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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 -
MedRxiv : the Preprint Server For... Apr 2024Measuring malaria transmission intensity using the traditional entomological inoculation rate is difficult. Antibody responses to mosquito salivary proteins such as SG6...
BACKGROUND
Measuring malaria transmission intensity using the traditional entomological inoculation rate is difficult. Antibody responses to mosquito salivary proteins such as SG6 have previously been used as biomarkers of exposure to mosquito bites. Here, we investigate four mosquito salivary proteins as potential biomarkers of human exposure to mosquitoes infected with : mosGILT, SAMSP1, AgSAP, and AgTRIO.
METHODS
We tested population-level human immune responses in longitudinal and cross-sectional plasma samples from individuals with known infection from low and moderate transmission areas in Senegal using a multiplexed magnetic bead-based assay.
RESULTS
AgSAP and AgTRIO were the best indicators of recent exposure to infected mosquitoes. Antibody responses to AgSAP, in a moderate endemic area, and to AgTRIO in both low and moderate endemic areas, were significantly higher than responses in a healthy non-endemic control cohort (p-values = 0.0245, 0.0064, and <0.0001 respectively). No antibody responses significantly differed between the low and moderate transmission area, or between equivalent groups during and outside the malaria transmission seasons. For AgSAP and AgTRIO, reactivity peaked 2-4 weeks after clinical infection and declined 3 months after infection.
DISCUSSION
Reactivity to both AgSAP and AgTRIO peaked after infection and did not differ seasonally nor between areas of low and moderate transmission, suggesting reactivity is likely reflective of exposure to infectious mosquitos or recent biting rather than general mosquito exposure. Kinetics suggest reactivity is relatively short-lived. AgSAP and AgTRIO are promising candidates to incorporate into multiplexed assays for serosurveillance of population-level changes in -infected mosquito exposure.
PubMed: 38712295
DOI: 10.1101/2024.04.20.24305430 -
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: Humans; Disease Eradication; Global Health; Malaria; Malaria Vaccines; Pharmaceutical Research; mRNA Vaccines; Africa
PubMed: 38711053
DOI: 10.1186/s12936-024-04972-5 -
Vaccine Jun 2024Recent data indicate increasing disease burden and importance of Plasmodium vivax (Pv) malaria. A robust assay will be essential for blood-stage Pv vaccine development....
Recent data indicate increasing disease burden and importance of Plasmodium vivax (Pv) malaria. A robust assay will be essential for blood-stage Pv vaccine development. Results of the in vitro growth inhibition assay (GIA) with transgenic P. knowlesi (Pk) parasites expressing the Pv Duffy-binding protein region II (PvDBPII) correlate with in vivo protection in the first PvDBPII controlled human malaria infection (CHMI) trials, making the PkGIA an ideal selection tool once the precision of the assay is defined. To determine the precision in percentage of inhibition in GIA (%GIA) and in GIA (antibody concentration that gave 50 %GIA), ten GIAs with transgenic Pk parasites were conducted with four different anti-PvDBPII human monoclonal antibodies (mAbs) at concentrations of 0.016 to 2 mg/mL, and three GIAs with eighty anti-PvDBPII human polyclonal antibodies (pAbs) at 10 mg/mL. A significant assay-to-assay variation was observed, and the analysis revealed a standard deviation (SD) of 13.1 in the mAb and 5.94 in the pAb dataset for %GIA, with a LogGIA SD of 0.299 (for mAbs). Moreover, the ninety-five percent confidence interval (95 %CI) for %GIA or GIA in repeat assays was calculated in this investigation. The error range determined in this study will help researchers to compare PkGIA results from different assays and studies appropriately, thus supporting the development of future blood-stage malaria vaccine candidates, specifically second-generation PvDBPII-based formulations.
Topics: Malaria Vaccines; Plasmodium knowlesi; Protozoan Proteins; Plasmodium vivax; Antigens, Protozoan; Humans; Receptors, Cell Surface; Antibodies, Protozoan; Malaria, Vivax; Antibodies, Monoclonal; Vaccine Development; Animals
PubMed: 38704253
DOI: 10.1016/j.vaccine.2024.04.073 -
Vaccine May 2024The Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) is the World Health Organization's key standing advisory body to conduct an...
Report from the World Health Organization's immunization and vaccines-related implementation research advisory committee (IVIR-AC) meeting, virtual gathering, 26 February-1 March 2024.
The Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) is the World Health Organization's key standing advisory body to conduct an independent review of research, particularly of transmission and economic modeling analyses that estimate the impact and value of vaccines. From 26th February-1st March 2024, at its first of two semi-annual meetings, IVIR-AC provided feedback and recommendations across four sessions; this report summarizes the proceedings and recommendations from that meeting. Session topics included modeling of the impact and cost-effectiveness of the R21/Matrix-M malaria vaccine, meta-analysis of economic evaluations of vaccines, a global analysis estimating the impact of vaccination over the last 50 years, and modeling the impact of different RTS,S malaria vaccine dose schedules in seasonal settings.
Topics: Humans; World Health Organization; Advisory Committees; Malaria Vaccines; Cost-Benefit Analysis; Vaccination; Malaria; Immunization
PubMed: 38704250
DOI: 10.1016/j.vaccine.2024.04.057 -
Malaria Journal May 2024Malaria is a potentially life-threatening disease caused by Plasmodium protozoa transmitted by infected Anopheles mosquitoes. Controlled human malaria infection (CHMI)...
BACKGROUND
Malaria is a potentially life-threatening disease caused by Plasmodium protozoa transmitted by infected Anopheles mosquitoes. Controlled human malaria infection (CHMI) trials are used to assess the efficacy of interventions for malaria elimination. The operating characteristics of statistical methods for assessing the ability of interventions to protect individuals from malaria is uncertain in small CHMI studies. This paper presents simulation studies comparing the performance of a variety of statistical methods for assessing efficacy of intervention in CHMI trials.
METHODS
Two types of CHMI designs were investigated: the commonly used single high-dose design (SHD) and the repeated low-dose design (RLD), motivated by simian immunodeficiency virus (SIV) challenge studies. In the context of SHD, the primary efficacy endpoint is typically time to infection. Using a continuous time survival model, five statistical tests for assessing the extent to which an intervention confers partial or full protection under single dose CHMI designs were evaluated. For RLD, the primary efficacy endpoint is typically the binary infection status after a specific number of challenges. A discrete time survival model was used to study the characteristics of RLD versus SHD challenge studies.
RESULTS
In a SHD study with the continuous time survival model, log-rank test and t-test are the most powerful and provide more interpretable results than Wilcoxon rank-sum tests and Lachenbruch tests, while the likelihood ratio test is uniformly most powerful but requires knowledge of the underlying probability model. In the discrete time survival model setting, SHDs are more powerful for assessing the efficacy of an intervention to prevent infection than RLDs. However, additional information can be inferred from RLD challenge designs, particularly using a likelihood ratio test.
CONCLUSIONS
Different statistical methods can be used to analyze controlled human malaria infection (CHMI) experiments, and the choice of method depends on the specific characteristics of the experiment, such as the sample size allocation between the control and intervention groups, and the nature of the intervention. The simulation results provide guidance for the trade off in statistical power when choosing between different statistical methods and study designs.
Topics: Humans; Malaria; Animals; Research Design; Controlled Clinical Trials as Topic; Models, Statistical; Anopheles
PubMed: 38702775
DOI: 10.1186/s12936-024-04959-2 -
Annals of Medicine and Surgery (2012) May 2024Malaria remains a significant global health challenge, demanding a deeper understanding of host immune responses for effective clearance of the parasitic infection.... (Review)
Review
Malaria remains a significant global health challenge, demanding a deeper understanding of host immune responses for effective clearance of the parasitic infection. Cytokines, as crucial mediators of the immune system, orchestrate a complex interplay during the various stages of malaria infection. Throughout the course of the disease, an intricate balance of pro-inflammatory and anti-inflammatory cytokines dictate the immune response's outcome, influencing parasitic clearance and disease severity. During the initial stages, interleukins such as interleukin-12 (IL-12), interferon-gamma (IFN-γ), and tumour necrosis factor-alpha (TNF-α) play pivotal roles in activating innate immune cells, initiating the anti-parasitic response. Simultaneously, regulatory cytokines like interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) modulate this immune activation, preventing excessive inflammation and tissue damage. As the infection progresses, a delicate shift occurs, characterized by a transition to adaptive immunity, guided by cytokines like interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), promoting antibody production and T-cell responses. Notably, the resolution of malaria infection crucially relies on a fine-tuned balance of cytokine networks. Dysregulation or imbalances in these mediators often result in immune hyperactivation, contributing to severe manifestations and prolonged infection. Understanding the multi-faceted roles of cytokines in malaria clearance offers promising avenues for therapeutic interventions. Targeting cytokine pathways to restore immune equilibrium or bolster protective responses could potentially enhance treatment strategies and vaccine development. In conclusion, the pivotal role of cytokines in immunomodulation during malaria clearance underscores their significance as potential targets for therapeutic interventions, offering promising prospects in the global fight against this infectious disease.
PubMed: 38694310
DOI: 10.1097/MS9.0000000000002019 -
BMC Immunology Apr 2024Bacillus Calmette-Guérin (BCG) vaccination has off-target protective effects against infections unrelated to tuberculosis. Among these, murine and human studies suggest... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Bacillus Calmette-Guérin (BCG) vaccination has off-target protective effects against infections unrelated to tuberculosis. Among these, murine and human studies suggest that BCG vaccination may protect against malaria. We investigated whether BCG vaccination influences neonatal in vitro cytokine responses to Plasmodium falciparum. Blood samples were collected from 108 participants in the Melbourne Infant Study BCG for Allergy and Infection Reduction (MIS BAIR) randomised controlled trial (Clinical trials registration NCT01906853, registered July 2013), seven days after randomisation to neonatal BCG (n = 66) or no BCG vaccination (BCG-naïve, n = 42). In vitro cytokine responses were measured following stimulation with P. falciparum-infected erythrocytes (PfIE) or E. coli.
RESULTS
No difference in the measured cytokines were observed between BCG-vaccinated and BCG-naïve neonates following stimulation with PfIE or E. coli. However, age at which blood was sampled was independently associated with altered cytokine responses to PfIE. Being male was also independently associated with increased TNF-a responses to both PfIE and E. coli.
CONCLUSION
These findings do not support a role for BCG vaccination in influencing in vitro neonatal cytokine responses to P. falciparum. Older neonates are more likely to develop P. falciparum-induced IFN-γ and IFN-γ-inducible chemokine responses implicated in early protection against malaria and malaria pathogenesis.
Topics: Humans; Plasmodium falciparum; BCG Vaccine; Infant, Newborn; Female; Malaria, Falciparum; Cytokines; Male; Vaccination; Erythrocytes; Escherichia coli; Infant
PubMed: 38689233
DOI: 10.1186/s12865-024-00611-5 -
BMJ Global Health Apr 2024In October 2021, the WHO recommended the world's first malaria vaccine-RTS,S/AS01-to prevent malaria in children living in areas with moderate-to-high transmission in... (Review)
Review
In October 2021, the WHO recommended the world's first malaria vaccine-RTS,S/AS01-to prevent malaria in children living in areas with moderate-to-high transmission in sub-Saharan Africa (SSA). A second malaria vaccine, R21/Matrix-M, was recommended for use in October 2023 and added to the WHO list of prequalified vaccines in December 2023. This study analysis assessed the country status of implementation and delivery strategies for RTS,S/AS01 by searching websites for national malaria policies, guidelines and related documents. Direct contact with individuals working in malaria programmes was made to obtain documents not publicly available. 10 countries had documents with information relating to malaria vaccine implementation, 7 referencing RTS,S/AS01 and 3 (Burkina Faso, Kenya and Nigeria) referencing RTS,S/AS01 and R21/Matrix-M. Five other countries reported plans for malaria vaccine roll-out without specifying which vaccine. Ghana, Kenya and Malawi, which piloted RTS,S/AS01, have now integrated the vaccine into routine immunisation services. Cameroon and Burkina Faso are the first countries outside the pilot countries to incorporate the vaccine into national immunisation services. Uganda plans a phased RTS,S/AS01 introduction, while Guinea plans to first pilot RTS,S/AS01 in five districts. The RTS,S/AS01 schedule varied by country, with the first dose administered at 5 or 6 months in all countries but the fourth dose at either 18, 22 or 24 months. SSA countries have shown widespread interest in rolling out the malaria vaccine, the Global Alliance for Vaccines and Immunization having approved financial support for 20 of 30 countries which applied as of March 2024. Limited availability of RTS,S/AS01 means that some approved countries will not receive the required doses. Vaccine availability and equity must be addressed even as R21/Matrix-M becomes available.
Topics: Humans; Malaria Vaccines; Africa South of the Sahara; World Health Organization; Malaria; Immunization Programs; Health Policy
PubMed: 38688566
DOI: 10.1136/bmjgh-2023-014719 -
JCI Insight Apr 2024A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical... (Randomized Controlled Trial)
Randomized Controlled Trial
A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.
Topics: Malaria Vaccines; Immunity, Innate; Humans; Animals; Malaria, Falciparum; Plasmodium falciparum; Mice; Vaccines, Attenuated; Sporozoites; CD8-Positive T-Lymphocytes; Infant; Protozoan Proteins; Antibodies, Protozoan; Female; Parasitemia; Immunoglobulin G; Vaccine Efficacy
PubMed: 38687615
DOI: 10.1172/jci.insight.167408