Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection associated with endothelial activation, neuroinflammation, and disruption of the blood-brain barrier (BBB). While curcumin (Cur) possesses antiplasmodial and anti-inflammatory properties, its therapeutic potential is limited by poor aqueous solubility, rapid metabolism, and insufficient brain bioavailability. In this study, we hypothesized that polysaccharide-driven surface engineering could regulate nanoparticles (NPs) interfacial properties to improve BBB compatibility and antiplasmodial efficacy. Cur-loaded polycaprolactone (PCL) NPs were fabricated through a single-emulsion solvent evaporation technique and sequentially coated with chitosan (CS) and hyaluronic acid (HA) to establish defined structure-property relationships. The resulting nanoformulations were characterized for particle size, surface charge, polysaccharide deposition, encapsulation efficiency (EE), and release kinetics. In-vitro biological performance was evaluated through hemocompatibility, brain endothelial cell viability, BBB integrity through transendothelial electrical resistance measurements, and in-vitro antiplasmodial activity against P. falciparum FCR3. Dual polysaccharide coating produced stable NPs with controlled size, enhanced surface charge, sustained Cur release, and significantly improved endothelial compatibility compared with free Cur and non-hyaluronic-acid formulations. Notably, HA coating strengthened BBB integrity and enhanced antiplasmodial potency. These findings demonstrate that CS- HA surface functionalization governs critical structure-property relationships, highlighting the potential of polysaccharide-engineered nanocarriers for adjunctive CM drug delivery.

Oxfendazole, a registered veterinary drug, has demonstrated broad-spectrum activity against multiple nematode species. First-in-human studies in healthy, predominantly Caucasian adults receiving a liquid formulation of oxfendazole demonstrated a favorable pharmacokinetic and safety profile, supporting its potential as a drug candidate for treating human helminth infections. To further advance its clinical development, we conducted a phase I bioavailability study using a field-applicable, immediate-release oxfendazole tablet. This trial investigated the pharmacokinetics, safety, and tolerability of the tablet formulation in healthy African adults residing in a filariasis-endemic country. Oxfendazole was administered as a single dose (100 or 400 mg) or as multiple doses (400 mg for 5 consecutive days) to 30 participants, randomized 8:2 to oxfendazole or placebo per cohort. Plasma concentrations of oxfendazole were measured using a validated high-performance liquid chromatography tandem mass spectrometry method, and pharmacokinetics were assessed using non-compartmental analysis. Peak plasma concentrations were reached after ~2.5-3 h. The median elimination half-life ranged from 11.6 to 13.9 h and was consistent across cohorts. Non-linear pharmacokinetics was observed, with exposure (AUC∞, Cmax) increasing less than dose-proportionally and showing high variability. Oxfendazole was well tolerated, with no adverse events reported and no clinically significant abnormalities in laboratory tests, vital signs, physical examinations, or electrocardiograms. These findings support the further development of oxfendazole in early proof-of-concept studies. Formulation optimization is suggested to reduce variability in exposure and improve the reliability of exposure-response assessments in future clinical trials.The study is registered with ClinicalTrials.gov as NCT04920292.

AIMS:Malaria remains a major global health burden, particularly in sub-Saharan Africa. Although quinine (QN) is an effective antimalarial, its clinical application is limited by dose-dependent toxicity from nonspecific biodistribution. This study developed heparin-functionalized PCL nanoparticles (Hep-QN-PCL) to target Plasmodium falciparum-infected RBCs and enhance QN's therapeutic efficacy. METHODS:QN-loaded PCL nanoparticles were formulated using a double emulsion solvent evaporation technique, followed by chitosan-mediated heparin conjugation. They were evaluated for physicochemical properties, in vitro drug release, hemolysis, cytotoxicity, targeting, and antiplasmodial activity against FCR3 Plasmodium falciparum. RESULTS:Optimized Hep-QN-PCL nanoparticles (353.2 ± 16.8 nm, PDI 0.252, zeta +20.8 ± 1.9 mV, encapsulation 77.9%) showed successful Hep conjugation as confirmed through FTIR and thermal analysis, sustained QN release over 96 h via Fickian diffusion, and enhanced release under iRBC-mimicking conditions. They were hemocompatible (<4% hemolysis), less cytotoxic (LD50 >527 µg/mL vs. 195.7 µg/mL for free QN), and demonstrated increased iRBC targeting (partition 8.50 ± 0.30 vs. 4.20 ± 0.12). Hep-QN-PCL achieved ~5.3-fold higher antiplasmodial potency (IC50 = 23.33 ng/mL vs. 122.86 ng/mL) and 14.2-fold greater selectivity index (22.60 vs. 1.59). CONCLUSION:These findings demonstrate a targeted nanomedicine platform with improved efficacy and safety for malaria therapy, suitable for further preclinical studies.

Human tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a global public health threat. Granulomas constitute a hallmark of TB pathogenesis that can clear, contain, or exacerbate an infection. Containment is exploited by Mtb as a hideout to persist in a dormant, antibiotic-tolerant state, only to resuscitate upon immunosuppression. The immune determinants of a granulomatous response driving Mtb persistence remain elusive. We here generated ex vivo granuloma-like structures from peripheral blood mononuclear cell specimens of TB patients and applied high-dimensional mass cytometry to elucidate immune factors prompting Mtb dormancy. Compared with healthy controls, patient-derived specimens rapidly forced Mtb to become dormant-like ex vivo. This observation correlated with an enrichment in activated, innate (-like) cytotoxic lymphocytes and required the presence of CD56+ lymphocytes or, more specifically, the content of their granules. Finally, we demonstrated that direct exposure to granulysin induces Mtb dormancy, thereby unravelling an immune escape mechanism to cytotoxic lymphocyte activity.

A critical impediment to efficient outbreak response is the availability of timely and complete data on cases and their linkage to care. To inform solutions to this issue, this study investigated the utility of self-testers reporting their coronavirus disease 2019 results using a mobile health platform. Our study has demonstrated that the mobile health platform is feasible; it achieved a 74.5% reporting rate, indicating a strong likelihood of data entry into the unstructured supplementary service data platform. Support from community health workers (CHWs) and healthcare professionals, particularly nurses, contributed to this success, especially among users with limited digital literacy. Specifically, 44.9% of self-test results were submitted by study participants themselves, 24.7% were submitted with the assistance of healthcare professionals, and 30.4% were submitted with the assistance of CHWs. The platform broadens the population base by increasing access and equity, allowing participation even among users without smartphones. Additionally, it integrates rapid antigen diagnostic tests with digital reporting, simplifying data processing and enabling standardized screening, real-time data capture, and effective patient follow-up. This technology also lays a foundation for pandemic preparedness in low- and middle-income countries by demonstrating the feasibility of fully integrating response loops for disease management and interventions. Future response loops could leverage artificial intelligence, machine learning, and integration with existing health surveillance systems, directly benefiting users through enhanced support.

The blood stage of malaria, where Plasmodium parasites invade red blood cells, accounts for most clinical symptoms and severe complications. However, current drugs and vaccines remain limited by drug resistance, toxicity, poor stability, and reduced overall efficacy. This review aimed to synthesize evidence on nanotechnology-based delivery systems for improving targeting specificity, enhancing drug and antigen stability, and optimizing therapeutic outcomes. Forty (40) studies from 2005 to 2025 were systematically analyzed, focusing on lipid, polymeric, inorganic, and protein-based nanoparticles targeting the blood stage. Results showed that functionalized nanocarriers with ligands targeting infected red blood cells significantly enhanced drug efficacy and reduced systemic toxicity. In vaccine development, nanoparticles used as antigen carriers elicited strong immune responses, achieving up to 83.3 % survival in in vivo preclinical models. Despite these promising outcomes, challenges such as scalable production, clinical translation, and regulatory approval persist. Overall, the findings highlight nanomedicine's transformative potential for malaria treatment and prevention.

The rapid diagnosis of coronavirus disease 2019 (COVID-19) is critical for comprehensive public health response strategies, and self-testing with antigen rapid diagnostic tests (Ag-RDTs) presents opportunities to test in hard-to-reach communities. Therefore, we evaluated the acceptability, feasibility, and uptake of Ag-RDT self-testing at the community level in Tanzania. From June to October 2022, symptomatic individuals or those with recent contact with a known or suspected COVID-19 patient were offered assisted testing and self-testing within mining communities and at transport hubs. This study included a cross-sectional survey before and after implementation. Participants were assessed for their acceptability and uptake of the nasal Ag-RDT self-test and their preference for nasal Ag-RDT self-testing. The survey data were collected in Open Data Kit, whereas the Ag-RDT results in the community were recorded by using the COVISUSPECT Mobile Application. Data analysis was performed by using STATA and R Statistical Software. A total of 538 individuals were screened, and 454 (84.4%) consented to be tested. The preference for self-testing was relatively low (33%), and the majority of participants (67%) opted to be assisted by a healthcare professional. Of the participants who opted for testing, 149 (32.8%) were able to self-test. Generally, there was no major difference in the various assessed parameters between the baseline and end-line surveys. The results from fitting multiple logistic regression indicated that after controlling for age, participants living in Dodoma were significantly less likely to opt for self-testing (odds ratio = 0.54; P-value = 0.023) compared with those living in Dar es Salaam. There was no significant difference in self-testing between participants living in Mara and those living in Dar es Salaam (odds ratio = 0.7; P-value = 0.179). After controlling for region, older (≥40 years) participants were significantly less likely to self-test compared with participants aged 18 to <40 years (odds ratio = 0.47; P-value = 0.002). The intervention was well-accepted in all areas in which Ag-RDTs were deployed. Our findings can therefore support the Ministry of Health by increasing accessibility to severe acute respiratory syndrome coronavirus 2 testing in the hard-to-reach communities in response to the next COVID-19 wave.

A pilot implementation of the rapid diagnostic test program was performed to collect evidence of the feasibility, acceptability, and uptake of the COVID-19 AgRDT in Tanzania. We conducted a prospective cross-sectional study in the community to provide quantitative details of the pilot implementation of the antigen rapid diagnostic test (AgRDT) in Tanzania. This study was undertaken between March 2022 and September 2022. The pilot was implemented by distributing and offering test kits to people suspected of having COVID-19 in Dar es Salaam through community health workers. A total of 1039 participants consented to participate in the survey. All the participants reported having heard about the disease. The radio was the main source (93.2%) of information on COVID-19. With regard to prevention measures, approximately 930 (89.5%) of the respondents thought that COVID-19 could be prevented. Approximately 1035 (99.6%) participants reported that they were willing to have a COVID-19 AgRDT test and wait for 20 min for the results. With regard to the participants’ opinions on the AgRDT device, the majority 907 (87.3%) felt comfortable with the test, and 1,029 (99.0%) were very likely to recommend the AgRDT test to their friends. The majority of participants 848 (83.1%) mentioned that they would be willing to pay for the test if it was not available for free. The results suggest overall good acceptance of the COVID-19 AgRDT test. It is evident that the use of trained community healthcare workers allows easy screening of all possible suspects and helps them receive early treatment.

BACKGROUND:PfSPZ Vaccine, a promising pre-erythrocytic stage malaria vaccine candidate based on whole, radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), has proven safe and effective in mediating sterile protection from malaria in malaria-naïve and exposed healthy adults. Vaccine-induced protection presumably depends on cellular responses to early parasite liver stages, but humoral immunity contributes. METHODS:On custom-made Pf protein microarrays, we profiled IgG and IgM responses to PfSPZ Vaccine and subsequent homologous controlled human malaria infection (CHMI) in 21 Tanzanian adults with (n = 12) or without (n = 9) HIV infection. Expression of the main identified immunogens in the pre-erythrocytic parasite stage was verified by immunofluorescence detection using freshly purified PfSPZ and an in vitro model of primary human hepatocytes. FINDINGS:Independent of HIV infection status, immunisation induced focused IgG and IgM responses to circumsporozoite surface protein (PfCSP) and merozoite surface protein 5 (PfMSP5). We show that PfMSP5 is detectable on the surface and in the apical complex of PfSPZ. INTERPRETATION:Our data demonstrate that HIV infection does not affect the quantity of the total IgG and IgM antibody responses to PfCSP and PfMSP5 after immunization with PfSPZ Vaccine. PfMSP5 represents a highly immunogenic, so far underexplored, target for vaccine-induced antibodies in malaria pre-exposed volunteers. FUNDING:This work was supported by the Equatorial Guinea Malaria Vaccine Initiative (EGMVI), the Clinical Trial Platform of the German Center for Infection Research (TTU 03.702), the Swiss Government Excellence Scholarships for Foreign Scholars and Artists (grant 2016.0056) and the Interdisciplinary Center for Clinical Research doctoral program of the Tübingen University Hospital. The funders had no role in design, analysis, or reporting of this study.

BACKGROUND. Sanaria 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. METHODS. This 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/mu L). Participants received 5 doses of PfSPZ Vaccine or normal saline (NS) over 28 days, followed by controlled human malaria infection (CHMI) 3 weeks later. RESULTS. There 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 V delta 2(+) gamma delta 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 Fc gamma 3B binding by anti-PfCSP and ADCD by anti-cell-traversal protein for ookinetes and SPZ (anti-PfCelTOS) antibodies. CONCLUSIONS. PfSPZ 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.

ABSTRACT. The radiation-attenuated Plasmodium falciparum sporozoites (PfSPZ) Vaccine has demonstrated safety and immunogenicity in 5-month-old to 50-year-old Africans in multiple trials. Except for one, each trial has restricted enrollment to either infants and children or adults < 50 years old. This trial was conducted in Equatorial Guinea and assessed the safety, tolerability, and immunogenicity of three direct venous inoculations of 1.8 × 10 6 or 2.7 × 10 6 PfSPZ, of PfSPZ Vaccine, or normal saline administered at 8-week intervals in a randomized, double-blind, placebo-controlled trial stratified by age (6–11 months and 1–5, 6–10, 11–17, 18–35, and 36–61 years). All doses were successfully administered. In all, 192/207 injections (93%) in those aged 6–61 years were rated as causing no or mild pain. There were no significant differences in solicited adverse events (AEs) between vaccinees and controls in any age group ( P ≥ 0.17). There were no significant differences between vaccinees and controls with respect to the rates or severity of unsolicited AEs or laboratory abnormalities. Development of antibodies to P. falciparum circumsporozoite protein occurred in 67/69 vaccinees (97%) and 0/15 controls. Median antibody levels were highest in infants and 1–5-year-olds and declined progressively with age. Antibody responses in children were greater than in adults protected against controlled human malaria infection. Robust immunogenicity, combined with a benign AE profile, indicates children are an ideal target for immunization with PfSPZ Vaccine.

Although studies on COVID-19 vaccine hesitancy are being undertaken widely worldwide, there is limited evidence in Tanzania. This study aims to assess the sociodemographic factors associated with COVID-19 vaccine hesitancy and the reasons given by unvaccinated study participants. We conducted a mixed-method cross-sectional study with two components-health facilities and communities-between March and September 2022. A structured questionnaire and in-depth interviews were used to collect quantitative and qualitative data, respectively. A total of 1,508 individuals agreed to participate in the survey and explained why they had not vaccinated against COVID-19. Of these participants, 62% indicated they would accept the vaccine, whereas 38% expressed skepticism. In a multivariate regression analysis, adult study participants 40 years and older were significantly more likely to report not intending to be vaccinated (adjusted odds ratio [AOR], 1.28; 95% CI, 1.01-1.61; P = 0.04) than youth and middle-aged study participants between 18 and 40 years. Furthermore, female study participants had a greater likelihood of not intending to be vaccinated (AOR, 1.51; 95% CI, 1.19-1.90; P = 0.001) than male study participants. The study identified fear of safety and short-term side effects, and lack of trust of the COVID-19 vaccine; belief in spiritual or religious views; and belief in local remedies and other precautions or preventive measures as the major contributors to COVID-19 vaccine hesitancy in Tanzania. Further empirical studies are needed to confirm these findings and to understand more fully the reasons for vaccine hesitancy in different demographic groups.

Background. A vaccine would be an ideal tool for reducing malaria's impact. PfSPZ Vaccine (radiation attenuated, aseptic, purified, cryopreserved Plasmodium falciparum [Pf] sporozoites [SPZ]) has been well tolerated and safe in >1526 malaria-naive and experienced 6-month to 65-year-olds in the United States, Europe, and Africa. When vaccine efficacy (VE) of 5 doses of 2.7 x 10(5) PfSPZ of PfSPZ Vaccine was assessed in adults against controlled human malaria infection (CHMI) in the United States and Tanzania and intense field transmission of heterogeneous Pf in Mali, Tanzanians had the lowest VE (20%). Methods. To increase VE in Tanzania, we increased PfSPZ/dose (9 x 10(5) or 1.8 x 10(6)) and decreased numbers of doses to 3 at 8-week intervals in a double blind, placebo-controlled trial. Results. All 22 CHMIs in controls resulted in parasitemia by quantitative polymerase chain reaction. For the 9 x 10(5) PfSPZ group, VE was 100% (5/5) at 3 or 11 weeks (P < .000l, Barnard test, 2-tailed). For 1.8 x 10(6) PfSPZ, VE was 33% (2/6) at 7.5 weeks (P = .028). VE of dosage groups (100% vs 33%) was significantly different (P = .022). Volunteers underwent repeat CHMI at 37-40 weeks after last dose. 6/6 and 5/6 volunteers developed parasitemia, but time to first parasitemia was significantly longer than controls in the 9 x 10(5) PfSPZ group (10.89 vs 7.80 days) (P = .039), indicating a significant reduction in parasites in the liver. Antibody and T-cell responses were higher in the 1.8 x 10(6) PfSPZ group. Conclusions. In Tanzania, increasing the dose from 2.7 x 10(5) to 9 x 10(5) PfSPZ increased VE from 20% to 100%, but increasing to 1.8 x 10(6) PfSPZ significantly reduced VE.

Children from low- and middle-income countries, where there is a high incidence of infectious disease, have the greatest need for the protection afforded by vaccination, but vaccines often show reduced efficacy in these populations. An improved understanding of how age, infection, nutrition, and genetics influence immune ontogeny and function is key to informing vaccine design for this at-risk population. We sought to identify factors that shape immune development in children under 5 years of age from Tanzania and Mozambique by detailed immunophenotyping of longitudinal blood samples collected during the RTS,S malaria vaccine phase 3 trial. In these cohorts, the composition of the immune system is dynamically transformed during the first years of life, and this was further influenced by geographical location, with some immune cell types showing an altered rate of development in Tanzanian children compared to Dutch children enrolled in the Generation R population-based cohort study. High-titer antibody responses to the RTS,S/AS01E vaccine were associated with an activated immune profile at the time of vaccination, including an increased frequency of antibody-secreting plasmablasts and follicular helper T cells. Anemic children had lower frequencies of recent thymic emigrant T cells, isotype-switched memory B cells, and plasmablasts; modulating iron bioavailability in vitro could recapitulate the B cell defects observed in anemic children. Our findings demonstrate that the composition of the immune system in children varies according to age, geographical location, and anemia status.

Abstract. Plasmodium falciparum sporozoite (PfSPZ) Vaccine (radiation-attenuated, aseptic, purified, cryopreserved PfSPZ) and PfSPZ-CVac (infectious, aseptic, purified, cryopreserved PfSPZ administered to subjects taking weekly chloroquine chemoprophylaxis) have shown vaccine efficacies (VEs) of 100% against homologous controlled human malaria infection (CHMI) in nonimmune adults. Plasmodium falciparum sporozoite-CVac has never been assessed against CHMI in African vaccinees. We assessed the safety, immunogenicity, and VE against homologous CHMI of three doses of 2.7 × 106 PfSPZ of PfSPZ Vaccine at 8-week intervals and three doses of 1.0 × 105 PfSPZ of PfSPZ-CVac at 4-week intervals with each arm randomized, double-blind, placebo-controlled, and conducted in parallel. There were no differences in solicited adverse events between vaccinees and normal saline controls, or between PfSPZ Vaccine and PfSPZ-CVac recipients during the 6 days after administration of investigational product. However, from days 7–13, PfSPZ-CVac recipients had significantly more AEs, probably because of Pf parasitemia. Antibody responses were 2.9 times higher in PfSPZ Vaccine recipients than PfSPZ-CVac recipients at time of CHMI. Vaccine efficacy at a median of 14 weeks after last PfSPZ-CVac dose was 55% (8 of 13, P = 0.051) and at a median of 15 weeks after last PfSPZ Vaccine dose was 27% (5 of 15, P = 0.32). The higher VE in PfSPZ-CVac recipients of 55% with a 27-fold lower dose was likely a result of later stage parasite maturation in the liver, leading to induction of cellular immunity against a greater quantity and broader array of antigens.

In 2016, there were more cases and deaths caused by malaria globally than in 2015. An effective vaccine would be an ideal additional tool for reducing malaria's impact. Sanaria® PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) has been well tolerated and safe in malaria-naïve and experienced adults in the United States and Mali and protective against controlled human malaria infection with Pf in the United States and field transmission of Pf in Mali, but had not been assessed in younger age groups. We, therefore, evaluated PfSPZ Vaccine in 93 Tanzanians aged 45 years to 6 months in a randomized, double-blind, normal saline placebo-controlled trial. There were no significant differences in adverse events between vaccinees and controls or between dosage regimens. Because all age groups received three doses of 9.0 × 105 PfSPZ of PfSPZ Vaccine, immune responses were compared at this dosage. Median antibody responses against Pf circumsporozoite protein and PfSPZ were highest in infants and lowest in adults. T-cell responses were highest in 6-10-year olds after one dose and 1-5-year olds after three doses; infants had no significant positive T-cell responses. The safety data were used to support initiation of trials in > 300 infants in Kenya and Equatorial Guinea. Because PfSPZ Vaccine-induced protection is thought to be mediated by T cells, the T-cell data suggest PfSPZ Vaccine may be more protective in children than in adults, whereas infants may not be immunologically mature enough to respond to the PfSPZ Vaccine immunization regimen assessed.