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Wellcome Open Research 2023Falciparum malaria remains a global health problem. Two vaccines, based on the circumsporozoite antigen, are available. RTS, S/AS01 was recommended for use in 2021...
Safety and immunogenicity of varied doses of R21/Matrix-M™ vaccine at three years follow-up: A phase 1b age de-escalation, dose-escalation trial in adults, children, and infants in Kilifi-Kenya.
BACKGROUND
Falciparum malaria remains a global health problem. Two vaccines, based on the circumsporozoite antigen, are available. RTS, S/AS01 was recommended for use in 2021 following the advice of the World Health Organisation (WHO) Strategic Advisory Group of Experts (SAGE) on Immunization and WHO Malaria Policy Advisory Group (MPAG). It has since been pre-qualified in 2022 by the WHO. R21 is similar to RTS, S/AS01, and recently licensed in Nigeria, Ghana and Burkina Faso following Phase 3 trial results.
METHODS
We conducted a Phase 1b age de-escalation, dose escalation bridging study after a change in the manufacturing process for R21. We recruited healthy adults and children and used a three dose primary vaccination series with a booster dose at 1-2 years. Variable doses of R21 and adjuvant (Matrix-M ™) were administered at 10µgR21/50 µg Matrix-M™, 5µgR21/25µg Matrix-M™ and 5µgR21/50µg Matrix-M™ to 20 adults, 20 children, and 51 infants.
RESULTS
Self-limiting adverse events were reported relating to the injection site and mild systemic symptoms. Two serious adverse events were reported, neither linked to vaccination. High levels of IgG antibodies to the circumsporozoite antigen were induced, and geometric mean titres in infants, the target group, were 1.1 (0.9 to 1.3) EU/mL at day 0, 10175 (7724 to 13404) EU/mL at day 84 and (following a booster dose at day 421) 6792 (5310 to 8687) EU/mL at day 456.
CONCLUSION
R21/Matrix-M™ is safe, and immunogenic when given at varied doses with the peak immune response seen in infants 28 days after a three dose primary vaccination series given four weeks apart. Antibody responses were restored 28 days after a 4 dose given one year post a three dose primary series in the young children and infants.
REGISTRATION
Clinicaltrials.gov (NCT03580824; 9 of July 2018; Pan African Clinical Trials Registry (PACTR202105682956280; 17 May 2021).
PubMed: 38813551
DOI: 10.12688/wellcomeopenres.19795.1 -
Targeting Prohibitin 2-Hu-Hsp70A1A complex as a unique approach towards malaria vaccine development.IScience Jun 2024Malaria parasite invasion to host erythrocytes is mediated by multiple interactions between merozoite ligands and erythrocyte receptors that contribute toward the...
Malaria parasite invasion to host erythrocytes is mediated by multiple interactions between merozoite ligands and erythrocyte receptors that contribute toward the development of disease pathology. Here, we report a novel antigen prohibitin "PHB2" and identify its cognate partner "Hsp70A1A" in host erythrocyte that plays a crucial role in mediating host-parasite interaction during merozoite invasion. Using small interfering RNA (siRNA)- and glucosamine-6-phosphate riboswitch (glmS) ribozyme-mediated approach, we show that loss of Hsp70A1A in red blood cells (RBCs) or PHB2 in infected red blood cells (iRBCs), respectively, inhibit PHB2-Hsp70A1A interaction leading to invasion inhibition. Antibodies targeting PHB2 and monoclonal antibody therapeutics against Hsp70A1A efficiently block parasite invasion. Recombinant PHB2 binds to RBCs which is inhibited by anti-PHB2 antibody and monoclonal antibody against Hsp70A1A. The validation of PHB2 to serve as antigen is further supported by detection of anti-PHB2 antibody in patient sera. Overall, this study proposes PHB2 as vaccine candidate and highlights the use of monoclonal antibody therapeutics for future malaria treatment.
PubMed: 38812541
DOI: 10.1016/j.isci.2024.109918 -
Journal, Genetic Engineering &... Jun 2024Malaria has remained a major health concern for decades among people living in tropical and sub-tropical countries. Plasmodium falciparum is one of the critical species...
BACKGROUND
Malaria has remained a major health concern for decades among people living in tropical and sub-tropical countries. Plasmodium falciparum is one of the critical species that cause severe malaria and is responsible for major mortality. Moreover, the parasite has generated resistance against all WHO recommended drugs and therapies. Therefore, there is an urgent need for preventive measures in the form of reliable vaccines to achieve the target of a malaria-free world. Surface proteins are the preferable choice for subunit vaccine development because they are rapidly detected and engaged by host immune cells and vaccination-induced antibodies. Additionally, abundant surface or membrane proteins may contribute to the opsonization of pathogens by vaccine-induced antibodies.
RESULTS
In our study, we have listed all those surface proteins from the literature that could be functionally important and essential for infection and immune evasion of the malaria parasite. Eight Plasmodium surface and membrane proteins from the pre-erythrocyte and erythrocyte stages were shortlisted. Thirty-seven epitopes (B-cell, CTL, and HTL epitopes) from these proteins were predicted using immune-informatic tools and joined with suitable peptide linkers to design a vaccine construct. A TLR-4 agonist peptide adjuvant was added at the N-terminus of the multi-epitope series, followed by the PADRE sequence and EAAAK linker. The TLR-4 receptor was docked with the construct's anticipated model structure. The complex of vaccine and TLR-4, with the lowest energy -1514, was found to be stable under simulated physiological settings.
CONCLUSION
This study has provided a novel multi-epitope construct that may be exploited further for the development of an efficient vaccine for malaria.
PubMed: 38797552
DOI: 10.1016/j.jgeb.2024.100377 -
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 -
Vaccines Apr 2024The WHO reported an estimated 249 million malaria cases and 608,000 malaria deaths in 85 countries in 2022. A total of 94% of malaria deaths occurred in Africa, 80% of... (Review)
Review
The WHO reported an estimated 249 million malaria cases and 608,000 malaria deaths in 85 countries in 2022. A total of 94% of malaria deaths occurred in Africa, 80% of which were children under 5. In other words, one child dies every minute from malaria. The RTS,S/AS01 malaria vaccine, which uses the circumsporozoite protein (CSP) to target sporozoite infection of the liver, achieved modest efficacy. The Malaria Vaccine Implementation Program (MVIP), coordinated by the WHO and completed at the end of 2023, found that immunization reduced mortality by only 13%. To further reduce malaria death, the development of a more effective malaria vaccine is a high priority. Three malaria vaccine targets being considered are the sporozoite liver infection (pre-erythrocytic stage), the merozoite red blood cell infection (asexual erythrocytic stage), and the gamete/zygote mosquito infection (sexual/transmission stage). These targets involve specific ligand-receptor interactions. However, most current malaria vaccine candidates that target two major parasite population bottlenecks, liver infection, and mosquito midgut infection, do not focus on such parasite ligands. Here, we evaluate the potential of newly identified parasite ligands with a phage peptide-display technique as novel malaria vaccine antigens.
PubMed: 38793735
DOI: 10.3390/vaccines12050484 -
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