of most pharmaceutical companies due to unattractive profit margins. New ways to accelerate the discovery of new, or the repositioning of existing drugs, are needed. To address this challenge, our study aimed to identify potential protein targets shared among clinically-relevant Leishmania species. We employed a subtractive proteomics and comparative genomics approach, integrating high-throughput multi-omics data to classify these targets based on different druggability metrics. This effort resulted in the ranking of 6502 ortholog groups of protein targets across 14 pathogenic Leishmania species. Among the top 20 highly ranked groups, metabolic processes known to be attractive drug targets, including the ubiquitination pathway, aminoacyl-tRNA synthetases, and purine synthesis, were rediscovered. Additionally, we unveiled novel promising targets such as the nicotinate phosphoribosyltransferase enzyme and dihydrolipoamide succinyltransferases. These groups exhibited appealing druggability features, including less than 40% sequence identity to the human host proteome, predicted essentiality, structural classification as highly druggable or druggable, and expression levels above the 50th percentile in the amastigote form. The resources presented in this work also represent a comprehensive collection of integrated data regarding trypanosomatid biology.
PubMed: 38669848
DOI: 10.1016/j.ijpddr.2024.100538 -
Journal of Biomedical Semantics Apr 2024Pathogenic parasites are responsible for multiple diseases, such as malaria and Chagas disease, in humans and livestock. Traditionally, pathogenic parasites have been...
BACKGROUND
Pathogenic parasites are responsible for multiple diseases, such as malaria and Chagas disease, in humans and livestock. Traditionally, pathogenic parasites have been largely an evasive topic for vaccine design, with most successful vaccines only emerging recently. To aid vaccine design, the VIOLIN vaccine knowledgebase has collected vaccines from all sources to serve as a comprehensive vaccine knowledgebase. VIOLIN utilizes the Vaccine Ontology (VO) to standardize the modeling of vaccine data. VO did not model complex life cycles as seen in parasites. With the inclusion of successful parasite vaccines, an update in parasite vaccine modeling was needed.
RESULTS
VIOLIN was expanded to include 258 parasite vaccines against 23 protozoan species, and 607 new parasite vaccine-related terms were added to VO since 2022. The updated VO design for parasite vaccines accounts for parasite life stages and for transmission-blocking vaccines. A total of 356 terms from the Ontology of Parasite Lifecycle (OPL) were imported to VO to help represent the effect of different parasite life stages. A new VO class term, 'transmission-blocking vaccine,' was added to represent vaccines able to block infectious transmission, and one new VO object property, 'blocks transmission of pathogen via vaccine,' was added to link vaccine and pathogen in which the vaccine blocks the transmission of the pathogen. Additionally, our Gene Set Enrichment Analysis (GSEA) of 140 parasite antigens used in the parasitic vaccines identified enriched features. For example, significant patterns, such as signal, plasma membrane, and entry into host, were found in the antigens of the vaccines against two parasite species: Plasmodium falciparum and Toxoplasma gondii. The analysis found 18 out of the 140 parasite antigens involved with the malaria disease process. Moreover, a majority (15 out of 54) of P. falciparum parasite antigens are localized in the cell membrane. T. gondii antigens, in contrast, have a majority (19/24) of their proteins related to signaling pathways. The antigen-enriched patterns align with the life cycle stage patterns identified in our ontological parasite vaccine modeling.
CONCLUSIONS
The updated VO modeling and GSEA analysis capture the influence of the complex parasite life cycles and their associated antigens on vaccine development.
Topics: Biological Ontologies; Animals; Parasites; Protozoan Vaccines; Humans; Vaccines; Models, Biological
PubMed: 38664818
DOI: 10.1186/s13326-024-00307-0 -
Malaria Journal Apr 2024There are giant steps taken in the introduction of the novel malaria vaccine poised towards reducing mortality and morbidity associated with malaria.
BACKGROUND
There are giant steps taken in the introduction of the novel malaria vaccine poised towards reducing mortality and morbidity associated with malaria.
OBJECTIVES
This study aimed to determine the knowledge of malaria vaccine and factors militating against willingness to accept the vaccine among mothers presenting in nine hospitals in Enugu metropolis.
METHODS
This was a cross-sectional study carried out among 491 mothers who presented with their children in nine hospitals in Enugu metropolis, South-East Nigeria. A pre-tested and interviewer-administered questionnaire was used in this study.
RESULTS
A majority of the respondents, 72.1% were aware of malaria vaccine. A majority of the respondents, 83.1% were willing to receive malaria vaccine. Similarly, a majority of the mothers, 92.9%, were willing to vaccinate baby with the malaria vaccine, while 81.1% were willing to vaccinate self and baby with the malaria vaccine. The subjects who belong to the low socio-economic class were five times less likely to vaccinate self and baby with malaria vaccine when compared with those who were in the high socio-economic class (AOR = 0.2, 95% CI 0.1-0.5). Mothers who had good knowledge of malaria vaccination were 3.3 times more likely to vaccinate self and baby with malaria vaccine when compared with those who had poor knowledge of malaria vaccination (AOR = 3.3, 95% CI 1-6-6.8).
CONCLUSION
Although the study documented a high vaccine acceptance among the mothers, there exists a poor knowledge of the malaria vaccine among them.
Topics: Humans; Nigeria; Cross-Sectional Studies; Female; Adult; Young Adult; Malaria Vaccines; Health Knowledge, Attitudes, Practice; Patient Acceptance of Health Care; Adolescent; Malaria; Mothers; Middle Aged; Surveys and Questionnaires; Ambulatory Care Facilities; Infant
PubMed: 38664783
DOI: 10.1186/s12936-024-04914-1