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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 -
Frontiers in Immunology 2024Attenuated sporozoites provide a valuable model for exploring protective immunity against the malarial liver stage, guiding the design of highly efficient vaccines to... (Review)
Review
Attenuated sporozoites provide a valuable model for exploring protective immunity against the malarial liver stage, guiding the design of highly efficient vaccines to prevent malaria infection. Liver tissue-resident CD8 T cells (CD8 Trm cells) are considered the host front-line defense against malaria and are crucial to developing prime-trap/target strategies for pre-erythrocytic stage vaccine immunization. However, the spatiotemporal regulatory mechanism of the generation of liver CD8 Trm cells and their responses to sporozoite challenge, as well as the protective antigens they recognize remain largely unknown. Here, we discuss the knowledge gap regarding liver CD8 Trm cell formation and the potential strategies to identify predominant protective antigens expressed in the exoerythrocytic stage, which is essential for high-efficacy malaria subunit pre-erythrocytic vaccine designation.
Topics: Humans; CD8-Positive T-Lymphocytes; Malaria; Liver; Malaria Vaccines; Immunization
PubMed: 38318178
DOI: 10.3389/fimmu.2024.1344941 -
International Immunology Apr 2024Toxoplasma gondii is a pathogenic protozoan parasite of the Apicomplexa family that affects approximately 30% of the world's population. Symptoms are usually mild in... (Review)
Review
Toxoplasma gondii is a pathogenic protozoan parasite of the Apicomplexa family that affects approximately 30% of the world's population. Symptoms are usually mild in immunocompetent hosts, but it can pose significant health risks to immunosuppressed patients and pregnant women. Current treatment options are limited, and new therapies and vaccines are needed. The innate immune system is the first to recognize T. gondii infection and activates pro-inflammatory cytokines and chemokines to promote acquired immunity. The IL-12/IFN-γ axis is particularly important, and when this pathway is inhibited, infection becomes uncontrolled and lethal. In mice, receptors such as Toll-like receptor 11 (TLR11), TLR12, and chemokine receptors are involved in T. gondii recognition and the modulation of immune responses. In humans, where TLR11 and TLR12 are absent, other mechanisms have been reported as the innate immune sensing system in T. gondii infection. Immune cells activated in response to infection produce interleukin (IL)-12, which stimulates the proliferation of natural killer cells and T cells and promotes the production of interferon (IFN)-γ. Several IFN-γ-induced anti-T. gondii defense mechanisms inhibit parasite growth. These include nitric oxide (NO) production, indoleamine 2,3-dioxygenase, and the destruction of parasitophorous vacuoles by IFN-γ-inducible immunity related GTPase groups (IRGs and GBPs). Recent studies focusing on the diversity of IRGs in rodents and effector molecules in T. gondii suggest that host immune mechanisms and pathogen immune evasion mechanisms have co-evolved. Furthermore, it has been suggested that cysts are not simply dormant during chronic infection. This review summarizes recent findings on anti-T. gondii innate, adaptive, and cell-autonomous immune responses.
Topics: Humans; Pregnancy; Female; Mice; Animals; Toxoplasmosis; Toxoplasma; Interleukin-12; Immunity, Cellular; Carrier Proteins
PubMed: 38175650
DOI: 10.1093/intimm/dxae001 -
MSphere Oct 2023Antibody responses to variant surface antigens (VSAs) produced by the malaria parasite may contribute to age-related natural immunity to severe malaria. One VSA family,...
Antibody responses to variant surface antigens (VSAs) produced by the malaria parasite may contribute to age-related natural immunity to severe malaria. One VSA family, erythrocyte membrane protein-1 (PfEMP1), includes a subset of proteins that binds endothelial protein C receptor (EPCR) in human hosts and potentially disrupts the regulation of inflammatory responses, which may lead to the development of severe malaria. We probed peptide microarrays containing segments spanning five PfEMP1 EPCR-binding domain variants with sera from 10 Malian adults and 10 children to determine the differences between adult and pediatric immune responses. We defined serorecognized peptides and amino acid residues as those that elicited a significantly higher antibody response than malaria-naïve controls. We aimed to identify regions consistently serorecognized among adults but not among children across PfEMP1 variants, potentially indicating regions that drive the development of immunity to severe malaria. Adult sera consistently demonstrated broader and more intense serologic responses to constitutive PfEMP1 peptides than pediatric sera, including peptides in EPCR-binding domains. Both adults and children serorecognized a significantly higher proportion of EPCR-binding peptides than peptides that do not directly participate in receptor binding, indicating a preferential development of serologic responses at functional residues. Over the course of a single malaria transmission season, pediatric serological responses increased between the start and the peak of the season, but waned as the transmission season ended. IMPORTANCE Severe malaria and death related to malaria disproportionately affect sub-Saharan children under 5 years of age, commonly manifesting as cerebral malaria and/or severe malarial anemia. In contrast, adults in malaria-endemic regions tend to experience asymptomatic or mild disease. Our findings indicate that natural immunity to malaria targets specific regions within the EPCR-binding domain, particularly peptides containing EPCR-binding residues. Epitopes containing these residues may be promising targets for vaccines or therapeutics directed against severe malaria. Our approach provides insight into the development of natural immunity to a binding target linked to severe malaria by characterizing an "adult-like" response as recognizing a proportion of epitopes within the PfEMP1 protein, particularly regions that mediate EPCR binding. This "adult-like" response likely requires multiple years of malaria exposure, as increases in pediatric serologic response over a single malaria transmission season do not appear significant.
Topics: Adult; Child; Humans; Child, Preschool; Endothelial Protein C Receptor; Protozoan Proteins; Malaria; Malaria, Falciparum; Epitopes; Peptides
PubMed: 37791774
DOI: 10.1128/msphere.00451-23 -
The Lancet. Infectious Diseases May 2024The R21/Matrix-M vaccine has demonstrated high efficacy against Plasmodium falciparum clinical malaria in children in sub-Saharan Africa. Using trial data, we aimed to...
BACKGROUND
The R21/Matrix-M vaccine has demonstrated high efficacy against Plasmodium falciparum clinical malaria in children in sub-Saharan Africa. Using trial data, we aimed to estimate the public health impact and cost-effectiveness of vaccine introduction across sub-Saharan Africa.
METHODS
We fitted a semi-mechanistic model of the relationship between anti-circumsporozoite protein antibody titres and vaccine efficacy to data from 3 years of follow-up in the phase 2b trial of R21/Matrix-M in Nanoro, Burkina Faso. We validated the model by comparing predicted vaccine efficacy to that observed over 12-18 months in the phase 3 trial. Integrating this framework within a mathematical transmission model, we estimated the cases, malaria deaths, and disability-adjusted life-years (DALYs) averted and cost-effectiveness over a 15-year time horizon across a range of transmission settings in sub-Saharan Africa. Cost-effectiveness was estimated incorporating the cost of vaccine introduction (dose, consumables, and delivery) relative to existing interventions at baseline. We report estimates at a median of 20% parasite prevalence in children aged 2-10 years (PfPR) and ranges from 3% to 65% PfPR.
FINDINGS
Anti-circumsporozoite protein antibody titres were found to satisfy the criteria for a surrogate of protection for vaccine efficacy against clinical malaria. Age-based implementation of a four-dose regimen of R21/Matrix-M vaccine was estimated to avert 181 825 (range 38 815-333 491) clinical cases per 100 000 fully vaccinated children in perennial settings and 202 017 (29 868-405 702) clinical cases per 100 000 fully vaccinated children in seasonal settings. Similar estimates were obtained for seasonal or hybrid implementation. Under an assumed vaccine dose price of US$3, the incremental cost per clinical case averted was $7 (range 4-48) in perennial settings and $6 (3-63) in seasonal settings and the incremental cost per DALY averted was $34 (29-139) in perennial settings and $30 (22-172) in seasonal settings, with lower cost-effectiveness ratios in settings with higher PfPR.
INTERPRETATION
Introduction of the R21/Matrix-M malaria vaccine could have a substantial public health benefit across sub-Saharan Africa.
FUNDING
The Wellcome Trust, the Bill & Melinda Gates Foundation, the UK Medical Research Council, the European and Developing Countries Clinical Trials Partnership 2 and 3, the NIHR Oxford Biomedical Research Centre, and the Serum Institute of India, Open Philanthropy.
Topics: Humans; Cost-Benefit Analysis; Malaria Vaccines; Malaria, Falciparum; Burkina Faso; Models, Theoretical; Child, Preschool; Public Health; Plasmodium falciparum; Child; Protozoan Proteins; Antibodies, Protozoan; Vaccine Efficacy; Infant; Male; Female
PubMed: 38342107
DOI: 10.1016/S1473-3099(23)00816-2 -
Cell Reports Jul 2023Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing...
Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing malaria infection. However, their mechanisms of protection remain unclear. Here, using 13 distinctive PfCSP hmAbs, we provide a comprehensive view of how PfCSP hmAbs neutralize sporozoites in host tissues. Sporozoites are most vulnerable to hmAb-mediated neutralization in the skin. However, rare but potent hmAbs additionally neutralize sporozoites in the blood and liver. Efficient protection in tissues mainly associates with high-affinity and high-cytotoxicity hmAbs inducing rapid parasite loss-of-fitness in the absence of complement and host cells in vitro. A 3D-substrate assay greatly enhances hmAb cytotoxicity and mimics the skin-dependent protection, indicating that the physical stress imposed on motile sporozoites by the skin is crucial for unfolding the protective potential of hmAbs. This functional 3D cytotoxicity assay can thus be useful for downselecting potent anti-PfCSP hmAbs and vaccines.
Topics: Animals; Humans; Plasmodium falciparum; Malaria Vaccines; Malaria; Protozoan Proteins; Immunoglobulins; Sporozoites; Malaria, Falciparum
PubMed: 37389992
DOI: 10.1016/j.celrep.2023.112681 -
Lab Animal Dec 2023Placental malaria vaccines (PMVs) are being developed to prevent severe sequelae of placental malaria (PM) in pregnant women and their offspring. The leading candidate...
Placental malaria vaccines (PMVs) are being developed to prevent severe sequelae of placental malaria (PM) in pregnant women and their offspring. The leading candidate vaccine antigen VAR2CSA mediates parasite binding to placental receptor chondroitin sulfate A (CSA). Despite promising results in small animal studies, recent human trials of the first two PMV candidates (PAMVAC and PRIMVAC) generated limited cross-reactivity and cross-inhibitory activity to heterologous parasites. Here we immunized Aotus nancymaae monkeys with three PMV candidates (PAMVAC, PRIMVAC and ID1-ID2a_M1010) adjuvanted with Alhydrogel, and exploited the model to investigate boosting of functional vaccine responses during PM episodes as well as with nanoparticle antigens. PMV candidates induced high levels of antigen-specific IgG with significant cross-reactivity across PMV antigens by enzyme-linked immunosorbent assay. Conversely, PMV antibodies recognized native VAR2CSA and blocked CSA adhesion of only homologous parasites and not of heterologous parasites. PM episodes did not significantly boost VAR2CSA antibody levels or serum functional activity; nanoparticle and monomer antigens alike boosted serum reactivity but not functional activities. Overall, PMV candidates induced functional antibodies with limited heterologous activity in Aotus monkeys, similar to responses reported in humans. The Aotus model appears suitable for preclinical downselection of PMV candidates and assessment of antibody boosting by PM episodes.
Topics: Animals; Humans; Female; Pregnancy; Placenta; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; Antigens, Protozoan; Antibodies, Protozoan; Malaria; Aotidae; Immunity
PubMed: 37932470
DOI: 10.1038/s41684-023-01274-2 -
International Journal of Molecular... Mar 2024Chagas disease (CD) is a vector-borne Neglected Zoonotic Disease (NZD) caused by a flagellate protozoan, , that affects various mammalian species across America,... (Review)
Review
Chagas disease (CD) is a vector-borne Neglected Zoonotic Disease (NZD) caused by a flagellate protozoan, , that affects various mammalian species across America, including humans and domestic animals. However, due to an increase in population movements and new routes of transmission, infection is presently considered a worldwide health concern, no longer restricted to endemic countries. Dogs play a major role in the domestic cycle by acting very efficiently as reservoirs and allowing the perpetuation of parasite transmission in endemic areas. Despite the significant progress made in recent years, still there is no vaccine against human and animal disease, there are few drugs available for the treatment of human CD, and there is no standard protocol for the treatment of canine CD. In this review, we highlight human and canine Chagas Disease in its different dimensions and interconnections. Dogs, which are considered to be the most important peridomestic reservoir and sentinel for the transmission of infection in a community, develop CD that is clinically similar to human CD. Therefore, an integrative approach, based on the One Health concept, bringing together the advances in genomics, immunology, and epidemiology can lead to the effective development of vaccines, new treatments, and innovative control strategies to tackle CD.
Topics: Humans; Dogs; Animals; Chagas Disease; Animals, Domestic; Trypanosoma cruzi; Animal Diseases; Dog Diseases; Mammals
PubMed: 38612650
DOI: 10.3390/ijms25073840 -
The Journal of Clinical Investigation Jan 2024BACKGROUNDSanaria PfSPZ Vaccine, composed of attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against malaria. We conducted this clinical trial to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDSanaria PfSPZ Vaccine, composed of attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against malaria. We conducted this clinical trial to assess the safety and efficacy of PfSPZ Vaccine in HIV-positive (HIV+) individuals, since the HIV-infection status of participants in mass vaccination programs may be unknown.METHODSThis randomized, double-blind, placebo-controlled trial enrolled 18- to 45-year-old HIV-negative (HIV-) and well-controlled HIV+ Tanzanians (HIV viral load <40 copies/mL, CD4 counts >500 cells/μL). Participants received 5 doses of PfSPZ Vaccine or normal saline (NS) over 28 days, followed by controlled human malaria infection (CHMI) 3 weeks later.RESULTSThere were no solicited adverse events in the 9 HIV- and 12 HIV+ participants. After CHMI, 6 of 6 NS controls, 1 of 5 HIV- vaccinees, and 4 of 4 HIV+ vaccinees were Pf positive by quantitative PCR (qPCR). After immunization, anti-Pf circumsporozoite protein (anti-PfCSP) (isotype and IgG subclass) and anti-PfSPZ antibodies, anti-PfSPZ CD4+ T cell responses, and Vδ2+ γδ CD3+ T cells were nonsignificantly higher in HIV- than in HIV+ vaccinees. Sera from HIV- vaccinees had significantly higher inhibition of PfSPZ invasion of hepatocytes in vitro and antibody-dependent complement deposition (ADCD) and Fcγ3B binding by anti-PfCSP and ADCD by anti-cell-traversal protein for ookinetes and SPZ (anti-PfCelTOS) antibodies.CONCLUSIONSPfSPZ Vaccine was safe and well tolerated in HIV+ vaccinees, but not protective. Vaccine efficacy was 80% in HIV- vaccinees (P = 0.012), whose sera had significantly higher inhibition of PfSPZ invasion of hepatocytes and enrichment of multifunctional PfCSP antibodies. A more potent PfSPZ vaccine or regimen is needed to protect those living with HIV against Pf infection in Africa.TRIAL REGISTRATIONClinicalTrials.gov NCT03420053.FUNDINGEquatorial Guinea Malaria Vaccine Initiative (EGMVI), made up of the Government of Equatorial Guinea Ministries of Mines and Hydrocarbons, and Health and Social Welfare, Marathon Equatorial Guinea Production Limited, Noble Energy, Atlantic Methanol Production Company, and EG LNG; Swiss government, through ESKAS scholarship grant no. 2016.0056; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; NIH grant 1U01AI155354-01.
Topics: Adolescent; Adult; Humans; Middle Aged; Young Adult; Antibodies, Protozoan; East African People; HIV Infections; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; Tanzania; HIV Seronegativity; HIV Seropositivity; Vaccine Efficacy
PubMed: 38194272
DOI: 10.1172/JCI169060 -
Acta Parasitologica Dec 2023Malaria is one of the most dangerous infectious diseases in the world. It occurs in tropical and subtropical regions and affects about 40% of the world´s population. In...
Malaria is one of the most dangerous infectious diseases in the world. It occurs in tropical and subtropical regions and affects about 40% of the world´s population. In endemic regions, an estimated 200 million people contract malaria each year. Three-quarters of all global deaths (about 600 per year) are children under 5 years of age. Thus, malaria is one of the most relevant tropical and also childhood diseases in the world. Thanks to various public health measures such as vector control through mosquito nets or the targeted use of insecticides as well as the use of antimalarial prophylaxis drugs, the incidence has already been successfully reduced in recent years. However, to reduce the risk of malaria and to protect children effectively, further measures are necessary. An important part of these measures is an effective vaccination against malaria. However, the history of research shows that the development of an effective malaria vaccine is not an easy undertaking and is associated with some complications. Research into possible vaccines began as early as the 1960s. However, the results achieved were rather sobering and the various vaccines fell short of their expectations. It was not until 2015 that the vaccine RTS,S/AS01 received a positive evaluation from the European Medicines Agency. Since then, the vaccine has been tested in Africa. However, with the COVID-19 pandemic, there are new developments in vaccine research that could also benefit malaria research. These include, among others, the so-called mRNA vaccines. Already in the early 1990s, an immune response triggered by an mRNA vaccine was described for the first time. Since then, mRNA vaccines have been researched and discussed for possible prophylaxis. However, it was not until the COVID-19 pandemic that these vaccines experienced a veritable progress. mRNA vaccines against SARS-CoV-2 were rapidly developed and achieved high efficacy in studies. Based on this success, it is not surprising that companies are also focusing on other diseases and pathogens. Besides viral diseases, such as influenza or AIDS, malaria is high on this list. Many pharmaceutical companies (including the German companies BioNTech and CureVac) have already confirmed that they are researching mRNA vaccines against malaria. However, this is not an easy task. The aim of this article is to describe and discuss possible antigens that could be considered for mRNA vaccination. However, this topic is currently still very speculative.
Topics: Child; Humans; Child, Preschool; Malaria Vaccines; COVID-19 Vaccines; Pandemics; Malaria; Communicable Diseases; COVID-19; Malaria, Falciparum
PubMed: 37828249
DOI: 10.1007/s11686-023-00712-y