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Frontiers in Immunology 2024() is an apicomplexan parasite that causes severe hemolytic anemia in equids. Presently, there is inadequate knowledge of the immune responses induced by in equid...
Expression of IL-10 and TGF-β1 in horses experimentally infected with merozoites is associated with antibody production but not modulation of pro-inflammatory responses.
() is an apicomplexan parasite that causes severe hemolytic anemia in equids. Presently, there is inadequate knowledge of the immune responses induced by in equid hosts impeding understanding of the host parasite relationship and development of potent vaccines for control of infections. The objective of this study was to evaluate the host-parasite dynamics between merozoites and infected horses by assessing cytokine expression during primary and secondary parasite exposure, and to determine whether the pattern of expression correlated with clinical indicators of disease. Our findings showed that the expression of pro-inflammatory cytokines was very low and inconsistent during both primary and secondary infection. There was also no correlation between the symptoms observed during primary infection and expression of the cytokines. This suggests that the symptoms might have occurred primarily due to hemolysis and likely not the undesirable effects of pro-inflammatory responses. However, IL-10 and TGF-β1 were highly expressed in both phases of infection, and their expression was linked to antibody production but not moderation of pro-inflammatory cytokine responses.
Topics: Animals; Horses; Theileriasis; Interleukin-10; Theileria; Transforming Growth Factor beta1; Horse Diseases; Merozoites; Antibodies, Protozoan; Antibody Formation; Cytokines; Host-Parasite Interactions
PubMed: 38803499
DOI: 10.3389/fimmu.2024.1370255 -
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 -
Malaria Journal May 2024Plasmodium vivax represents the most geographically widespread human malaria parasite affecting civilian and military populations in endemic areas. Targeting the...
Evaluation of naturally acquired immune responses against novel pre-erythrocytic Plasmodium vivax proteins in a low endemic malaria population located in the Peruvian Amazon Basin.
BACKGROUND
Plasmodium vivax represents the most geographically widespread human malaria parasite affecting civilian and military populations in endemic areas. Targeting the pre-erythrocytic (PE) stage of the parasite life cycle is especially appealing for developing P. vivax vaccines as it would prevent disease and transmission. Here, naturally acquired immunity to a panel of P. vivax PE antigens was explored, which may facilitate vaccine development and lead to a better understanding of naturally acquired PE immunity.
METHODS
Twelve P. vivax PE antigens orthologous to a panel of P. falciparum antigens previously identified as highly immunogenic in protected subjects after immunization with radiation attenuated sporozoites (RAS) were used for evaluation of humoral and cellular immunity by ELISA and IFN-γ ELISpot. Samples from P. vivax infected individuals (n = 76) from a low endemic malaria region in the Peruvian Amazon Basin were used.
RESULTS
In those clinical samples, all PE antigens evaluated showed positive IgG antibody reactivity with a variable prevalence of 58-99% in recently P. vivax diagnosed patients. The magnitude of the IgG antibody response against PE antigens was lower compared with blood stage antigens MSP1 and DBP-II, although antibody levels persisted better for PE antigens (average decrease of 6% for PE antigens and 43% for MSP1, p < 0.05). Higher IgG antibodies was associated with one or more previous malaria episodes only for blood stage antigens (p < 0.001). High IgG responders across PE and blood stage antigens showed significantly lower parasitaemia compared to low IgG responders (median 1,921 vs 4,663 par/µl, p < 0.05). In a subgroup of volunteers (n = 17),positive IFN-γ T cell response by ELISPOT was observed in 35% vs 9-35% against blood stage MSP1 and PE antigens, respectively, but no correlation with IgG responses.
CONCLUSIONS
These results demonstrate clear humoral and T cell responses against P. vivax PE antigens in individuals naturally infected with P. vivax. These data identify novel attractive PE antigens suitable for use in the potential development and selection of new malaria vaccine candidates which can be used as a part of malaria prevention strategies in civilian and military populations living in P. vivax endemic areas.
Topics: Plasmodium vivax; Peru; Humans; Malaria, Vivax; Adult; Male; Young Adult; Adolescent; Female; Middle Aged; Protozoan Proteins; Antigens, Protozoan; Immunoglobulin G; Antibodies, Protozoan; Enzyme-Linked Immunosorbent Assay; Child; Aged; Enzyme-Linked Immunospot Assay
PubMed: 38783317
DOI: 10.1186/s12936-024-04978-z -
Characterization of Argonaute-containing protein complexes in Leishmania-infected human macrophages.PloS One 2024The intracellular protozoan parasite Leishmania causes leishmaniasis in humans, leading to serious illness and death in tropical and subtropical areas worldwide....
The intracellular protozoan parasite Leishmania causes leishmaniasis in humans, leading to serious illness and death in tropical and subtropical areas worldwide. Unfortunately, due to the unavailability of approved vaccines for humans and the limited efficacy of available drugs, leishmaniasis is on the rise. A comprehensive understanding of host-pathogen interactions at the molecular level could pave the way to counter leishmaniasis. There is growing evidence that several intracellular pathogens target RNA interference (RNAi) pathways in host cells to facilitate their persistence. The core elements of the RNAi system are complexes of Argonaute (Ago) proteins with small non-coding RNAs, also known as RNA-induced silencing complexes (RISCs). Recently, we have shown that Leishmania modulates Ago1 protein of host macrophages for its survival. In this study, we biochemically characterize the Ago proteins' interactome in Leishmania-infected macrophages compared to non-infected cells. For this, a quantitative proteomic approach using stable isotope labelling by amino acids in cell culture (SILAC) was employed, followed by purification of host Ago-complexes using a short TNRC6 protein-derived peptide fused to glutathione S-transferase beads as an affinity matrix. Proteomic-based detailed biochemical analysis revealed Leishmania modulated host macrophage RISC composition during infection. This analysis identified 51 Ago-interacting proteins with a broad range of biological activities. Strikingly, Leishmania proteins were detected as part of host Ago-containing complexes in infected cells. Our results present the first report of comprehensive quantitative proteomics of Ago-containing complexes isolated from Leishmania-infected macrophages and suggest targeting the effector complex of host RNAi machinery. Additionally, these results expand knowledge of RISC in the context of host-pathogen interactions in parasitology in general.
Topics: Argonaute Proteins; Humans; Macrophages; Proteomics; Leishmania; RNA Interference; Leishmaniasis
PubMed: 38781128
DOI: 10.1371/journal.pone.0303686 -
Frontiers in Immunology 2024Among spp. responsible for human malaria, ranks as the second most prevalent and has the widest geographical range; however, vaccine development has lagged behind that...
Among spp. responsible for human malaria, ranks as the second most prevalent and has the widest geographical range; however, vaccine development has lagged behind that of , the deadliest species. Recently, we developed a multistage vaccine for based on a heterologous prime-boost immunization regimen utilizing the attenuated vaccinia virus strain LC16m8Δ (m8Δ)-prime and adeno-associated virus type 1 (AAV1)-boost, and demonstrated 100% protection and more than 95% transmission-blocking (TB) activity in the mouse model. In this study, we report the feasibility and versatility of this vaccine platform as a multistage vaccine, which can provide 100% sterile protection against sporozoite challenge and >95% TB efficacy in the mouse model. Our vaccine comprises m8Δ and AAV1 viral vectors, both harboring the gene encoding two circumsporozoite (PvCSP) protein alleles (VK210; PvCSP-Sal and VK247; -PNG) and P25 (Pvs25) expressed as a Pvs25-PvCSP fusion protein. For protective efficacy, the heterologous m8Δ-prime/AAV1-boost immunization regimen showed 100% (short-term; Day 28) and 60% (long-term; Day 242) protection against PvCSP VK210 transgenic sporozoites. For TB efficacy, mouse sera immunized with the vaccine formulation showed >75% TB activity and >95% transmission reduction activity by a direct membrane feeding assay using isolates in blood from an infected patient from the Brazilian Amazon region. These findings provide proof-of-concept that the m8Δ/AAV1 vaccine platform is sufficiently versatile for vaccine development. Future studies are needed to evaluate the safety, immunogenicity, vaccine efficacy, and synergistic effects on protection and transmission blockade in a non-human primate model for Phase I trials.
Topics: Animals; Malaria Vaccines; Plasmodium vivax; Malaria, Vivax; Mice; Genetic Vectors; Dependovirus; Female; Protozoan Proteins; Antibodies, Protozoan; Disease Models, Animal; Vaccinia virus; Humans; Mice, Inbred BALB C; Immunization, Secondary; Vaccine Efficacy
PubMed: 38745665
DOI: 10.3389/fimmu.2024.1372584 -
Malaria Journal May 2024The newly developed malaria vaccine called "R21/Matrix-M malaria vaccine" showed a high safety and efficacy level, and Ghana is the first country to approve this new...
BACKGROUND
The newly developed malaria vaccine called "R21/Matrix-M malaria vaccine" showed a high safety and efficacy level, and Ghana is the first country to approve this new vaccine. The present study aimed to evaluate the rate of vaccine hesitancy (VH) towards the newly developed malaria vaccine among parents who currently have children who are not eligible for the vaccine but may be eligible in the near future. Additionally, the study aimed to identify the factors that could potentially influence VH.
METHODS
A cross-sectional survey using both online-based questionnaires and face-to-face interviews was conducted in Ghana from June to August 2023. The survey specifically targeted parents of ineligible children for vaccination, including those aged less than 5 months or between 3 and 12 years. The Parent Attitudes about Childhood Vaccination (PACV) scale was used to assess parental VH.
RESULTS
A total of 765 people participated in this study. Their median age was 36.0 years with an interquartile range of 31.0-41.0 years, 67.7% were females, 41.8% completed their tertiary education, 63.3% were married, 81.6% worked in non-healthcare sectors, and 59.7% reported that their monthly income was insufficient. About one-third (34.5%) of the parents were hesitant to give their children the R21/Matrix-M malaria vaccine. The following predictors were associated with VH: working in the healthcare sector (adjusted odds ratio (AOR) = 0.50; 95% confidence interval (CI) 0.30-0.80; p = 0.005), having the other parent working in the healthcare sector (AOR = 0.54; 95% CI 0.30-0.94; p = 0.034), and not taking scheduled routine vaccinations (AOR = 1.90; 95% CI 1.27-2.84; p = 0.002).
CONCLUSIONS
Addressing VH is crucial for optimizing R21/Matrix-M vaccine coverage in Ghana's malaria control strategy. By tackling VH issues, Ghana can effectively safeguard children's health in malaria-prone areas.
Topics: Humans; Ghana; Cross-Sectional Studies; Female; Male; Malaria Vaccines; Adult; Parents; Child, Preschool; Child; Vaccination Hesitancy; Infant; Surveys and Questionnaires; Vaccination; Malaria; Middle Aged
PubMed: 38734664
DOI: 10.1186/s12936-024-04921-2 -
Frontiers in Immunology 2024, a tick-borne apicomplexan parasite causing bovine babesiosis, remains a significant threat worldwide, and improved and practical vaccines are needed. Previous studies...
INTRODUCTION
, a tick-borne apicomplexan parasite causing bovine babesiosis, remains a significant threat worldwide, and improved and practical vaccines are needed. Previous studies defined the members of the rhoptry associated protein-1 (RAP-1), and the neutralization-sensitive rhoptry associated protein-1 related antigen (RRA) superfamily in , as strong candidates for the development of subunit vaccines. Both RAP-1 and RRA share conservation of a group of 4 cysteines and amino acids motifs at the amino terminal end (NT) of these proteins.
METHODS AND RESULTS
Sequence comparisons among the RRA sequences of several strains and other spp parasites indicate a high level of conservation of a 15-amino acid (15-mer) motif located at the NT of the protein. BlastP searches indicate that the 15-mer motif is also present in adenylate cyclase, dynein, and other ATP binding proteins. AlphaFold2 structure predictions suggest partial exposure of the 15-mer on the surface of RRA of three distinct species. Antibodies in protected cattle recognize a synthetic peptide representing the 15-mer motif sequence in iELISA, and rabbit antibodies against the 15-mer react with the surface of free merozoites in immunofluorescence.
DISCUSSION AND CONCLUSION
The presence of the 15-mer-like regions in dynein and ATP-binding proteins provides a rationale for investigating possible functional roles for RRA. The demonstrated presence of a surface exposed B-cell epitope in the 15-mer motif of the RRA, which is recognized by sera from protected bovines, supports its inclusion in future subunit epitope-based vaccines against .
Topics: Animals; Cattle; Babesia bovis; Epitopes, B-Lymphocyte; Babesiosis; Antibodies, Protozoan; Protozoan Proteins; Antigens, Protozoan; Amino Acid Motifs; Conserved Sequence; Cattle Diseases; Amino Acid Sequence; Protozoan Vaccines
PubMed: 38720894
DOI: 10.3389/fimmu.2024.1380660 -
Malaria Journal May 2024In 2021 and 2023, the World Health Organization approved RTS,S/AS01 and R21/Matrix M malaria vaccines, respectively, for routine immunization of children in African...
Genetic polymorphism and evidence of signatures of selection in the Plasmodium falciparum circumsporozoite protein gene in Tanzanian regions with different malaria endemicity.
BACKGROUND
In 2021 and 2023, the World Health Organization approved RTS,S/AS01 and R21/Matrix M malaria vaccines, respectively, for routine immunization of children in African countries with moderate to high transmission. These vaccines are made of Plasmodium falciparum circumsporozoite protein (PfCSP), but polymorphisms in the gene raise concerns regarding strain-specific responses and the long-term efficacy of these vaccines. This study assessed the Pfcsp genetic diversity, population structure and signatures of selection among parasites from areas of different malaria transmission intensities in Mainland Tanzania, to generate baseline data before the introduction of the malaria vaccines in the country.
METHODS
The analysis involved 589 whole genome sequences generated by and as part of the MalariaGEN Community Project. The samples were collected between 2013 and January 2015 from five regions of Mainland Tanzania: Morogoro and Tanga (Muheza) (moderate transmission areas), and Kagera (Muleba), Lindi (Nachingwea), and Kigoma (Ujiji) (high transmission areas). Wright's inbreeding coefficient (F), Wright's fixation index (F), principal component analysis, nucleotide diversity, and Tajima's D were used to assess within-host parasite diversity, population structure and natural selection.
RESULTS
Based on F (< 0.95), there was high polyclonality (ranging from 69.23% in Nachingwea to 56.9% in Muheza). No population structure was detected in the Pfcsp gene in the five regions (mean F = 0.0068). The average nucleotide diversity (π), nucleotide differentiation (K) and haplotype diversity (Hd) in the five regions were 4.19, 0.973 and 0.0035, respectively. The C-terminal region of Pfcsp showed high nucleotide diversity at Th2R and Th3R regions. Positive values for the Tajima's D were observed in the Th2R and Th3R regions consistent with balancing selection. The Pfcsp C-terminal sequences revealed 50 different haplotypes (H_1 to H_50), with only 2% of sequences matching the 3D7 strain haplotype (H_50). Conversely, with the NF54 strain, the Pfcsp C-terminal sequences revealed 49 different haplotypes (H_1 to H_49), with only 0.4% of the sequences matching the NF54 strain (Hap_49).
CONCLUSIONS
The findings demonstrate high diversity of the Pfcsp gene with limited population differentiation. The Pfcsp gene showed positive Tajima's D values, consistent with balancing selection for variants within Th2R and Th3R regions. The study observed differences between the intended haplotypes incorporated into the design of RTS,S and R21 vaccines and those present in natural parasite populations. Therefore, additional research is warranted, incorporating other regions and more recent data to comprehensively assess trends in genetic diversity within this important gene. Such insights will inform the choice of alleles to be included in the future vaccines.
Topics: Humans; Endemic Diseases; Malaria, Falciparum; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins; Selection, Genetic; Tanzania
PubMed: 38720288
DOI: 10.1186/s12936-024-04974-3 -
JCI Insight May 2024Vaccination of malaria-naive volunteers with a high dose of Plasmodium falciparum sporozoites chemoattenuated by chloroquine (CQ) (PfSPZ-CVac [CQ]) has previously... (Randomized Controlled Trial)
Randomized Controlled Trial
Vaccination of malaria-naive volunteers with a high dose of Plasmodium falciparum sporozoites chemoattenuated by chloroquine (CQ) (PfSPZ-CVac [CQ]) has previously demonstrated full protection against controlled human malaria infection (CHMI). However, lower doses of PfSPZ-CVac [CQ] resulted in incomplete protection. This provides the opportunity to understand the immune mechanisms needed for better vaccine-induced protection by comparing individuals who were protected with those not protected. Using mass cytometry, we characterized immune cell composition and responses of malaria-naive European volunteers who received either lower doses of PfSPZ-CVac [CQ], resulting in 50% protection irrespective of the dose, or a placebo vaccination, with everyone becoming infected following CHMI. Clusters of CD4+ and γδ T cells associated with protection were identified, consistent with their known role in malaria immunity. Additionally, EMRA CD8+ T cells and CD56+CD8+ T cell clusters were associated with protection. In a cohort from a malaria-endemic area in Gabon, these CD8+ T cell clusters were also associated with parasitemia control in individuals with lifelong exposure to malaria. Upon stimulation with P. falciparum-infected erythrocytes, CD4+, γδ, and EMRA CD8+ T cells produced IFN-γ and/or TNF, indicating their ability to mediate responses that eliminate malaria parasites.
Topics: Humans; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; CD8-Positive T-Lymphocytes; Adult; Sporozoites; Male; CD4-Positive T-Lymphocytes; Chloroquine; Female; Young Adult; Gabon; Vaccination; Antimalarials; Europe; Parasitemia; Adolescent; Vaccines, Attenuated; European People
PubMed: 38716733
DOI: 10.1172/jci.insight.170210 -
Malaria Journal May 2024Malaria vaccine introduction in endemic countries is a game-changing milestone in the fight against the disease. This article examines the inequity in the global... (Review)
Review
Malaria vaccine introduction in endemic countries is a game-changing milestone in the fight against the disease. This article examines the inequity in the global pharmaceutical research, development, manufacturing, and trade landscape. The role of inequity in hindering progress towards malaria elimination is explored. The analysis finds that transformational changes are required to create an equity-enabling environment. Addressing the inequity is critical to maximizing the public health impact of vaccines and attaining sustainability. Avenues to catalyze progress by leveraging malaria vaccines and messenger ribonucleic acid (mRNA) technology are discussed.
Topics: Malaria Vaccines; Humans; Malaria; Disease Eradication; RNA, Messenger; Global Health; Pharmaceutical Research
PubMed: 38711053
DOI: 10.1186/s12936-024-04972-5