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Malaria Journal Apr 2024There are giant steps taken in the introduction of the novel malaria vaccine poised towards reducing mortality and morbidity associated with malaria.
BACKGROUND
There are giant steps taken in the introduction of the novel malaria vaccine poised towards reducing mortality and morbidity associated with malaria.
OBJECTIVES
This study aimed to determine the knowledge of malaria vaccine and factors militating against willingness to accept the vaccine among mothers presenting in nine hospitals in Enugu metropolis.
METHODS
This was a cross-sectional study carried out among 491 mothers who presented with their children in nine hospitals in Enugu metropolis, South-East Nigeria. A pre-tested and interviewer-administered questionnaire was used in this study.
RESULTS
A majority of the respondents, 72.1% were aware of malaria vaccine. A majority of the respondents, 83.1% were willing to receive malaria vaccine. Similarly, a majority of the mothers, 92.9%, were willing to vaccinate baby with the malaria vaccine, while 81.1% were willing to vaccinate self and baby with the malaria vaccine. The subjects who belong to the low socio-economic class were five times less likely to vaccinate self and baby with malaria vaccine when compared with those who were in the high socio-economic class (AOR = 0.2, 95% CI 0.1-0.5). Mothers who had good knowledge of malaria vaccination were 3.3 times more likely to vaccinate self and baby with malaria vaccine when compared with those who had poor knowledge of malaria vaccination (AOR = 3.3, 95% CI 1-6-6.8).
CONCLUSION
Although the study documented a high vaccine acceptance among the mothers, there exists a poor knowledge of the malaria vaccine among them.
Topics: Humans; Nigeria; Cross-Sectional Studies; Female; Adult; Young Adult; Malaria Vaccines; Health Knowledge, Attitudes, Practice; Patient Acceptance of Health Care; Adolescent; Malaria; Mothers; Middle Aged; Surveys and Questionnaires; Ambulatory Care Facilities; Infant
PubMed: 38664783
DOI: 10.1186/s12936-024-04914-1 -
BioRxiv : the Preprint Server For... Apr 202448/45, a gametocyte surface protein, is a promising candidate for malaria transmission-blocking (TB) vaccine. Due to its relevance for a multispecies vaccine, we...
BACKGROUND
48/45, a gametocyte surface protein, is a promising candidate for malaria transmission-blocking (TB) vaccine. Due to its relevance for a multispecies vaccine, we explored the cross-reactivity and TB activity of a recombinant 48/45 protein (r48/45) with sera from -exposed African donors.
METHODS
r48/45 was produced in Chinese hamster ovary cell lines and tested by ELISA for its cross-reactivity with sera from Burkina Faso, Tanzania, Mali, and Nigeria - In addition, BALB/c mice were immunized with the r48/45 protein formulated in Montanide ISA-51 and inoculated with a crude extract of NF-54 gametocytes to evaluate the parasite-boosting effect on r48/45 antibody titers. Specific anti-48/45 IgG purified from African sera was used to evaluate the TB activity on using standard mosquito membrane feeding assays (SMFA).
RESULTS
r48/45 protein showed cross-reactivity with sera of individuals from all four African countries, in proportions ranging from 94% (Tanzania) to 40% (Nigeria). Also, the level of cross-reactive antibodies varied significantly between countries (p<0.0001), with a higher antibody level in Mali and the lowest in Nigeria. In addition, antibody levels were higher in adults (≥ 17 years) than young children (≤ 5 years) in both Mali and Tanzania, with a higher proportion of responders in adults (90%) than in children (61%) (p<0.0001) in Mali, where male (75%) and female (80%) displayed similar antibody responses. Furthermore, immunization of mice with gametocytes boosted anti-48/45 antibody responses, recognizing gametocytes in indirect immunofluorescence antibody test. Notably, r48/45 affinity-purified African IgG exhibited a TB activity of 61% against in SMFA.
CONCLUSION
African sera (exposed only to cross-recognized the r48/45 protein. This, together with the functional activity of IgG, warrants further studies for the potential development of a and cross-protective TB vaccine.
PubMed: 38659832
DOI: 10.1101/2024.04.10.588966 -
BioRxiv : the Preprint Server For... Apr 2024Circulating T-follicular helper (cT ) cells have the potential to provide an additional correlate of protection against ( as they are essential to promote B cell...
BACKGROUND
Circulating T-follicular helper (cT ) cells have the potential to provide an additional correlate of protection against ( as they are essential to promote B cell production of long-lasting antibodies. Assessing the specificity of cT subsets to individual malaria antigens is vital to understanding the variation observed in antibody responses and identifying promising malaria vaccine candidates.
METHODS
Using spectral flow cytometry and unbiased clustering analysis we assessed antigen-specific cT cell recall responses to malaria vaccine candidates SEA-1A and GARP within a cross-section of children and adults living in a malaria holoendemic region of western Kenya.
FINDINGS
In children, a broad array of cT subsets (defined by cytokine and transcription factor expression) were reactive to both malaria antigens, SEA-1A and GARP, while adults had a narrow profile centering on cT 17- and cT 1/17-like subsets following stimulation with GARP only.
INTERPRETATION
Because T 17 cells are involved in the maintenance of memory antibody responses within the context of parasitic infections, our results suggest that GARP might generate longer lived antibody responses compared to SEA-1A. These findings have intriguing implications for evaluating malaria vaccine candidates as they highlight the importance of including cT profiles when assessing interdependent correlates of protective immunity.
PubMed: 38659768
DOI: 10.1101/2024.04.13.589352 -
Journal of Epidemiology and Global... Apr 2024The African continent carries the greatest malaria burden in the world. Falciparum malaria especially has long been the leading cause of death in Africa. Climate,... (Review)
Review
The African continent carries the greatest malaria burden in the world. Falciparum malaria especially has long been the leading cause of death in Africa. Climate, economic factors, geographical location, human intervention and unstable security are factors influencing malaria transmission. Due to repeated infections and early interventions, the proportion of clinically atypical malaria or asymptomatic plasmodium carriers has increased significantly, which easily lead to misdiagnosis and missed diagnosis. African countries have made certain progress in malaria control and elimination, including rapid diagnosis of malaria, promotion of mosquito nets and insecticides, intermittent prophylactic treatment in high-risk groups, artemisinin based combination therapies, and the development of vaccines. Between 2000 and 2022, there has been a 40% decrease in malaria incidence and a 60% reduction in mortality rate in the WHO African Region. However, many challenges are emerging in the fight against malaria in Africa, such as climate change, poverty, substandard health services and coverage, increased outdoor transmission and the emergence of new vectors, and the growing threat of resistance to antimalarial drugs and insecticides. Joint prevention and treatment, identifying molecular determinants of resistance, new drug development, expanding seasonal malaria chemo-prevention intervention population, and promoting the vaccination of RTS, S/AS01 and R21/Matrix-M may help to solve the dilemma. China's experience in eliminating malaria is conducive to Africa's malaria prevention and control, and China-Africa cooperation needs to be constantly deepened and advanced. Our review aims to help the global public develop a comprehensive understanding of malaria in Africa, thereby contributing to malaria control and elimination.
PubMed: 38656731
DOI: 10.1007/s44197-024-00228-2 -
The Journal of Clinical Investigation Apr 2024BACKGROUNDFeatures of consumptive coagulopathy and thromboinflammation are prominent in cerebral malaria (CM). We hypothesized that thrombogenic autoantibodies... (Clinical Trial)
Clinical Trial
BACKGROUNDFeatures of consumptive coagulopathy and thromboinflammation are prominent in cerebral malaria (CM). We hypothesized that thrombogenic autoantibodies contribute to a procoagulant state in CM.METHODSPlasma from children with uncomplicated malaria (UM) (n = 124) and CM (n = 136) was analyzed by ELISA for a panel of 8 autoantibodies including anti-platelet factor 4/polyanion (anti-PF4/P), anti-phospholipid, anti-phosphatidylserine, anti-myeloperoxidase, anti-proteinase 3, anti-dsDNA, anti-β-2-glycoprotein I, and anti-cardiolipin. Plasma samples from individuals with nonmalarial coma (NMC) (n = 49) and healthy controls (HCs) (n = 56) were assayed for comparison. Associations with clinical and immune biomarkers were determined using univariate and logistic regression analyses.RESULTSMedian anti-PF4/P and anti-PS IgG levels were elevated in individuals with malaria infection relative to levels in HCs (P < 0.001) and patients with NMC (PF4/P: P < 0.001). Anti-PF4/P IgG levels were elevated in children with CM (median = 0.27, IQR: 0.19-0.41) compared with those with UM (median = 0.19, IQR: 0.14-0.22, P < 0.0001). Anti-PS IgG levels did not differ between patients with UM and those with CM (P = 0.39). When patients with CM were stratified by malaria retinopathy (Ret) status, the levels of anti-PF4/P IgG correlated negatively with the peripheral platelet count in patients with Ret+ CM (Spearman's rho [Rs] = 0.201, P = 0.04) and associated positively with mortality (OR = 15.2, 95% CI: 1.02-275, P = 0.048). Plasma from patients with CM induced greater platelet activation in an ex vivo assay relative to plasma from patients with UM (P = 0.02), and the observed platelet activation was associated with anti-PF4/P IgG levels (Rs= 0.293, P = 0.035).CONCLUSIONSThrombosis mediated by elevated anti-PF4/P autoantibodies may be one mechanism contributing to the clinical complications of CM.
Topics: Humans; Malaria, Cerebral; Autoantibodies; Female; Male; Platelet Factor 4; Child; Child, Preschool; Infant; Polyelectrolytes; Thrombosis
PubMed: 38652559
DOI: 10.1172/JCI176466 -
Frontiers in Immunology 2024Malaria remains a global health challenge, necessitating the development of effective vaccines. The RTS,S vaccination prevents (Pf) malaria but is ineffective against...
Malaria remains a global health challenge, necessitating the development of effective vaccines. The RTS,S vaccination prevents (Pf) malaria but is ineffective against (Pv) disease. Herein, we evaluated the murine immunogenicity of a recombinant PvCSP incorporating prevalent polymorphisms, adjuvanted with Alhydrogel or Poly I:C. Both formulations induced prolonged IgG responses, with IgG1 dominance by the Alhydrogel group and high titers of all IgG isotypes by the Poly I:C counterpart. Poly I:C-adjuvanted vaccination increased splenic plasma cells, terminally-differentiated memory cells (MBCs), and precursors relative to the Alhydrogel-combined immunization. Splenic B-cells from Poly I:C-vaccinated mice revealed an antibody-secreting cell- and MBC-differentiating gene expression profile. Biological processes such as antibody folding and secretion were highlighted by the Poly I:C-adjuvanted vaccination. These findings underscore the potential of Poly I:C to strengthen immune responses against Pv malaria.
Topics: Poly I-C; Plasmodium vivax; Immunity, Humoral; Immunity, Cellular; Protozoan Proteins; Malaria Vaccines; Aluminum Hydroxide; Immunoglobulin G; Male; Animals; Plasma Cells; Female; Mice, Inbred C57BL; Recombinant Proteins; Vaccination; Adjuvants, Vaccine; Immunogenicity, Vaccine; Malaria, Vivax
PubMed: 38650939
DOI: 10.3389/fimmu.2024.1331474 -
BMC Medicine Apr 2024The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines. Transmission-blocking vaccines aim to induce human antibodies that block parasite development in the mosquito and mosquitoes becoming infectious. The Pfs48/45 protein is a leading Plasmodium falciparum transmission-blocking vaccine candidate. The R0.6C fusion protein, consisting of Pfs48/45 domain 3 (6C) and the N-terminal region of P. falciparum glutamate-rich protein (R0), has previously been produced in Lactococcus lactis and elicited functional antibodies in rodents. Here, we assess the safety and transmission-reducing efficacy of R0.6C adsorbed to aluminium hydroxide with and without Matrix-M™ adjuvant in humans.
METHODS
In this first-in-human, open-label clinical trial, malaria-naïve adults, aged 18-55 years, were recruited at the Radboudumc in Nijmegen, the Netherlands. Participants received four intramuscular vaccinations on days 0, 28, 56 and 168 with either 30 µg or 100 µg of R0.6C and were randomised for the allocation of one of the two different adjuvant combinations: aluminium hydroxide alone, or aluminium hydroxide combined with Matrix-M1™ adjuvant. Adverse events were recorded from inclusion until 84 days after the fourth vaccination. Anti-R0.6C and anti-6C IgG titres were measured by enzyme-linked immunosorbent assay. Transmission-reducing activity of participants' serum and purified vaccine-specific immunoglobulin G was assessed by standard membrane feeding assays using laboratory-reared Anopheles stephensi mosquitoes and cultured P. falciparum gametocytes.
RESULTS
Thirty-one participants completed four vaccinations and were included in the analysis. Administration of all doses was safe and well-tolerated, with one related grade 3 adverse event (transient fever) and no serious adverse events occurring. Anti-R0.6C and anti-6C IgG titres were similar between the 30 and 100 µg R0.6C arms, but higher in Matrix-M1™ arms. Neat participant sera did not induce significant transmission-reducing activity in mosquito feeding experiments, but concentrated vaccine-specific IgGs purified from sera collected two weeks after the fourth vaccination achieved up to 99% transmission-reducing activity.
CONCLUSIONS
R0.6C/aluminium hydroxide with or without Matrix-M1™ is safe, immunogenic and induces functional Pfs48/45-specific transmission-blocking antibodies, albeit at insufficient serum concentrations to result in transmission reduction by neat serum. Future work should focus on identifying alternative vaccine formulations or regimens that enhance functional antibody responses.
TRIAL REGISTRATION
The trial is registered with ClinicalTrials.gov under identifier NCT04862416.
Topics: Adolescent; Adult; Animals; Female; Humans; Male; Middle Aged; Young Adult; Adjuvants, Immunologic; Aluminum Hydroxide; Antibodies, Protozoan; Malaria Vaccines; Malaria, Falciparum; Membrane Glycoproteins; Netherlands; Plasmodium falciparum; Protozoan Proteins
PubMed: 38649867
DOI: 10.1186/s12916-024-03379-y -
Therapeutic Advances in Infectious... 2024Malaria is a leading cause of death among children under 5 years of age in sub-Saharan Africa. The malaria vaccine is an important preventive measure introduced by the...
BACKGROUND
Malaria is a leading cause of death among children under 5 years of age in sub-Saharan Africa. The malaria vaccine is an important preventive measure introduced by the World Health Organization to reduce malaria and its associated mortality and morbidity. We aimed to assess the acceptance of the malaria vaccine among next of kin of children under 5 years of age in Gulu City, Northern Uganda.
METHODS
Between October and December 2023, we conducted a cross-sectional study in Pece-Laroo division, Gulu City, Uganda. Socio-demographic, vaccine profile and health system factors were collected. Multivariable logistic regression was performed using STATA 16 to determine factors associated with acceptance of the malaria vaccine among next of kin of children under 5 years.
RESULTS
A total of 432 participants were enrolled. Of these, the majority were female (72.5%, = 313) with most aged 30 years and above (51.2%, = 221). Overall, 430 (99.5%) participants had good knowledge about malaria. The majority (91.4%, = 395) had good acceptance of the malaria vaccine. Factors independently associated with acceptance of the malaria vaccine were knowing a child who died of malaria [adjusted prevalence ratio (aPR): 1.07, 95% confidence interval (CI): 1.01-1.13, = 0.022] and preferring the injection route for a malaria vaccine (aPR: 1.1, 95% CI: 1.06-1.22, < 0.001). All 395 participants with good knowledge of malaria had good acceptance of the malaria vaccine ( = 0.007).
CONCLUSION
There was a high acceptance of the malaria vaccine in Laroo-Pece division, Gulu, Uganda. However, there is a need for further health education to achieve universal acceptability of the malaria vaccine in preparation for the malaria vaccine implementation program in Uganda.
PubMed: 38645298
DOI: 10.1177/20499361241247467 -
Malaria Journal Apr 2024Sporozoites (SPZ), the infective form of Plasmodium falciparum malaria, can be inoculated into the human host skin by Anopheline mosquitoes. These SPZ migrate at...
BACKGROUND
Sporozoites (SPZ), the infective form of Plasmodium falciparum malaria, can be inoculated into the human host skin by Anopheline mosquitoes. These SPZ migrate at approximately 1 µm/s to find a blood vessel and travel to the liver where they infect hepatocytes and multiply. In the skin they are still low in number (50-100 SPZ) and vulnerable to immune attack by antibodies and skin macrophages. This is why whole SPZ and SPZ proteins are used as the basis for most malaria vaccines currently deployed and undergoing late clinical testing. Mosquitoes typically inoculate SPZ into a human host between 14 and 25 days after their previous infective blood meal. However, it is unknown whether residing time within the mosquito affects SPZ condition, infectivity or immunogenicity. This study aimed to unravel how the age of P. falciparum SPZ in salivary glands (14, 17, or 20 days post blood meal) affects their infectivity and the ensuing immune responses.
METHODS
SPZ numbers, viability by live/dead staining, motility using dedicated sporozoite motility orienting and organizing tool software (SMOOT), and infectivity of HC-04.j7 liver cells at 14, 17 and 20 days after mosquito feeding have been investigated. In vitro co-culture assays with SPZ stimulated monocyte-derived macrophages (MoMɸ) and CD8 T-cells, analysed by flow cytometry, were used to investigate immune responses.
RESULTS
SPZ age did not result in different SPZ numbers or viability. However, a markedly different motility pattern, whereby motility decreased from 89% at day 14 to 80% at day 17 and 71% at day 20 was observed (p ≤ 0.0001). Similarly, infectivity of day 20 SPZ dropped to ~ 50% compared with day 14 SPZ (p = 0.004). MoMɸ were better able to take up day 14 SPZ than day 20 SPZ (from 7.6% to 4.1%, p = 0.03) and displayed an increased expression of pro-inflammatory CD80, IL-6 (p = 0.005), regulatory markers PDL1 (p = 0.02), IL-10 (p = 0.009) and cytokines upon phagocytosis of younger SPZ. Interestingly, co-culture of these cells with CD8 T-cells revealed a decreased expression of activation marker CD137 and cytokine IFNγ compared to their day 20 counterparts. These findings suggest that older (day 17-20) P. falciparum SPZ are less infectious and have decreased immune regulatory potential.
CONCLUSION
Overall, this data is a first step in enhancing the understanding of how mosquito residing time affects P. falciparum SPZ and could impact the understanding of the P. falciparum infectious reservoir and the potency of whole SPZ vaccines.
Topics: Animals; Humans; Sporozoites; CD8-Positive T-Lymphocytes; Malaria, Falciparum; Malaria Vaccines; Culicidae; Aging; Plasmodium falciparum
PubMed: 38641838
DOI: 10.1186/s12936-024-04946-7 -
The Lancet. Infectious Diseases Apr 2024Despite a global epidemiological transition towards increased burden of non-communicable diseases, communicable diseases continue to cause substantial morbidity and...
BACKGROUND
Despite a global epidemiological transition towards increased burden of non-communicable diseases, communicable diseases continue to cause substantial morbidity and mortality worldwide. Understanding the burden of a wide range of infectious diseases, and its variation by geography and age, is pivotal to research priority setting and resource mobilisation globally.
METHODS
We estimated disability-adjusted life-years (DALYs) associated with 85 pathogens in 2019, globally, regionally, and for 204 countries and territories. The term pathogen included causative agents, pathogen groups, infectious conditions, and aggregate categories. We applied a novel methodological approach to account for underlying, immediate, and intermediate causes of death, which counted every death for which a pathogen had a role in the pathway to death. We refer to this measure as the burden associated with infection, which was estimated by combining different sources of information. To compare the burden among all pathogens, we used pathogen-specific ratios to incorporate the burden of immediate and intermediate causes of death for pathogens modelled previously by the GBD. We created the ratios by using multiple cause of death data, hospital discharge data, linkage data, and minimally invasive tissue sampling data to estimate the fraction of deaths coming from the pathway to death chain. We multiplied the pathogen-specific ratios by age-specific years of life lost (YLLs), calculated with GBD 2019 methods, and then added the adjusted YLLs to age-specific years lived with disability (YLDs) from GBD 2019 to produce adjusted DALYs to account for deaths in the chain. We used standard GBD methods to calculate 95% uncertainty intervals (UIs) for final estimates of DALYs by taking the 2·5th and 97·5th percentiles across 1000 posterior draws for each quantity of interest. We provided burden estimates pertaining to all ages and specifically to the under 5 years age group.
FINDINGS
Globally in 2019, an estimated 704 million (95% UI 610-820) DALYs were associated with 85 different pathogens, including 309 million (250-377; 43·9% of the burden) in children younger than 5 years. This burden accounted for 27·7% (and 65·5% in those younger than 5 years) of the previously reported total DALYs from all causes in 2019. Comparing super-regions, considerable differences were observed in the estimated pathogen-associated burdens in relation to DALYs from all causes, with the highest burden observed in sub-Saharan Africa (314 million [270-368] DALYs; 61·5% of total regional burden) and the lowest in the high-income super-region (31·8 million [25·4-40·1] DALYs; 9·8%). Three leading pathogens were responsible for more than 50 million DALYs each in 2019: tuberculosis (65·1 million [59·0-71·2]), malaria (53·6 million [27·0-91·3]), and HIV or AIDS (52·1 million [46·6-60·9]). Malaria was the leading pathogen for DALYs in children younger than 5 years (37·2 million [17·8-64·2]). We also observed substantial burden associated with previously less recognised pathogens, including Staphylococcus aureus and specific Gram-negative bacterial species (ie, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Helicobacter pylori). Conversely, some pathogens had a burden that was smaller than anticipated.
INTERPRETATION
Our detailed breakdown of DALYs associated with a comprehensive list of pathogens on a global, regional, and country level has revealed the magnitude of the problem and helps to indicate where research funding mismatch might exist. Given the disproportionate impact of infection on low-income and middle-income countries, an essential next step is for countries and relevant stakeholders to address these gaps by making targeted investments.
FUNDING
Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.
PubMed: 38640940
DOI: 10.1016/S1473-3099(24)00158-0