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Frontiers in Immunology 2024is a protozoan parasite that causes the tropical ailment known as Chagas disease, which has its origins in South America. Globally, it has a major impact on health and...
INTRODUCTION
is a protozoan parasite that causes the tropical ailment known as Chagas disease, which has its origins in South America. Globally, it has a major impact on health and is transported by insect vector that serves as a parasite. Given the scarcity of vaccines and the limited treatment choices, we conducted a comprehensive investigation of core proteomics to explore a potential reverse vaccine candidate with high antigenicity.
METHODS
To identify the immunodominant epitopes, T. cruzi core proteomics was initially explored. Consequently, the vaccine sequence was engineered to possess characteristics of non-allergenicity, antigenicity, immunogenicity, and enhanced solubility. After modeling the tertiary structure of the human TLR4 receptor, the binding affinities were assessed employing molecular docking and molecular dynamics simulations (MDS).
RESULTS
Docking of the final vaccine design with TLR4 receptors revealed substantial hydrogen bond interactions. A server-based methodology for immunological simulation was developed to forecast the effectiveness against antibodies (IgM + IgG) and interferons (IFN-g). The MDS analysis revealed notable levels of structural compactness and binding stability with average RMSD of 5.03 Aring;, beta-factor 1.09e+5 Å, Rg is 44.7 Aring; and RMSF of 49.50 Aring;. This is followed by binding free energies calculation. The system stability was compromised by the complexes, as evidenced by their corresponding Gibbs free energies of -54.6 kcal/mol.
DISCUSSION
Subtractive proteomics approach was applied to determine the antigenic regions of the T cruzi. Our study utilized computational techniques to identify B- and T-cell epitopes in the T. cruzi core proteome. In current study the developed vaccine candidate exhibits immunodominant features. Our findings suggest that formulating a vaccine targeting the causative agent of Chagas disease should be the initial step in its development.
Topics: Trypanosoma cruzi; Molecular Dynamics Simulation; Chagas Disease; Humans; Proteome; Toll-Like Receptor 4; Protozoan Vaccines; Animals; Molecular Docking Simulation; Immunodominant Epitopes; Proteomics; Antigens, Protozoan; Antibodies, Protozoan; Protozoan Proteins; Vaccine Development; Epitopes, T-Lymphocyte
PubMed: 38915396
DOI: 10.3389/fimmu.2024.1413893 -
Expert Review of Vaccines 2024Malaria continues to remain a major global health problem with nearly a quarter of a billion clinical cases and more than 600,000 deaths in 2022. There has been... (Review)
Review
INTRODUCTION
Malaria continues to remain a major global health problem with nearly a quarter of a billion clinical cases and more than 600,000 deaths in 2022. There has been significant progress toward vaccine development, however, poor efficacy of approved vaccines requiring multiple immunizing doses emphasizes the need for continued efforts toward improved vaccines. Progress to date, nonetheless, has provided impetus for malaria elimination.
AREAS COVERED
In this review we will focus on diverse immune mechanisms targeting gametocytes in the human host and gametocyte-mediated malaria transmission via the mosquito vector.
EXPERT OPINION
To march toward the goal of malaria elimination it will be critical to target the process of malaria transmission by mosquitoes, mediated exclusively by the sexual stages, i.e. male, and female gametocytes, ingested from infected vertebrate host. Studies over several decades have established antigens in the parasite sexual stages developing in the mosquito midgut as attractive targets for the development of transmission blocking vaccines (TBVs). Immune clearance of gametocytes in the vertebrate host can synergize with TBVs and directly aid in maintaining effective transmission reducing immune potential.
Topics: Humans; Malaria Vaccines; Animals; Malaria; Vaccine Development; Mosquito Vectors; Plasmodium
PubMed: 38888098
DOI: 10.1080/14760584.2024.2369583 -
Medicine Jun 2024Malaria remains an endemic public health concern in Africa, significantly contributing to morbidity and mortality rates. The inadequacies of traditional prevention... (Review)
Review
Malaria remains an endemic public health concern in Africa, significantly contributing to morbidity and mortality rates. The inadequacies of traditional prevention measures, like integrated vector management and antimalarial drugs, have spurred efforts to strengthen the development and deployment of malaria vaccines. In addition to existing interventions like insecticide-treated bed nets and artemisinin-based combination therapies, malaria vaccine introduction and implementation in Africa could drastically reduce the disease burden and hasten steps toward malaria elimination. The malaria vaccine rollout is imminent as optimistic results from final clinical trials are anticipated. Thus, determining potential hurdles to malaria vaccine delivery and uptake in malaria-endemic regions of sub-Saharan Africa will enhance decisions and policymakers' preparedness to facilitate efficient and equitable vaccine delivery. A multisectoral approach is recommended to increase funding and resources, active community engagement and participation, and the involvement of healthcare providers.
Topics: Humans; Malaria Vaccines; Malaria; Africa; Vaccination; Africa South of the Sahara
PubMed: 38875411
DOI: 10.1097/MD.0000000000038565 -
PLoS Neglected Tropical Diseases Jun 2024Malaria transmission-blocking vaccines (TBVs) aim to inhibit malaria parasite development in mosquitoes and prevent further transmission to the human host. The...
BACKGROUND
Malaria transmission-blocking vaccines (TBVs) aim to inhibit malaria parasite development in mosquitoes and prevent further transmission to the human host. The putative-secreted ookinete protein 25 (PSOP25), highly conserved in Plasmodium spp., is a promising TBV target. Here, we investigated PvPSOP25 from P. vivax as a TBV candidate using transgenic murine parasite P. berghei and clinical P. vivax isolates.
METHODS AND FINDINGS
A transgenic P. berghei line expressing PvPSOP25 (TrPvPSOP25Pb) was generated. Full-length PvPSOP25 was expressed in the yeast Pichia pastoris and used to immunize mice to obtain anti-rPvPSOP25 sera. The transmission-blocking activity of the anti-rPvPSOP25 sera was evaluated through in vitro assays and mosquito-feeding experiments. The antisera generated by immunization with rPvPSOP25 specifically recognized the native PvPSOP25 antigen expressed in TrPvPSOP25Pb ookinetes. In vitro assays showed that the immune sera significantly inhibited exflagellation and ookinete formation of the TrPvPSOP25Pb parasite. Mosquitoes feeding on mice infected with the transgenic parasite and passively transferred with the anti-rPvPSOP25 sera showed a 70.7% reduction in oocyst density compared to the control group. In a direct membrane feeding assay conducted with five clinical P. vivax isolates, the mouse anti-rPvPSOP25 antibodies significantly reduced the oocyst density while showing a negligible influence on mosquito infection prevalence.
CONCLUSIONS
This study supported the feasibility of transgenic murine malaria parasites expressing P. vivax antigens as a useful tool for evaluating P. vivax TBV candidates. Meanwhile, the moderate transmission-reducing activity of the generated anti-rPvPSOP25 sera necessitates further research to optimize its efficacy.
Topics: Animals; Mice; Plasmodium vivax; Malaria Vaccines; Plasmodium berghei; Protozoan Proteins; Humans; Malaria, Vivax; Female; Antigens, Protozoan; Antibodies, Protozoan; Malaria; Mice, Inbred BALB C
PubMed: 38865344
DOI: 10.1371/journal.pntd.0012231 -
Frontiers in Immunology 2024Despite decades of effort, malaria remains a leading killer of children. The absence of a highly effective vaccine and the emergence of parasites resistant to both...
BACKGROUND
Despite decades of effort, malaria remains a leading killer of children. The absence of a highly effective vaccine and the emergence of parasites resistant to both diagnosis as well as treatment hamper effective public health interventions.
METHODS AND RESULTS
To discover new vaccine candidates, we used our whole proteome differential screening method and identified PfGBP130 as a parasite protein uniquely recognized by antibodies from children who had developed resistance to infection but not from those who remained susceptible. We formulated PfGBP130 as lipid encapsulated mRNA, DNA plasmid, and recombinant protein-based immunogens and evaluated the efficacy of murine polyclonal anti-PfGBP130 antisera to inhibit parasite growth in vitro. Immunization of mice with PfGBP130-A (aa 111-374), the region identified in our differential screen, formulated as a DNA plasmid or lipid encapsulated mRNA, but not as a recombinant protein, induced antibodies that inhibited RBC invasion . mRNA encoding the full ectodomain of PfGBP130 (aa 89-824) also generated parasite growth-inhibitory antibodies.
CONCLUSION
We are currently advancing PfGBP130-A formulated as a lipid-encapsulated mRNA for efficacy evaluation in non-human primates.
Topics: Animals; Plasmodium falciparum; Antibodies, Protozoan; Mice; Erythrocytes; Malaria, Falciparum; Humans; Malaria Vaccines; Protozoan Proteins; Antigens, Protozoan; Immunization; Female
PubMed: 38863702
DOI: 10.3389/fimmu.2024.1350560 -
Malaria Journal Jun 2024The World Health Organization novel malaria vaccine for at-risk children has the potential to greatly reduce the current malaria burden in sub-Saharan Africa. However,... (Review)
Review
BACKGROUND
The World Health Organization novel malaria vaccine for at-risk children has the potential to greatly reduce the current malaria burden in sub-Saharan Africa. However, most studies have reported contradictory findings regarding community willingness for the vaccine, which could easily undermine the expected benefits of the vaccine. This study aims to ascertain the current state of community readiness and acceptance for the implementation of a novel malaria vaccine (RTS,S/ASO1) among at-risk children in sub-Saharan Africa, based on available evidence.
METHODS
This study will follow the Preferred Reporting Items for Systematic Reviews and Meta-analyses protocol (PRISMA-P) guidelines. Relevant studies will be comprehensively searched from PubMed, ScienceDirect, Web of Science, Google Scholar, and African journals online, in accordance with the Cochrane search guidelines. Two independent reviewers will screen titles, abstracts and full texts of eligible studies based on some specified eligibility criteria. When it is feasible to conduct a meta-analysis, a random effects model will be employed to estimate the common effect due to anticipated high heterogeneity of the data. The effect measure for readiness or acceptance will be reported as a pooled proportion with corresponding 95% confidence interval. Additionally, odds ratios with 95% confidence interval will be estimated to assess factors associated with readiness. These will be presented on a forest plot.
DISSEMINATION PLANS
The findings of the study will be peer-reviewed and published in a scientific journal. Conference presentations will also be made to the different stakeholders in the malaria vaccination campaigns.
SYSTEMATIC REVIEW REGISTRATION
The protocol has been registered with PROSPERO Registration Number: CRD42023480528.
Topics: Africa South of the Sahara; Malaria Vaccines; Systematic Reviews as Topic; Humans; Malaria; Child; Child, Preschool; Patient Acceptance of Health Care
PubMed: 38858779
DOI: 10.1186/s12936-024-04995-y -
PLoS Neglected Tropical Diseases Jun 2024Leishmania donovani surface glycoprotein 63 (GP63) is a major virulence factor involved in parasite escape and immune evasion. In this study, we generated virus-like...
Leishmania donovani surface glycoprotein 63 (GP63) is a major virulence factor involved in parasite escape and immune evasion. In this study, we generated virus-like particles (VLPs) expressing L. donovani GP63 using the baculovirus expression system. Mice were intramuscularly immunized with GP63-VLPs and challenged with L. donovani promastigotes. GP63-VLP immunization elicited higher levels of L. donovani antigen-specific serum antibodies and enhanced splenic B cell, germinal center B cell, CD4+, and CD8+ T cell responses compared to unimmunized controls. GP63-VLPs inhibited the influx of pro-inflammatory cytokines IFN-γ and IL-6 in the livers, as well as thwarting the development of splenomegaly in immunized mice. Upon L. donovani challenge infection, a drastic reduction in splenic parasite burden was observed in VLP-immunized mice. These results indicate that GP63-VLPs immunization conferred protection against L. donovani challenge infection by inducing humoral and cellular immunity in mice.
Topics: Animals; Leishmania donovani; Mice; Vaccines, Virus-Like Particle; Mice, Inbred BALB C; Female; Leishmaniasis, Visceral; Antibodies, Protozoan; Leishmaniasis Vaccines; Vaccine Efficacy; Immunity, Cellular; Spleen; CD8-Positive T-Lymphocytes; B-Lymphocytes; Immunity, Humoral; Membrane Glycoproteins; Cytokines; Metalloendopeptidases
PubMed: 38857253
DOI: 10.1371/journal.pntd.0012229 -
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 -
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