-
Immunity Jun 2024Malaria is a life-threatening disease of global health importance, particularly in sub-Saharan Africa. The growth inhibition assay (GIA) is routinely used to evaluate,...
Malaria is a life-threatening disease of global health importance, particularly in sub-Saharan Africa. The growth inhibition assay (GIA) is routinely used to evaluate, prioritize, and quantify the efficacy of malaria blood-stage vaccine candidates but does not reliably predict either naturally acquired or vaccine-induced protection. Controlled human malaria challenge studies in semi-immune volunteers provide an unparalleled opportunity to robustly identify mechanistic correlates of protection. We leveraged this platform to undertake a head-to-head comparison of seven functional antibody assays that are relevant to immunity against the erythrocytic merozoite stage of Plasmodium falciparum. Fc-mediated effector functions were strongly associated with protection from clinical symptoms of malaria and exponential parasite multiplication, while the gold standard GIA was not. The breadth of Fc-mediated effector function discriminated clinical immunity following the challenge. These findings present a shift in the understanding of the mechanisms that underpin immunity to malaria and have important implications for vaccine development.
Topics: Humans; Plasmodium falciparum; Malaria, Falciparum; Antibodies, Protozoan; Malaria Vaccines; Adult; Immunoglobulin Fc Fragments; Merozoites; Erythrocytes; Female; Male; Young Adult
PubMed: 38788711
DOI: 10.1016/j.immuni.2024.05.001 -
One Health Outlook May 2024Yellow Fever (YF) is an acute viral hemorrhagic disease. Uganda is located within the Africa YF belt. Between 2019 and 2022, the Ugandan Health Authorities reported at... (Review)
Review
Yellow Fever (YF) is an acute viral hemorrhagic disease. Uganda is located within the Africa YF belt. Between 2019 and 2022, the Ugandan Health Authorities reported at least one outbreak of YF annually with an estimated 892 suspected cases, on average per year. The persistent recurrence of this disease raises significant concerns about the efficacy of current response strategies and prevention approaches. YF has been recognized as a One Health issue due to its interrelatedness with the animal and environmental domains. Monkeys have been recognized as the virus primary reservoir. The YF virus is transmitted through bites of infected Aedes or Haemagogus species mosquitoes between monkeys and humans. Human activities, monkey health, and environmental health issues (e.g., climate change and land use) impact YF incidence in Uganda. Additionally, disease control programs for other tropical diseases, such as mosquitoes control programs for malaria, impact YF incidence.This review adopts the One Health approach to highlight the limitations in the existing segmented YF control and prevention strategies in Uganda, including the limited health sector surveillance, the geographically localized outbreak response efforts, the lack of a comprehensive vaccination program, the limited collaboration and communication among relevant national and international agencies, and the inadequate vector control practices. Through a One Health approach, we propose establishing a YF elimination taskforce. This taskforce would oversee coordination of YF elimination initiatives, including implementing a comprehensive surveillance system, conducting mass YF vaccination campaigns, integrating mosquito management strategies, and enhancing risk communication. It is anticipated that adopting the One Health approach will reduce the risk of YF incidence and outbreaks.
PubMed: 38783349
DOI: 10.1186/s42522-024-00103-x -
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 -
Heliyon May 2024Malaria, a major public health burden, is caused by spp parasites that first replicate in the human liver to establish infection before spreading to erythrocytes....
Malaria, a major public health burden, is caused by spp parasites that first replicate in the human liver to establish infection before spreading to erythrocytes. Liver-stage malaria research has remained challenging due to the lack of a clinically relevant and scalable model of the human liver. Here, we demonstrate that organoids derived from intrahepatic ductal cells differentiated into a hepatocyte-like fate can support the infection and intrahepatic maturation of . The exoerythrocytic forms observed expressed both early and late-stage parasitic proteins and decreased in frequency in response to treatment with both known and putative antimalarial drugs that target intrahepatic . The -infected human liver organoids thus provide a platform not only for fundamental studies that characterise intrahepatic parasite-host interaction but can also serve as a powerful translational tool in pre-erythrocytic vaccine development and to identify new antimalarial drugs that target the liver stage infection.
PubMed: 38770342
DOI: 10.1016/j.heliyon.2024.e30740 -
MedRxiv : the Preprint Server For... May 2024A highly effective vaccine for malaria remains an elusive target, at least in part due to the under-appreciated natural parasite variation. This study aimed to...
BACKGROUND
A highly effective vaccine for malaria remains an elusive target, at least in part due to the under-appreciated natural parasite variation. This study aimed to investigate genetic and structural variation, and immune selection of leading malaria vaccine candidates across the 's life cycle.
METHODS
We analyzed 325 whole genome sequences from Zambia, in addition to 791 genomes from five other African countries available in the MalariaGEN Pf3k Rdatabase. Ten vaccine antigens spanning three life-history stages were examined for genetic and structural variations, using population genetics measures, haplotype network analysis, and 3D structure selection analysis.
FINDINGS
Among the ten antigens analyzed, only three in the transmission-blocking vaccine category display . 3D7 as the dominant haplotype. The antigens and are much more diverse than the other antigens, and their epitope regions are under moderate to strong balancing selection. In contrast, , a blood stage antigen, displays low diversity yet slightly stronger immune selection in the merozoite-blocking epitope region. Except for , the transmission-blocking antigens , , , , and exhibit minimal diversity and no immune selection in epitopes that induce strain-transcending antibodies, suggesting potential effectiveness of 3D7-based vaccines in blocking transmission.
INTERPRETATIONS
These findings offer valuable insights into the selection of optimal vaccine candidates against . Based on our results, we recommend prioritizing conserved merozoite antigens and transmission-blocking antigens. Combining these antigens in multi-stage approaches may be particularly promising for malaria vaccine development initiatives.
FUNDING
Purdue Department of Biological Sciences; Puskas Memorial Fellowship; National Institute of Allergy and Infectious Diseases (U19AI089680).
PubMed: 38766239
DOI: 10.1101/2024.05.11.24307175 -
Malaria Journal May 2024Plasmodium falciparum malaria is a public health issue mostly seen in tropical countries. Until now, there is no effective malaria vaccine against antigens specific to...
BACKGROUND
Plasmodium falciparum malaria is a public health issue mostly seen in tropical countries. Until now, there is no effective malaria vaccine against antigens specific to the blood-stage of P. falciparum infection. Because the pathogenesis of malarial disease results from blood-stage infection, it is essential to identify the most promising blood-stage vaccine candidate antigens under natural exposure to malaria infection.
METHODS
A cohort of 400 pregnant women and their infants was implemented in South Benin. An active and passive protocol of malaria surveillance was established during pregnancy and infancy to precisely ascertain malaria infections during the follow-up. Twenty-eight antibody (Ab) responses specific to seven malaria candidate vaccine antigens were repeatedly quantified during pregnancy (3 time points) and infancy (6 time points) in order to study the Ab kinetics and their protective role. Abs were quantified by ELISA and logistic, linear and cox-proportional hazard model were performed to analyse the associations between Ab responses and protection against malaria in mothers and infants, taking into account socio-economic factors and for infants an environmental risk of exposure.
RESULTS
The levels of IgM against MSP1, MSP2 and MSP3 showed an early protective response against the onset of symptomatic malaria infections starting from the 18th month of life, whereas no association was found for IgG responses during infancy. In women, some IgG responses tend to be associated with a protection against malaria risk along pregnancy and at delivery, among them IgG3 against GLURP-R0 and IgG2 against MSP1.
CONCLUSION
The main finding suggests that IgM should be considered in vaccine designs during infanthood. Investigation of the functional role played by IgM in malaria protection needs further attention.
Topics: Humans; Female; Plasmodium falciparum; Malaria, Falciparum; Pregnancy; Infant; Immunoglobulin M; Immunoglobulin G; Antibodies, Protozoan; Benin; Antigens, Protozoan; Adult; Young Adult; Enzyme-Linked Immunosorbent Assay; Infant, Newborn; Pregnancy Complications, Parasitic; Cohort Studies
PubMed: 38764069
DOI: 10.1186/s12936-024-04970-7 -
Infection, Genetics and Evolution :... Aug 2024Plasmodium vivax Merozoite Surface Protein 8 (PvMSP8) is a promising candidate target for the development of multi-component vaccines. Therefore, determining the genetic...
Plasmodium vivax Merozoite Surface Protein 8 (PvMSP8) is a promising candidate target for the development of multi-component vaccines. Therefore, determining the genetic variation pattern of Pvmsp8 is essential in providing a reference for the rational design of the P. vivax malaria vaccines. This study delves into the genetic characteristics of the Pvmsp8 gene, specifically focusing on samples from the China-Myanmar border (CMB) region, and contrasts these findings with broader global patterns. The study uncovers that Pvmsp8 exhibits a notable level of conservation across different populations, with limited polymorphisms and relatively low nucleotide diversity (0.00023-0.00120). This conservation contrasts starkly with the high polymorphisms found in other P. vivax antigens such as Pvmsp1. A total of 25 haplotypes and 14 amino acid mutation sites were identified in the global populations, and all mutation sites were confined to non-functional regions. The study also notes that most CMB Pvmsp8 haplotypes are shared among Burmese, Cambodian, Thai, and Vietnamese populations, indicating less geographical variance, but differ notably from those found in Pacific island regions or the Panama. The findings underscore the importance of considering regional genetic diversity in P. vivax when developing targeted malaria vaccines. Non departure from neutral evolution were found by Tajima's D test, however, statistically significant differences were observed between the kn/ks rates. The study's findings are crucial in understanding the evolution and population structure of the Pvmsp8 gene, particularly during regional malaria elimination efforts. The highly conserved nature of Pvmsp8, combined with the lack of mutations in its functional domain, presents it as a promising candidate for developing a broad and effective P. vivax vaccine. This research thus lays a foundation for the rational development of multivalent malaria vaccines targeting this genetically stable antigen.
Topics: Plasmodium vivax; Selection, Genetic; Protozoan Proteins; Haplotypes; Humans; Genetic Variation; Malaria, Vivax; Mutation; Phylogeny; Antigens, Protozoan
PubMed: 38759940
DOI: 10.1016/j.meegid.2024.105605 -
Wellcome Open Research 2023Malaria remains a public health problem in Malawi and has a serious socio-economic impact on the population. In the past two decades, available malaria control measures...
BACKGROUND
Malaria remains a public health problem in Malawi and has a serious socio-economic impact on the population. In the past two decades, available malaria control measures have been substantially scaled up, such as insecticide-treated bed nets, artemisinin-based combination therapies, and, more recently, the introduction of the malaria vaccine, the RTS,S/AS01. In this paper, we describe the epidemiology of malaria for the last two decades to understand the past transmission and set the scene for the elimination agenda.
METHODS
A collation of parasite prevalence surveys conducted between the years 2000 and 2022 was done. A spatio-temporal geostatistical model was fitted to predict the yearly malaria risk for children aged 2-10 years (PfPR 2-10) at 1×1 km spatial resolutions. Parameter estimation was done using the Monte Carlo maximum likelihood method. District-level prevalence estimates adjusted for population are calculated for the years 2000 to 2022.
RESULTS
A total of 2,595 sampled unique locations from 2000 to 2022 were identified through the data collation exercise. This represents 70,565 individuals that were sampled in the period. In general, the PfPR2_10 declined over the 22 years. The mean modelled national PfPR2_10 in 2000 was 43.93 % (95% CI:17.9 to 73.8%) and declined to 19.2% (95%CI 7.49 to 37.0%) in 2022. The smoothened estimates of PfPR2_10 indicate that malaria prevalence is very heterogeneous with hotspot areas concentrated on the southern shores of Lake Malawi and the country's central region.
CONCLUSIONS
The last two decades are associated with a decline in malaria prevalence, highly likely associated with the scale-up of control interventions. The country should move towards targeted malaria control approaches informed by surveillance data.
PubMed: 38756913
DOI: 10.12688/wellcomeopenres.19390.2 -
Malaria Journal May 2024Sporozoite invasion of hepatocytes is an essential step in the Plasmodium life-cycle and has similarities, at the cellular level, to merozoite invasion of erythrocytes....
BACKGROUND
Sporozoite invasion of hepatocytes is an essential step in the Plasmodium life-cycle and has similarities, at the cellular level, to merozoite invasion of erythrocytes. In the case of the Plasmodium blood-stage, efforts to identify host-pathogen protein-protein interactions have yielded important insights including vaccine candidates. In the case of sporozoite-hepatocyte invasion, the host-pathogen protein-protein interactions involved are poorly understood.
METHODS
To gain a better understanding of the protein-protein interaction between the sporozoite ligands and host receptors, a systematic screen was performed. The previous Plasmodium falciparum and human surface protein ectodomain libraries were substantially extended, resulting in the creation of new libraries comprising 88 P. falciparum sporozoite protein coding sequences and 182 sequences encoding human hepatocyte surface proteins. Having expressed recombinant proteins from these sequences, a plate-based assay was used, capable of detecting low affinity interactions between recombinant proteins, modified for enhanced throughput, to screen the proteins for interactions. The novel interactions identified in the screen were characterized biochemically, and their essential role in parasite invasion was further elucidated using antibodies and genetically manipulated Plasmodium parasites.
RESULTS
A total of 7540 sporozoite-hepatocyte protein pairs were tested under conditions capable of detecting interactions of at least 1.2 µM K. An interaction between the human fibroblast growth factor receptor 4 (FGFR4) and the P. falciparum protein Pf34 is identified and reported here, characterizing its affinity and demonstrating the blockade of the interaction by reagents, including a monoclonal antibody. Furthermore, further interactions between Pf34 and a second P. falciparum rhoptry neck protein, PfRON6, and between human low-density lipoprotein receptor (LDLR) and the P. falciparum protein PIESP15 are identified. Conditional genetic deletion confirmed the essentiality of PfRON6 in the blood-stage, consistent with the important role of this protein in parasite lifecycle. Pf34 was refractory to attempted genetic modification. Antibodies to Pf34 abrogated the interaction and had a modest effect upon sporozoite invasion into primary human hepatocytes.
CONCLUSION
Pf34 and PfRON6 may be members of a functionally important invasion complex which could be a target for future interventions. The modified interaction screening assay, protein expression libraries and P. falciparum mutant parasites reported here may be a useful tool for protein interaction discovery and antigen candidate screening which could be of wider value to the scientific community.
Topics: Plasmodium falciparum; Hepatocytes; Humans; Sporozoites; Protozoan Proteins; Host-Pathogen Interactions; Membrane Proteins; Receptors, Cell Surface; Host-Parasite Interactions; Protein Binding
PubMed: 38755636
DOI: 10.1186/s12936-024-04913-2 -
Clinical and Experimental Vaccine... Apr 2024The global burden of disease and mortality is greatly influenced by malaria, particularly in children. Nigeria alone accounts for about 25% of global malaria cases and...
PURPOSE
The global burden of disease and mortality is greatly influenced by malaria, particularly in children. Nigeria alone accounts for about 25% of global malaria cases and fatalities. Despite efforts to control and eliminate malaria, conventional treatments have limitations, prompting the need for a vaccine. However, while efforts have focused on researching and developing malaria vaccines, less attention has been given to public acceptance and preparedness for vaccination.
MATERIALS AND METHODS
The study employed a cross-sectional approach to assess the knowledge, perceptions, and readiness of caregivers towards the malaria vaccine. Data were collected through a physical and online survey among a representative sample of caregivers across the six geopolitical regions of Nigeria. The data was analyzed using principal component analysis and percentages.
RESULTS
Out of 347 respondents, 180 (51%) men, 165 (46.6%) women, 2 (0.5%) transgender, 156 (45%) rural settlers, and 191 (55%) urban settlers were identified in this study. The study reported an overall acceptance rate of 78.4% and 21.6% resistance rate. The age group between 21-30 years recorded the highest 207 (59.6%). A significant number of participants, 252 (59.6%), held at least a higher or post-secondary certificate, out of which 193 (55.6%) demonstrated strong readiness to accept the malaria vaccine. The study showed that fear of adverse effects was the main reason for malaria vaccine resistance among caregivers.
CONCLUSION
This study's findings offer valuable insights into caregivers' knowledge about the malaria vaccine, highlighting the factors that impact the acceptance of the malaria vaccine.
PubMed: 38752001
DOI: 10.7774/cevr.2024.13.2.121