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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 -
ACS Infectious Diseases Jun 2024Leishmaniasis, one of the most overlooked tropical diseases, is a life-threatening illness caused by the parasite that is prevalent in underdeveloped nations. Over 350... (Review)
Review
Leishmaniasis, one of the most overlooked tropical diseases, is a life-threatening illness caused by the parasite that is prevalent in underdeveloped nations. Over 350 million individuals in more than 90 different nations worldwide are at risk of contracting the disease, which has a current fatality rate of 50 000 mortalities each year. The administration of liposomal Amp B, pentavalent antimonials, and miltefosine are still considered integral components of the chemotherapy regimen. Antileishmanial medications fail to treat leishmaniasis because of their numerous drawbacks. These include inadequate effectiveness, toxicity, undesired side effects, drug resistance, treatment duration, and cost. Consequently, there is a need to overcome the limitations of conventional therapeutics. Nanotechnology has demonstrated promising outcomes in addressing these issues because of its small size and distinctive characteristics, such as enhanced bioavailability, lower toxicity, biodegradability, and targeted drug delivery. This review is an effort to highlight the recent progress in various nanodrug delivery systems (nDDSs) over the past five years for treating leishmaniasis. Although the preclinical outcomes of nDDSs have shown promising treatment for leishmaniasis, further research is needed for their clinical translation. Advancement in three primary priority domains─molecular diagnostics, clinical investigation, and knowledge dissemination and standardization─is imperative to propel the leishmaniasis field toward translational outcomes.
Topics: Humans; Antiprotozoal Agents; Leishmaniasis; Drug Delivery Systems; Animals; Nanoparticles; Leishmania donovani; Leishmaniasis Vaccines; Nanovaccines
PubMed: 38829047
DOI: 10.1021/acsinfecdis.4c00010 -
Journal of Biomedical Science Jun 2024A vaccine against Trypanosoma cruzi, the agent of Chagas disease, would be an excellent additional tool for disease control. A recombinant vaccine based on Tc24 and TSA1...
BACKGROUND
A vaccine against Trypanosoma cruzi, the agent of Chagas disease, would be an excellent additional tool for disease control. A recombinant vaccine based on Tc24 and TSA1 parasite antigens was found to be safe and immunogenic in naïve macaques.
METHODS
We used RNA-sequencing and performed a transcriptomic analysis of PBMC responses to vaccination of naïve macaques after each vaccine dose, to shed light on the immunogenicity of this vaccine and guide the optimization of doses and formulation. We identified differentially expressed genes and pathways and characterized immunoglobulin and T cell receptor repertoires.
RESULTS
RNA-sequencing analysis indicated a clear transcriptomic response of PBMCs after three vaccine doses, with the up-regulation of several immune cell activation pathways and a broad non-polarized immune profile. Analysis of the IgG repertoire showed that it had a rapid turnover with novel IgGs produced following each vaccine dose, while the TCR repertoire presented several persisting clones that were expanded after each vaccine dose.
CONCLUSIONS
These data suggest that three vaccine doses may be needed for optimum immunogenicity and support the further evaluation of the protective efficacy of this vaccine.
Topics: Animals; Macaca mulatta; Chagas Disease; Receptors, Antigen, T-Cell; Protozoan Vaccines; Trypanosoma cruzi; Immunoglobulins
PubMed: 38824576
DOI: 10.1186/s12929-024-01050-5 -
Heliyon May 2024() is a cosmopolitan protozoan parasite in humans and animals. It infects about 30 % of the human population worldwide and causes potentially fatal diseases in... (Review)
Review
() is a cosmopolitan protozoan parasite in humans and animals. It infects about 30 % of the human population worldwide and causes potentially fatal diseases in immunocompromised hosts and neonates. For this study, five English-language databases (ScienceDirect, ProQuest, Web of Science, PubMed, and Scopus) and the internet search engine Google Scholar were searched. This review was accomplished to draw a global perspective of what is known about the pathogenesis of and various factors affecting it. Virulence and immune responses can influence the mechanisms of parasite pathogenesis and these factors are in turn influenced by other factors. In addition to the host's genetic background, the type of strain, the routes of transmission of infection, the number of passages, and different phases of parasite life affect virulence. The identification of virulence factors of the parasite could provide promising insights into the pathogenesis of this parasite. The results of this study can be an incentive to conduct more intensive research to design and develop new anti- agents (drugs and vaccines) to treat or prevent this infection. In addition, further studies are needed to better understand the key agents in the pathogenesis of .
PubMed: 38818168
DOI: 10.1016/j.heliyon.2024.e31558 -
Protective efficacy of Eimeria maxima EmLPL and EmTregIM-1 against homologous challenge in chickens.Poultry Science Jul 2024Chicken coccidiosis has inflicted significant economic losses upon the poultry industry. The primary strategies for preventing and controlling chicken coccidiosis...
Chicken coccidiosis has inflicted significant economic losses upon the poultry industry. The primary strategies for preventing and controlling chicken coccidiosis include anticoccidial drugs and vaccination. However, these approaches face limitations, such as drug residues and resistance associated with anticoccidial drugs, and safety concerns related to live vaccines. Consequently, the urgent development of innovative vaccines, such as subunit vaccines, is imperative. In previous study, we screened 2 candidate antigens: Eimeria maxima lysophospholipase (EmLPL) and E. maxima regulatory T cell inducing molecule 1 (EmTregIM-1). To investigate the immune protective effect of the 2 candidate antigens against Eimeria maxima (E. maxima) infection, we constructed recombinant plasmids, namely pET-28a-EmLPL and pET-28a-EmTregIM-1, proceeded to induce the expression of recombinant proteins of EmLPL (rEmLPL) and EmTregIM-1 (rEmTregIM-1). The immunogenic properties of these proteins were confirmed through western blot analysis. Targeting EmLPL and EmTregIM-1, we developed subunit vaccines and encapsulated them in PLGA nanoparticles, resulting in nano-vaccines: PLGA-rEmLPL and PLGA-rEmTregIM-1. The efficacy of these vaccines was assessed through animal protection experiments. The results demonstrated that rEmLPL and rEmTregIM-1 were successfully recognized by anti-E. maxima chicken sera and His-conjugated mouse monoclonal antibodies. Immunization with both subunit and nano-vaccines containing EmLPL and EmTregIM-1 markedly mitigated weight loss and reduced oocyst shedding in chickens infected with E. maxima. Furthermore, the anticoccidial indexes (ACI) for both rEmLPL and PLGA-rEmLPL exceeded 160, whereas those for rEmTregIM-1 and PLGA-rEmTregIM-1 were above 120 but did not reach 160, indicating superior protective efficacy of the rEmLPL and PLGA-rEmLPL formulations. By contrast, the protection afforded by rEmTregIM-1 and PLGA-rEmTregIM-1 was comparatively lower. Thus, EmLPL is identified as a promising candidate antigen for vaccine development against E. maxima infection.
Topics: Animals; Eimeria; Coccidiosis; Chickens; Poultry Diseases; Protozoan Vaccines; Vaccines, Subunit; Antigens, Protozoan
PubMed: 38810564
DOI: 10.1016/j.psj.2024.103865