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Malaria sterile immunity has been reproducibly induced by immunization with Plasmodium radiation-attenuated sporozoites (RAS). Analyses of sera from RAS-immunized individuals allowed the identification of P. falciparum antigens, such as the circumsporozoite protein (CSP), the basis for the RTS, S and R21Matrix-M vaccines. Similar advances in P. vivax (Pv) vaccination have been elusive. We previously reported 42% (5/12) of sterile protection in malaria-unexposed, Duffy-positive (Fy +) volunteers immunized with PvRAS followed by a controlled human malaria infection (CHMI). Using a custom protein microarray displaying 515 Pv antigens, we found a significantly higher reactivity to PvCSP and one hypothetical protein (PVX_089630) in volunteers protected against P. vivax infection. In mock-vaccinated Fy + volunteers, a strong antibody response to CHMI was also observed. Although the Fy- volunteers immunized with non-irradiated Pv-infected mosquitoes (live sporozoites) did not develop malaria after CHMI, they recognized a high number of antigens, indicating the temporary presence of asexual parasites in peripheral blood. Together, our findings contribute to the understanding of the antibody response to P. vivax infection and allow the identification of novel parasite antigens as vaccine candidates.Trial registration: ClinicalTrials.gov number: NCT01082341.

Preventing malaria during pregnancy is of critical importance, yet there are no approved malaria vaccines for pregnant women due to lack of efficacy results within this population. Conducting a randomized trial in pregnant women throughout the entire duration of pregnancy is impractical. Instead, a randomized trial was conducted among women of childbearing potential (WOCBP), and some participants became pregnant during the 2‐year study. We explore a statistical method for estimating vaccine effect within the target subpopulation—women who can naturally become pregnant, namely, women who can become pregnant under a placebo condition—within the causal inference framework. Two vaccine effect estimators are employed to effectively utilize baseline characteristics and account for the fact that certain baseline characteristics were only available from pregnant participants. The first estimator considers all participants but can only utilize baseline variables collected from the entire participant pool. In contrast, the second estimator, which includes only pregnant participants, utilizes all available baseline information. Both estimators are evaluated numerically through simulation studies and applied to the WOCBP trial to assess vaccine effect against pregnancy malaria. [ABSTRACT FROM AUTHOR]

BACKGROUND Currently licensed and approved malaria subunit vaccines provide modest, short-lived protection against malaria. Immunization with live-attenuated Plasmodiumfalciparum malaria parasites is an alternative vaccination strategy that has potential to improve protection. METHODS We conducted a double-blind, controlled clinical trial to evaluate the safety, side-effect profile, and efficacy of immunization, by means of mosquito bites, with second-generation genetically attenuated parasite (GA2) - a mei2 single knockout P. falciparum NF54 parasite (sporozoite form) with extended development into the liver stage. After an open-label dose-escalation safety phase in which participants were exposed to the bites of 15 or 50 infected mosquitoes (stage A), healthy adults who had not had malaria were randomly assigned to be exposed to 50 mosquito bites per immunization of GA2, an early-arresting parasite (GAl), or placebo (bites from uninfected mosquitoes) (stage B). After the completion of three immunization sessions with 50 mosquito bites per session, we compared the protective efficacy of GA2 against homologous P.falciparum controlled human malaria infection with that of GAl and placebo. The primary end points were the number and severity of adverse events (in stages A and B) and blood-stage parasitemia greater than 100 P.Yalciparum parasites per milliliter after bites from GA2-infected mosquitoes (in stage A) and after controlled human malaria infection (in stage B). RESULTS Adverse events were similar across the trial groups. Protective efficacy against subsequent controlled human malaria in fection was observed in 8 of 9 participants (89%) in the GA2 group, in 1 of 8 participants (13%) in the GAl group, and in 0 of 3 participants in the placebo group. A significantly higher frequency of P.Jalciparumspecific polyfunctional CD4+ and Vδ2+ γδ T cells were observed among participants who received GA2 than among those who received GAl, whereas GA2 and GAl induced similar antibody titers targeting the Rfalciparum circumsporozoite protein. CONCLUSIONS In this small trial, GA2 was associated with a favorable immune induction profile and protective efficacy, findings that warrant further evaluation. [ABSTRACT FROM AUTHOR]

RTS,S and R21 are the only vaccines recommended by the WHO to protect children from Plasmodium falciparum (Pf) clinical malaria. Both vaccines target the Pf sporozoite surface protein circumsporozoite protein (CSP). Recent studies showed that human antibodies neutralize Pf sporozoites most efficiently when simultaneously binding to the PfCSP NANP repeat and the NPDP junction domain. However, neither RTS,S nor R21 targets this junction domain. To test the potential of the NPDP junction domain and other sites of PfCSP as innovative vaccine targets, we developed multiple vaccine candidates based on cucumber mosaic virus-like particles (CuMVTT-VLPs). These candidates vary in several aspects: the number of targeted NANP repeats, the presence or absence of the junction domain, the cleavage site, and up to three NVDP repeats within the target sequence. Immunogenicity and efficacy studies were conducted in BALB/c mice, utilizing chimeric Plasmodium berghei (Pb) sporozoites, in which the endogenous CSP has been replaced by PfCSP (Pb/PfCSP). We observed a positive association between the number of targeted NANP repeats and the induction of specific IgM/IgG antibodies. Elevated humoral responses led to enhanced protection against parasitemia after Pb/PfCSP sporozoite challenge. Especially high-avidity/affinity antibody formation and vaccine protection were NANP repeat-dependent. Intriguingly, vaccine efficacy was not enhanced by targeting sites on PfCSP other than the NANP repeats. Our data emphasize the dominant role of the NANP repeat region for induction of protective antibodies. Furthermore, we present here novel malaria vaccine candidates with an excellent immunogenic profile that confer sterile protection in mice, even in absence of adjuvants. [ABSTRACT FROM AUTHOR]

Introduction: ProC6C is a multi-stage malaria vaccine which includes Plasmodium falciparum Circumsporozoite Protein (PfCSP), Pfs48/45 and Pfs230 sequences, designed to elicit functional antibodies that prevent sporozoite invasion of human hepatocytes (PfCSP) and parasite development in mosquitoes (Pfs48/45 and Pfs230). ProC6C formulated on Alhydrogel was evaluated in combination with Matrix-M in a Phase 1 trial in Burkina Faso. The PfCSP antibody responses were assessed for magnitude, specificity, avidity and functionality. These results compliment the prior reported safety and tolerability of ProC6C as well as the transmission reducing activity of ProC6C. Methods: The PfCSP response of ProC6C in Burkinabes in the Phase 1 trial (PACTR202201848463189) was profiled through the three vaccine administrations of 100 µg protein on Alhydrogel® alone (AlOH) or combined with 50 µg Matrix-M™ adjuvant (AlOH/Matrix-M). Serology was completed against full-length PfCSP and major/minor repeat peptides using antibody equivalence to PfCSP monoclonal antibodies (mAb 311, mAb 317 and mAb L9). Comparison of the ProC6C responses were made to those that received RTS,S/AS01 in a study conducted in Thailand. Bio-Layer Interferometry was further used to determine antibody avidity. The human IgG was subsequently purified, pooled, and evaluated in a mouse sporozoite challenge model to determine functionality. Results: A single administration of ProC6C-AlOH/Matrix-M seroconverted 19 of 20 volunteers against PfCSP and significantly enhanced antibody titers to major and minor repeats (and present through D180). At D70, ProC6C-AlOH/Matrix-M PfCSP antibodies were found to be similar to responder pools generated from Thai adults receiving RTS,S/AS01. Additionally, ProC6C antibodies were found to be competitive to established PfCSP antibodies such as mAb 317 and mAb L9. The purified and pooled IgG from human volunteers, used in a passive transfer mouse sporozoite challenge model, showed a median of 50% inhibition (P=0.0058). ProC6C PfCSP antibodies were functional in this in vivo assessment and consistent with inhibition seen by other Circumsporozoite vaccines in this model. Discussion: This analysis supports continued investigation of the antibody responses elicited by the ProC6C multi-stage malaria vaccine. This Phase 1 clinical trial demonstrated the short PfCSP sequence included in ProC6C can induce significant PfCSP antibodies in humans, which importantly were determined to be functional. [ABSTRACT FROM AUTHOR]

Plasmodium vivax, a challenging species to eliminate, causes millions of malaria cases globally annually. Developing an effective vaccine is crucial in the fight against vivax malaria, but considering the limited number of studies focusing on the identification and development of P. vivax-specific vaccine candidates, exploring new antigens is an urgent need. The merozoite protein CyRPA is essential for P. falciparum growth and erythrocyte invasion and corresponds to a promising candidate antigen. In P. vivax, a single study with multiple vaccine candidates indicates PvCyRPA with strong association with protection, outperforming classic malaria vaccine candidates. However, little is known about the specific naturally acquired response in the Americas, as well as the antigen epitope mapping. For this reason, we aimed to investigate the cellular and humoral immune response elicited against PvCyRPA in Brazilian endemic areas to identify the existence of immunodominant regions and the potential of this protein as a single or even a multi-stage specific malaria vaccine candidate for P. vivax. The results demonstrated that PvCyRPA is naturally immunogenic in Brazilian Amazon individuals previously exposed to malaria, which presented anti-PvCyRPA cytophilic antibodies. Moreover, our data show that the protein also possesses important immunogenic regions with an overlap of B and T cell epitopes. These data reinforce the possibility of including PvCyRPA in vaccine formulations for P. vivax. [ABSTRACT FROM AUTHOR]

Malaria remains a significant global health challenge, with millions of cases and high mortality rates annually, especially in low-income countries. Africa bears a substantial burden, with direct costs of malaria among children under five reaching millions of dollars in countries like Ghana, Tanzania, and Kenya. In 2021, over 610,000 malaria-related deaths were reported, 96% of which occurred in sub-Saharan Africa. Despite existing interventions, such as long-lasting insecticidal nets, indoor residual spraying, and intermittent preventive treatment, the re-emergence of malaria underscores the need for innovative preventive strategies. This study explores the potential of utilizing mobile phone caller tunes to raise awareness and promote the uptake of the RTS,S malaria vaccine. The technology acceptance model (TAM) provides a framework for understanding how users perceive and adopt new technologies. Caller tunes, a mobile phone feature that plays audio for callers waiting to be connected, have been effective in health communication campaigns in Asia and Africa. This approach could be leveraged to enhance malaria vaccine awareness, particularly in low-income countries where vaccine hesitancy is prevalent and malaria endemic. Overall, mobile technologies have significantly improved healthcare delivery in Africa, facilitating communication, monitoring, and treatment adherence in remote areas. Integrating caller tunes with health messages about the malaria vaccine could address vaccine hesitancy and improve uptake. This would require collaboration with telecommunication companies, healthcare providers, and policymakers to design culturally and linguistically appropriate messages. However, the cost of caller tune services, the need for internet access, and cultural differences are the expected challenge that may occur in this approach. Therefore, strategic partnerships and intersectoral approaches can mitigate these issues, making caller tunes a viable tool for public health communication. Raising awareness through this innovative method could enhance the adoption of the RTS,S vaccine and support ongoing malaria control efforts in Africa. [ABSTRACT FROM AUTHOR]

Malaria blood‐stage parasite is a critical pathogenic stage responsible for serious adverse outcomes in pregnant women and their neonates. Immunoglobulin G (IgG) antibody responses specific to various asexual blood‐stage antigens were well reported in non‐pregnant individuals. However, little is still known during placental malaria. To assess the antibody responses specific to Plasmodium falciparum‐derived MSP3 and UB05 malaria vaccine candidates in mother‐neonate couples, mother's peripheral blood and neonate's cord blood samples were collected at delivery. After malaria diagnostic, plasma levels of IgG and IgG subclass responses specific to UB05, MSP3 and UB05‐MSP3 were determined using ELISA. As outcomes, both mothers and neonates had significantly higher IgG responses to UB05 and UB05‐MSP3 compared to anti‐MSP3 IgG (p < 0.05), irrespective of malaria status. Significant negative correlations were observed between IgG levels specific to the three antigens and parasitaemia (p < 0.01). Anti‐UB05 and anti‐UB05‐MSP3 IgG levels in neonates showed a significant positive correlation with the corresponding mothers' antibodies (rs = 0.25 with p = 0.04; rs = 0.31 with p = 0.01, respectively). UB05MSP3‐specific IgG3 and IgG1 subclass responses were significantly higher than the IgG4 subclass (p < 0.01). The neonates IgG1 and IgG3 levels positively correlated with the corresponding antibody subclasses of mothers. These findings suggest an association between UB05 and UB05‐MSP3‐specific antibody responses and malaria control during pregnancy. Maternal–foetal transfer of MSP3 and UB05‐specific IgG occurs during pregnancy, suggesting the interest in the future malaria vaccination strategies in pregnant women to generate early protective immunity in baby against malaria. [ABSTRACT FROM AUTHOR]

Background: Plasmodium falciparum merozoite surface proteins 1 (PfMSP1) and 2 (PfMSP2) are potential candidates for malaria vaccine development. However, the genetic diversity of these genes in the global P. falciparum population presents a significant challenge in developing an effective vaccine. Hence, understanding the genetic diversity and evolutionary trends in the global P. falciparum population is crucial. Methods: This study analyzed the genetic variations and evolutionary changes of pfmsp1 and pfmsp2 in P. falciparum isolates from the Central Highland and South-Central regions of Vietnam. DNASTAR and MEGA7 programs were utilized for analyses. The polymorphic nature of global pfmsp1 and pfmsp2 was also investigated. Results: A total of 337 sequences of pfmsp1 and 289 sequences of pfmsp2 were obtained. The pfmsp1 and pfmsp2 from Vietnam revealed a higher degree of genetic homogeneity compared to those from other malaria-endemic countries. Remarkably, the allele diversity patterns of Vietnam pfmsp1 and pfmsp2 differed significantly from those of neighboring countries in the Greater Mekong Subregion. Declines in allele diversity and polymorphic patterns of Vietnam pfmsp1 and pfmsp2 were observed. Conclusions: The Vietnam P. falciparum population might be genetically isolated from the parasite populations in other neighboring GMS countries, likely due to geographical barriers and distinct evolutionary pressures. Furthermore, bottleneck effects or selective sweeps may have contributed to the genetic homogeneity of Vietnam pfmsp1 and pfmsp2. [ABSTRACT FROM AUTHOR]

Aim: Malaria vaccine is one of the critical areas in tropical health research, considering the success recorded in other vaccine‐preventable diseases. This study is aimed at reviewing recent trends in global malaria vaccine research from 2005 to 2022. Method: A validated search strategy was undertaken to identify scientific literature on the malaria vaccine in the Scopus database. Bibliometric indicators identified include a pattern of publication growth and citations over the study period; top authors, countries, funding organizations, and journals; keywords, including different malarial parasite species, and the overall research themes. Result: A total of 6457 documents were found from 2005 to 2022, published in 160 journals/sources in 189 countries/territories. Malaria Journal published the highest number of research outputs (478, 7.4%) within the study period, and the highest number of documents (468, 7.3%) were published in 2021. There were 214,323 total citations, with 33.2 average citations per document and 167 documents' h‐index. The United States, United Kingdom, and Australia combined produced more than 60% of the publication output, with most collaboration with African countries such as Kenya. Plasmodium falciparum is the most occurring parasite species keyword (754, 11.7%), with a growing interest in Plasmodium knowlesi (30, 0.5%). Merozoite surface protein, characterization, trials, infant/children, traveler, and research/review were the six themes that emerged from the studies. Conclusion: The last one and half decades have seen a significant increase in malaria vaccine research and citations, mainly targeting vaccine development, safety, and efficacy in Africa. This necessitates more international efforts to improve the vaccines' effectiveness considering different Plasmodium species. [ABSTRACT FROM AUTHOR]

Background: The RTS,S malaria vaccine has been prequalified for use in endemic settings prioritizing areas with moderate to high disease transmission. The impact of a vaccine at the population level may differ from observations during clinical trial due to programmatic, and individual-related factors, among others. The objective of this study was to assess the impact of the RTS,S malaria vaccine on uncomplicated malaria among children aged 12–59 months in the Phase IV study districts, Upper East Region, Ghana. Methods: A retrospective study was conducted using routine malaria surveillance data for the period 2020–2022. The burden of uncomplicated malaria was compared between the implementing (Kasena Nankana East and West districts) and comparator areas (Builsa North and South districts). The impact of RTS,S malaria vaccine was assessed by estimating the percentage reduction in uncomplicated malaria and incidence averted in the implementing area, accounting for the effect of confounders. Results: Over 50,000 episodes of uncomplicated malaria among children aged 12–59 months were included in the study. Uncomplicated malaria was reduced by 33% (95%CI 29–36) over the entire study period, but the malaria incidence averted declined from 324/1,000 (95% CI 298–339; p < 0.0001) in 2020 to 287/1000 (95% CI 274–299; p < 0.0001) in 2022. Conclusion: The RTS,S malaria vaccine significantly reduced the burden of uncomplicated malaria among children aged 12–59 months in the implementing area. The sequential marginal declines in malaria incidence averted over the study period might be due to waning of protective immunity and acquisition of natural immunity as children age. Strengthening uptake of the currently recommended vaccines and other malaria control interventions is required to improve public health impact. [ABSTRACT FROM AUTHOR]

[Display omitted] • A NanoLuc reporter allows rapid quantification of Plasmodium falciparum transfection outcome. • Optimized hypotonic lysis and resealing improves erythrocyte plasmid loading. • Improved plasmid loading increases malaria parasite transfection efficiency. • The hypotonic loading method is broadly accessible and less effort-intensive. • Improved transfection outcomes will accelerate antimalarial therapy research. In vitro modification of Plasmodium falciparum genes is the cornerstone of basic and translational malaria research. Achieved through DNA transfection, these modifications may entail altering protein sequence or abundance. Such experiments are critical for defining the molecular mechanisms of key parasite phenotypes and for validation of drug and vaccine targets. Despite its importance, successful transfection remains difficult and is a resource-intensive, rate-limiting step in P. falciparum research. Here, we report that inefficient loading of plasmid into erythrocytes limits transfection efficacy with commonly used electroporation methods. As these methods also require expensive instrumentation and consumables that are not broadly available, we explored a simpler method based on plasmid loading through hypotonic lysis and resealing of erythrocytes. We used parasite expression of a sensitive NanoLuc reporter for rapid evaluation and optimization of each step. Hypotonic buffer composition, resealing buffer volume and composition, and subsequent incubation affected plasmid retention and successful transfection. While ATP was critical for erythrocyte resealing, addition of Ca++ or glutathione did not improve transfection efficiency, with increasing Ca++ concentrations proving detrimental to outcomes. Compared with either the standard electroporation method or a previously reported hypotonic loading protocol, the optimized method yields greater plasmid loading and higher expression of the NanoLuc reporter 48 h after transfection. It also produced significantly faster outgrowth of parasites in transfections utilizing either episomal expression or CRISPR-Cas9 mediated integration. This new method produces higher P. falciparum transfection efficiency, reduces resource requirements and should accelerate molecular studies of malaria drug and vaccine targets. [ABSTRACT FROM AUTHOR]

A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. RH5.1 is a soluble protein vaccine candidate for blood-stage P falciparum , formulated with Matrix-M adjuvant to assess safety and immunogenicity in a malaria-endemic adult and paediatric population for the first time. We did a non-randomised, phase 1b, single-centre, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M in Bagamoyo, Tanzania. We recruited healthy adults (aged 18–45 years) and children (aged 5–17 months) to receive the RH5.1/Matrix-M vaccine candidate in the following three-dose regimens: 10 μg RH5.1 at 0, 1, and 2 months (Adults 10M), and the higher dose of 50 μg RH5.1 at 0 and 1 month and 10 μg RH5.1 at 6 months (delayed-fractional third dose regimen; Adults DFx). Children received either 10 μg RH5.1 at 0, 1, and 2 months (Children 10M) or 10 μg RH5.1 at 0, 1, and 6 months (delayed third dose regimen; Children 10D), and were recruited in parallel, followed by children who received the dose-escalation regimen (Children DFx) and children with higher malaria pre-exposure who also received the dose-escalation regimen (High Children DFx). All RH5.1 doses were formulated with 50 μg Matrix-M adjuvant. Primary outcomes for vaccine safety were solicited and unsolicited adverse events after each vaccination, along with any serious adverse events during the study period. The secondary outcome measures for immunogenicity were the concentration and avidity of anti-RH5.1 serum IgG antibodies and their percentage growth inhibition activity (GIA) in vitro, as well as cellular immunogenicity to RH5.1. All participants receiving at least one dose of vaccine were included in the primary analyses. This trial is registered at ClinicalTrials.gov , NCT04318002 , and is now complete. Between Jan 25, 2021, and April 15, 2021, we recruited 12 adults (six [50%] in the Adults 10M group and six [50%] in the Adults DFx group) and 48 children (12 each in the Children 10M, Children 10D, Children DFx, and High Children DFx groups). 57 (95%) of 60 participants completed the vaccination series and 55 (92%) completed 22 months of follow-up following the third vaccination. Vaccinations were well-tolerated across both age groups. There were five serious adverse events involving four child participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum IgG antibody responses were induced by vaccination and purified total IgG showed in vitro GIA against P falciparum. We found similar functional quality (ie, GIA per μg RH5-specific IgG) across all age groups and dosing regimens at 14 days after the final vaccination; the concentration of RH5.1-specific polyclonal IgG required to give 50% GIA was 14·3 μg/mL (95% CI 13·4–15·2). 11 children were vaccinated with the delayed third dose regimen and showed the highest median anti-RH5 serum IgG concentration 14 days following the third vaccination (723 μg/mL [IQR 511–1000]), resulting in all 11 who received the full series showing greater than 60% GIA following dilution of total IgG to 2·5 mg/mL (median 88% [IQR 81–94]). The RH5.1/Matrix-M vaccine candidate shows an acceptable safety and reactogenicity profile in both adults and 5–17-month-old children residing in a malaria-endemic area, with all children in the delayed third dose regimen reaching a level of GIA previously associated with protective outcome against blood-stage P falciparum challenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African children. The European and Developing Countries Clinical Trials Partnership; the UK Medical Research Council; the UK Department for International Development; the National Institute for Health and Care Research Oxford Biomedical Research Centre; the Division of Intramural Research, National Institute of Allergy and Infectious Diseases; the US Agency for International Development; and the Wellcome Trust. [ABSTRACT FROM AUTHOR]

Background/Objectives: We developed a multistage Plasmodium falciparum vaccine using a heterologous prime-boost immunization strategy. This involved priming with a highly attenuated, replication-competent vaccinia virus strain LC16m8Δ (m8Δ) and boosting with adeno-associated virus type 1 (AAV1). This approach demonstrated 100% efficacy in both protection and transmission-blocking in a murine model. In this study, we compared our LC16m8∆/AAV1 vaccine, which harbors a gene encoding Pfs25-PfCSP fusion protein, to RTS,S/AS01 (RTS,S) in terms of immune responses, protective efficacy, and transmission-blocking activity (TBA) in murine models. Methods: Mice were immunized following prime-boost vaccine regimens m8∆/AAV1 or RTS,S and challenged with transgenic Plasmodium berghei parasites. Immune responses were assessed via ELISA, and TB efficacy was evaluated using direct feeding assays. Results: m8∆/AAV1 provided complete protection (100%) in BALB/c mice and moderate (40%) protection in C57BL/6 mice, similar to RTS,S. Unlike RTS,S's narrow focus (repeat region), m8∆/AAV1 triggered antibodies for all PfCSP regions (N-terminus, repeat, and C-terminus) with balanced Th1/Th2 ratios. Regarding transmission blockade, serum from m8∆/AAV1-vaccinated BALB/c mice achieved substantial transmission-reducing activity (TRA = 83.02%) and TB activity (TBA = 38.98%)—attributes not observed with RTS,S. Furthermore, m8∆/AAV1 demonstrated durable TB efficacy (94.31% TRA and 63.79% TBA) 100 days post-immunization. Conclusions: These results highlight m8∆/AAV1′s dual action in preventing sporozoite invasion and onward transmission, a significant advantage over RTS,S. Consequently, m8∆/AAV1 represents an alternative and a promising vaccine candidate that can enhance malaria control and elimination strategies. [ABSTRACT FROM AUTHOR]

Background: In May 2019, Ghana piloted the introduction of RTS,S malaria vaccine into routine immunization in 42 districts of seven of the 16 regions. The RTS,S malaria vaccine implementation programme (MVIP) post-introduction evaluation (PIE) conducted in Ghana, assessed the immunization system as well as healthcare worker and caregiver experiences during the phase-one rollout but was less expressive on quantitative grading of the respective thematic areas of the vaccine introduction plan. Given the utility of summary statistics in programme evaluation and communication, this follow-up study aimed to provide an overall rating of the country's performance regarding the MVIP. Methods: A retrospective study was conducted from 10th January to 5th February 2024. It involved review of records to assess key thematic areas of the national MVIP plan, using a study tool adapted from the WHO New Vaccine Introduction (NVI) checklist. A composite score ranging from zero to 100 per cent was generated to assess the country's overall performance regarding introduction of the malaria vaccine, rated on a Likert scale as comprehensive, good, fair, and poor. Results: The overall performance in the MVIP was rated 78.9% (30/38) corresponding to a grading of "good" on the Likert scale. Performance indicators under thematic areas including policy, national coordination mechanisms, waste management, health worker training, and pharmacovigilance were completely achieved. However, some weaknesses were exhibited in areas such as financial consideration, cold chain, logistics, and vaccine management, and monitoring and evaluation. Conclusion: Ghana's MVIP demonstrated remarkable strengths worth leveraging to improve the national immunization programme. The weaknesses observed in some of the thematic areas present opportunities to engage key immunization partners and stakeholders towards aligning efforts to ensure a more robust expansion phase. The lessons from the MVIP may be relevant to areas introducing malaria vaccine irrespective of the product type—RTS,S or R21. [ABSTRACT FROM AUTHOR]

Background: Malaria is a mosquito-transmitted disease that kills more than half a million people annually. The lack of effective malaria vaccines and recently increasing malaria cases urge innovative approaches to prevent malaria. Previously, we reported that the extract from the soil-dwelling fungus Purpureocillium lilacinum, a common fungus from the soil, reduced Plasmodium falciparum oocysts in Anopheles gambiae midguts after mosquitoes contacted the treated surface before feeding. Methods: We used liquid chromatography to fraction fungal crude extract and tract the active fraction using a contact-wise approach and standard membrane feeding assays. The purified small molecules were analyzed using precise mass spectrometry and tandem mass spectrometry. Results: We isolated four active small molecules from P. lilacinum and determined them as leucinostatin A, B, A2, and B2. Pre-exposure of mosquitoes via contact with very low-concentration leucinostatin A significantly reduced the number of oocysts. The half-maximal response or inhibition concentration (EC50) via pre-exposure was 0.7 mg/m2, similar to atovaquone but lower than other known antimalarials. The inhibitory effect of leucinostatin A against P. falciparum during intraerythrocytic development, gametogenesis, sporogonic development, and ookinete formation, with the exception of oocyst development, suggests that leucinostatins play a part during parasite invasion of new cells. Conclusions: Leucinostatins, secondary metabolites from P. lilacinum disrupt malaria development, particular transmission to mosquitoes by contact. The contact-wise malaria control as a nonconventional approach is highly needed in malaria-endemic areas. [ABSTRACT FROM AUTHOR]

Maintaining high-affinity antibodies after vaccination may be important for long-lasting immunity to malaria, but data on induction and kinetics of affinity is lacking. In a phase 1 malaria vaccine trial, antibody affinity increased following a second vaccination but declined substantially over 12 months, suggesting poor maintenance of high-affinity antibodies. Clinical Trials Registration Australian New Zealand Clinical Trials Registry ACTRN12607000552482. [ABSTRACT FROM AUTHOR]

We previously described a novel Plasmodium vivax invasion mechanism into human reticulocytes via the PvRBP2a-CD98 receptor-ligand pair. Using linear epitope mapping, we assessed the PvRBP2a epitopes involved in CD98 binding and recognized by antibodies from patients who were infected. We identified 2 epitope clusters mediating PvRBP2a-CD98 interaction. Cluster B (PvRBP2a431-448, TAALKEKGKLLANLYNKL) was the target of antibody responses in humans infected by P vivax. Peptides from each cluster were able to prevent live parasite invasion of human reticulocytes. These results provide new insights for development of a malaria blood-stage vaccine against P vivax. [ABSTRACT FROM AUTHOR]

The first licensed malaria vaccine, RTS,S/AS01 E , confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy. Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5–17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01 E regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov , NCT03281291. We observed significant and similar vaccine efficacy (25–43%; 95% CI union 9–53) against first new infection for all four RTS,S/AS01 E regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01 E regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1·1–1·6 infections (95% CI union 0·6–2·1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50–80) than in those who were uninfected (37%; 23–48) at the first vaccination (p=0·0053). All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research. [ABSTRACT FROM AUTHOR]

Background The RTS,S/AS01E (RTS,S) malaria vaccine is recommended for children in malaria endemic areas. This phase 2b trial evaluates RTS,S fractional- and full-dose regimens in Ghana and Kenya. Methods In total, 1500 children aged 5–17 months were randomized (1:1:1:1:1) to receive RTS,S or rabies control vaccine. RTS,S groups received 2 full RTS,S doses at months 0 and 1 and either full (groups R012-20, R012-14-26) or fractional doses (one-fifth; groups Fx012-14-26, Fx017-20-32). Results At month 32 post-dose 1, vaccine efficacy against clinical malaria (all episodes) ranged from 38% (R012-20; 95% confidence interval [CI]: 24%–49%) to 53% (R012-14-26; 95% CI: 42%–62%). Vaccine impact (cumulative number of cases averted/1000 children vaccinated) was 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), and 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional vs full dose; post hoc analysis), we estimated cases averted/1000 RTS,S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), and 880 (Fx017-20-32). Conclusions Vaccine efficacy was similar across RTS,S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If maintained through trial end, these observations underscore the means to reduce cost per regimen thus maximizing impact and optimizing supply. Clinical Trials Registration NCT03276962 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

The impact of adjuvants on malaria vaccine-induced antibody repertoire is poorly understood. Here, we characterize the impact of two adjuvants, Alhydrogel® and AS01, on antibody clonotype diversity, binding and function, post malaria vaccination. We expressed 132 recombinant anti-Pfs230D1 human monoclonal antibodies (mAbs) from participants immunized with malaria transmission-blocking vaccine Pfs230D1, formulated with either Alhydrogel® or AS01. Anti-Pfs230D1 mAbs generated by Alhydrogel® formulation showed higher binding frequency to Pfs230D1 compared to AS01 formulation, although the frequency of functional mAbs was similar between adjuvant groups. Overall, the AS01 formulation induced anti-Pfs230D1 functional antibodies from a broader array of germline sequences versus the Alhydrogel® formulation. All mAbs using IGHV1-69 gene from the Alhydrogel® cohort bound to recombinant Pfs230D1, but did not block parasite transmission to mosquitoes, similar to the IGHV1-69 mAbs isolated from the AS01 cohort. These findings may help inform vaccine design and adjuvant selection for immunization with Plasmodium antigens. [ABSTRACT FROM AUTHOR]

Background: Production of anti-phosphatidylserine (anti-PS) antibodies has been associated with malaria and can aggravate pathology. How these autoantibodies develop during early childhood in a malaria context is not known. We examined levels of anti-PS IgG and IgM antibodies in a longitudinal cohort of mother-baby pairs during birth, in the infants at 2.5, 6 months, and in mothers and their babies at 9 months postpartum. Results: There was no difference between levels of anti-PS IgG in cord blood and the mothers' peripheral blood at birth. However, anti-PS IgM levels were significantly higher in the mothers compared to the infants' cord blood, and IgM levels were steadily increasing during the first 9 months of the infants' life. In infants that had the highest anti-PS IgM levels at birth, there was a decline until 6 months with a rise at 9 months. Infants that possessed high anti-PS IgG at birth also exhibited a progressive decline in levels. When anti-PS were correlated to different fractions of B-cells, there were several correlations with P. falciparum specific atypical B cells both at birth and at 2.5 months for the infants, especially for anti-PS IgM. Anti-PS also correlated strongly to C1q-fixing antibodies at birth. Conclusion: These results show that anti-PS IgG acquired by mothers could be transferred transplacentally and that IgM antibodies targeting PS are acquired during the first year of life. These results have increased the knowledge about autoimmune responses associated with infections in early life and is critical for a comprehensive understanding of malaria vaccine functionality in endemic areas. [ABSTRACT FROM AUTHOR]

A vaccine protecting against malaria caused by Plasmodium falciparum is urgently needed. The blood-stage invasion complex PCRCR consists of the five malarial proteins PfPTRAMP, PfCSS, PfRipr, PfCyRPA, and PfRH5. As each subcomponent represents an essential and highly conserved antigen, PCRCR is considered a promising vaccine target. Furthermore, antibodies targeting the complex can block red blood cell invasion by the malaria parasite. However, extremely high titers of neutralizing antibodies are needed for this invasion-blocking effect, and a vaccine based on soluble PfRH5 protein has proven insufficient in inducing a protective response in a clinical trial. Here, we present the results of two approaches to increase the neutralizing antibody titers: (A) immunofocusing and (B) increasing the immunogenicity of the antigen via multivalent display on capsid virus-like particles (cVLPs). The immunofocusing strategies included vaccinating with peptides capable of binding the invasion-blocking anti-PfCyRPA monoclonal antibody CyP1.9, as well as removing non-neutralizing epitopes of PfCyRPA through truncation. Vaccination with PfCyRPA coupled to the AP205 cVLP induced nearly two-fold higher IgG responses compared to vaccinating with soluble PfCyRPA protein. Immunofocusing using a linear peptide greatly increased the neutralizing capacity of the anti-PfCyRPA antibodies. However, significantly lower total anti-PfCyRPA titers were achieved using this strategy. Our results underline the potential of a cVLP-based malaria vaccine including full-length PfCyRPA, which could be combined with other leading malaria vaccine antigens presented on cVLPs. [ABSTRACT FROM AUTHOR]

Background: Globally, malaria continues to pose a major health challenge, with approximately 247 million cases of the illness and 627,000 deaths reported in 2021. However, the threat is particularly pronounced in sub-Saharan African countries, where pregnant women and children under the age of five face heightened vulnerability to the disease. As a result, the imperative to develop malaria vaccines especially for these vulnerable populations, remains crucial in the pursuit of malaria eradication. However, despite decades of research, effective vaccine development faces technical challenges, including the rapid spread of drug-resistant parasite strains, the complex parasite lifecycle, the development of liver hypnozoites with potential for relapse, and evasion of the host immune system. This review aims to discuss the different malaria vaccine candidates in the pipeline, highlighting different approaches used for adjuvating these candidates, their benefits, and outcomes, and summarizing the progress of these vaccine candidates under development. Method: A comprehensive web-based search for peer-reviewed journal articles published in SCOPUS, MEDLINE (via PubMed), Science Direct, WHO, and Advanced Google Scholar databases was conducted from 1990 to May 2022. Context-specific keywords such as "Malaria", "Malaria Vaccine", "Malaria Vaccine Candidates", "Vaccine Development", "Vaccine Safety", "Clinical Trials", "mRNA Vaccines", "Viral Vector Vaccines", "Protein-based Vaccines", "Subunit Vaccines", "Vaccine Adjuvants", "Vaccine-induced Immune Responses", and "Immunogenicity" were emphatically considered. Articles not directly related to malaria vaccine candidates in preclinical and clinical stages of development were excluded. Results: Various approaches have been studied for malaria vaccine development, targeting different parasite lifecycle stages, including the pre-erythrocytic, erythrocytic, and sexual stages. The RTS, S/AS01 vaccine, the first human parasite vaccine reaching WHO-listed authority maturity level 4, has demonstrated efficacy in preventing clinical malaria in African children. However, progress was slow in introducing other safe, and feasible malaria vaccines through clinical trials. Recent studies highlight the potential effectiveness of combining pre-erythrocytic and blood-stage vaccines, along with the advantages of mRNA vaccines for prophylaxis and treatment, and nonstructural vaccines for large-scale production. Conclusion: Malaria vaccine candidates targeting different lifecycle stages of the parasite range from chemoprophylaxis vaccination to cross-species immune protection. The use of a multi-antigen, multi-stage combinational vaccine is therefore essential in the context of global health. This demands careful understanding and critical consideration of the long-term multi-faceted interplay of immune interference, co-dominance, complementary immune response, molecular targets, and adjuvants affecting the overall vaccine-induced immune response. Despite challenges, advancements in clinical trials and vaccination technology offer promising possibilities for novel approaches in malaria vaccine development. [ABSTRACT FROM AUTHOR]

Authorization of the Matrix-M (MM)–adjuvanted R21 vaccine by three countries and its subsequent endorsement by the World Health Organization for malaria prevention in children are a milestone in the fight against malaria. Yet, our understanding of the innate and adaptive immune responses elicited by this vaccine remains limited. Here, we compared three clinically relevant adjuvants [3M-052 + aluminum hydroxide (Alum) (3M), a TLR7/8 agonist formulated in Alum; GLA-LSQ, a TLR4 agonist formulated in liposomes with QS-21; and MM, the now-approved adjuvant for R21] for their capacity to induce durable immune responses to R21 in macaques. R21 adjuvanted with 3M on a 0, 8, and 23–week schedule elicited anti-circumsporozoite antibody responses comparable in magnitude to the R21/MM vaccine administered using a 0-4-8–week regimen and persisted up to 72 weeks with a half-life of 337 days. A booster dose at 72 weeks induced a recall response similar to the R21/MM vaccination. In contrast, R21/GLA-LSQ immunization induced a lower, short-lived response at the dose used. Consistent with the durable serum antibody responses, MM and 3M induced long-lived plasma cells in the bone marrow and other tissues, including the spleen. Furthermore, whereas 3M stimulated potent and persistent antiviral transcriptional and cytokine signatures after primary and booster immunizations, MM induced enhanced expression of interferon- and TH2-related signatures more highly after the booster vaccination. Collectively, these findings provide a resource on the immune responses of three clinically relevant adjuvants with R21 and highlight the promise of 3M as another adjuvant for malarial vaccines. Editor's summary: Most vaccines based on recombinant antigens rely on coadministration with an adjuvant to elicit a robust immune response. Although adjuvants are needed for many vaccines, it is less clear which adjuvant(s) should be paired with each immunogen. In two papers, Bechtold et al. and Arunachalam et al. performed comparative analyses to assess the effect of different adjuvants on the immune response. Bechtold et al. showed that an AS01-adjuvanted hepatitis B virus vaccine, which induces robust CD4+ T cell responses against the vaccine antigen, also elicited trained immunity in human recipients, which was not observed in an alum-adjuvanted vaccine. Arunachalam et al. found that Matrix-M and 3M-052 + aluminum hydroxide (Alum) adjuvantation induced robust immune responses to the R21 malaria vaccine in nonhuman primates, but a third comparator, GLA-LSQ, elicited a lower magnitude of response that was short lived. Although Matrix-M and 3M-052 + Alum induced robust and durable antibody responses, they elicited distinct innate immune responses, demonstrating that multiple innate immune mechanisms can program durable vaccine-induced immunity. These head-to-head comparisons in both humans and nonhuman primates demonstrate that selecting an adjuvant should be done carefully and that different adjuvants have distinct effects on both innate and adaptive immunity. —Courtney Malo [ABSTRACT FROM AUTHOR]

Backgrounds: Malaria, a preventive and treatable disease, is still responsible for annual deaths reported in most tropical regions, principally in sub-Saharan Africa. Subunit recombinant transmission-blocking vaccines (TBVs) have been proposed as promising vaccines to succeed in malaria elimination and eradication. Here, a provisional study was designed to assess the immunogenicity and functional activity of alanyl aminopeptidase N (APN1) of Anopheles stephensi, as a TBV candidate, administered with MPL, CpG, and QS21 adjuvants in the murine model. Methodology/Principal findings: The mouse groups were immunized with recombinant APN1 (rAPN1) alone or formulated with CpG, MPL, QS-21, or a combination of adjuvants (CMQ), and the elicited immune responses were evaluated after the third immunization. The standard membrane feeding assay (SMFA) measured the functional activity of antibodies against bacterial-expressed APN1 protein in adjuvanted vaccine groups on transmission of P. falciparum (NF54) to An. stephensi mosquitoes. Evaluation of mice vaccinated with rAPN1 formulated with distinct adjuvants manifested a significant increase in the high-avidity level of anti-APN1 IgG and IgG subclasses; however, rAPN1 induced the highest level of high-avidity anti-APN1 IgG1, IgG2a, and IgG2b antibodies in the immunized vaccine group 5 (APN1/CMQ). In addition, vaccine group 5 (receiving APN1/CMQ), had still the highest level of anti-APN1 IgG antibodies relative to other immunized groups after six months, on day 180. The SMFA data indicates a trend towards higher transmission-reducing activity in groups 2 and 5, which received the antigen formulated with CpG or a combination of three adjuvants. Conclusions/Significance: The results have shown the capability of admixture to stimulate high-affinity and long-lasting antibodies against the target antigen to hinder Plasmodium parasite development in the mid-gut of An. stephensi. The attained results authenticated APN1/CMQ and APN1/CpG as a potent APN1-based TBV formulation which will be helpful in designing a vaccine in the future. [ABSTRACT FROM AUTHOR]

The most severe form of malaria, caused by infection with Plasmodium falciparum parasites, continues to be an important cause of human suffering and poverty. The P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of clonally variant antigens, which mediates the adhesion of infected erythrocytes to the vascular endothelium in various tissues and organs, is a central component of the pathogenesis of the disease and a key target of the acquired immune response to malaria. Much new knowledge has accumulated since we published a systematic overview of the PfEMP1 family almost ten years ago. In this chapter, we therefore aim to summarize research progress since 2015 on the structure, function, regulation etc. of this key protein family of arguably the most important human parasite. Recent insights regarding PfEMP1-specific immune responses and PfEMP1-specific vaccination against malaria, as well as an outlook for the coming years are also covered. [ABSTRACT FROM AUTHOR]

Malaria is a mosquito-borne, life-threatening illness caused by the parasite, Plasmodium. Around 50% of the world’s population is endangered by this infectious disease. The antimalarial drug, artemisinin (ART), which is extracted from the plant Artemisia annua, has become a fundamental part of the treatment regime for malaria across the world. The use of ART-based combination therapies against uncomplicated malaria has been endorsed by the World Health Organization (WHO). As per the latest World Malaria Report in 2022, around 247 million malaria cases were reported in 2021 from 84 malariaendemic nations, including the territory of French Guiana, a considerable upsurge from the 245 million reported in 2020. One of the foremost reasons for this increase was linked with disturbances to services for prevention, diagnosis, and treatment measures during the recent COVID-19 pandemic. On October 6, 2021, the WHO suggested the RTS,S vaccine as the first malaria vaccine to be used against Plasmodium falciparum malaria in children residing in areas with moderate to high transmission. In July 2022, the WHO granted prequalification support for this vaccine. Over one million children living in African countries, mainly in Ghana, Kenya, and Malawi, have gotten at least one dose of this groundbreaking malaria vaccine through programs coordinated by the WHO, as well as international and country-level partners. RTS,S is a significant initial step in the path to the production of other highly protective and multi-stage vaccines that may become part of malaria eradication programs in the near future. Several malariologists are working on the early clinical development or trial phases of first-generation and next-generation malaria vaccines, such as R21/Matrix-M, using mRNA technology. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a unique asexual blood-stage malaria vaccine candidate because of its high conservation and essential biological function of binding to basigin on the erythrocyte surface. Recent studies by Barrett et al. , Wang et al. , and King et al. , have brought RH5-based vaccine development a step forward based on a rational antigen design strategy. [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) has recommended two vaccines for malaria prevention, but neither vaccine meets the desired efficacy and durability for an optimal malaria vaccine. However, there are multiple next-generation vaccines in clinical testing that aim to provide higher efficacy, decrease vaccine delivery demands, and improve cost effectiveness. Computational biology plays a crucial role in informing the design of these vaccines, with techniques such as mRNA-lipid nanoparticle technology offering advantages such as quick manufacturing and safety for infants and pregnant women. The article also discusses the strategy of combining existing vaccines with additional antigens to improve efficacy and the potential of transmission-blocking vaccines. Overall, next-generation vaccines are seen as crucial in achieving malaria elimination goals and improving child health in endemic areas. [Extracted from the article]

Background Malaria is preventable yet causes >600 000 deaths annually. RTS,S, the first marketed malaria vaccine, has modest efficacy, but improvements are needed for eradication. Methods We conducted an open-label, dose escalation phase 1 study of a full-length recombinant circumsporozoite protein vaccine (rCSP) administered with adjuvant glucopyranosyl lipid A–liposome Quillaja saponaria 21 formulation (GLA-LSQ) on days 1, 29, and 85 or 1 and 490 to healthy, malaria-naive adults. The primary end points were safety and reactogenicity. The secondary end points were antibody responses and Plasmodium falciparum parasitemia after homologous controlled human malaria infection. Results Participants were enrolled into 4 groups receiving rCSP/GLA-LSQ: 10 µg × 3 (n = 20), 30 µg × 3 (n = 10), 60 µg × 3 (n = 10), or 60 µg × 2 (n = 9); 10 participants received 30 µg rCSP alone × 3, and there were 6 infectivity controls. Participants experienced no serious adverse events. Rates of solicited and unsolicited adverse events were similar among groups. All 26 participants who underwent controlled human malaria infection 28 days after final vaccinations developed malaria. Increasing vaccine doses induced higher immunoglobulin G titers but did not achieve previously established RTS,S benchmarks. Conclusions rCSP/GLA-LSQ had favorable safety results. However, tested regimens did not induce protective immunity. Further investigation could assess whether adjuvant or schedule adjustments improve efficacy. Clinical Trials Registration NCT03589794 [ABSTRACT FROM AUTHOR]

• The Pk GIA will be an essential selection tool for P. vivax vaccine development. • The error of the assay was evaluated with human anti- Pv DBPII antibodies. • Significant assay-to-assay variation was observed. • 95 % confidence interval of inhibition for a given number of PkGIA was determined. 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 (Pv DBPII) correlate with in vivo protection in the first Pv DBPII controlled human malaria infection (CHMI) trials, making the Pk GIA 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 50 (antibody concentration that gave 50 %GIA), ten GIAs with transgenic Pk parasites were conducted with four different anti- Pv DBPII human monoclonal antibodies (mAbs) at concentrations of 0.016 to 2 mg/mL, and three GIAs with eighty anti- Pv DBPII 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 50 SD of 0.299 (for mAbs). Moreover, the ninety-five percent confidence interval (95 %CI) for %GIA or GIA 50 in repeat assays was calculated in this investigation. The error range determined in this study will help researchers to compare Pk GIA results from different assays and studies appropriately, thus supporting the development of future blood-stage malaria vaccine candidates, specifically second-generation Pv DBPII-based formulations. [ABSTRACT FROM AUTHOR]

Immunization through repeated direct venous inoculation of Plasmodium falciparum (Pf) sporozoites (PfSPZ) under chloroquine chemoprophylaxis, using the PfSPZ Chemoprophylaxis Vaccine (PfSPZ-CVac), induces high-level protection against controlled human malaria infection (CHMI). Humoral and cellular immunity contribute to vaccine efficacy but only limited information about the implicated Pf-specific antigens is available. Here, we examined Pf-specific antibody profiles, measured by protein arrays representing the full Pf proteome, of 40 placebo- and PfSPZ-immunized malaria-naïve volunteers from an earlier published PfSPZ-CVac dose-escalation trial. For this purpose, we both utilized and adapted supervised machine learning methods to identify predictive antibody profiles at two different time points: after immunization and before CHMI. We developed an adapted multitask support vector machine (SVM) approach and compared it to standard methods, i.e. single-task SVM, regularized logistic regression and random forests. Our results show, that the multitask SVM approach improved the classification performance to discriminate the protection status based on the underlying antibody-profiles while combining time- and dose-dependent data in the prediction model. Additionally, we developed the new fEature diStance exPlainabilitY (ESPY) method to quantify the impact of single antigens on the non-linear multitask SVM model and make it more interpretable. In conclusion, our multitask SVM model outperforms the studied standard approaches in regard of classification performance. Moreover, with our new explanation method ESPY, we were able to interpret the impact of Pf-specific antigen antibody responses that predict sterile protective immunity against CHMI after immunization. The identified Pf-specific antigens may contribute to a better understanding of immunity against human malaria and may foster vaccine development. Author summary: Developing an effective malaria vaccine is challenging. Malaria is a life-threatening disease caused by the plasmodium parasite, which has a complex multi-stage life-cycle and expresses several thousand proteins in a highly coordinated manner. To date, our understanding of the immune mechanisms mediating protection against Plasmodium falciparum (Pf) is incomplete. Proteome microarrays have been used earlier by our clinical collaboration partners to identify Pf-specific antibody profiles of malaria-naïve volunteers during immunization with attenuated Pf sporozoites (PfSPZ). We reused this data to compare the ability of three supervised machine learning methods to identify predictive antibody profiles after immunization and before controlled human malaria infection (CHMI). We adapted a multitask support vector machine (SVM) approach to analyze time-dependent Pf-induced antibody profiles from several time points in a single prediction model. Our multitask SVM approach outperforms the studied standard approaches in classification performance. Additionally, we developed a new explanation method, named fEature diStance exPlainabilitY (ESPY), to interpret the impact of Pf-specific antigens. We applied ESPY on the multitask SVM model and identified diverse Pf-specific antigen sets after immunization and before CHMI. Furthermore, we showed that the identified Pf-induced antibody profiles vary among protected and non-protected individuals who had been exposed to different doses of PfSPZ. [ABSTRACT FROM AUTHOR]

Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called "R78C", combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial. RH5, which is part of the trimeric RCR-complex essential for invasion, is a vaccine candidate for malaria. Here, Williams et al. show that monoclonal antibodies targeting each of the three proteins in the RCR-complex can work together to more effectively block the invasion of red blood cells by Plasmodium falciparum and design a combination vaccine candidate. [ABSTRACT FROM AUTHOR]

Introduction: Between 2000 and 2015, significant gains were recorded in reducing the global burden of malaria due to enhanced global collaboration and increased funding. However, progress has stagnated post‐2015, and the COVID‐19 pandemic seems to have reversed some of these gains, necessitating a critical reevaluation of interventions. This paper aims to analyze the setbacks and offer recommendations for advancement in malaria control and prevention in sub‐Saharan Africa. Methods: We conducted searches on Google Scholar, PubMed, and relevant organization websites to identify relevant studies on malaria control and prevention and associated challenges in sub‐Saharan Africa from 2015 to the present. Additionally, studies on individual sub‐Saharan African countries were reviewed to ensure comprehensiveness. Data from selected studies were extracted and analyzed using a narrative synthesis approach to offer a concise overview of the evidence. Findings: We observe that the halt in progress of malaria control in sub‐Saharan Africa has deep roots in socioeconomic, political, and environmental factors. These challenges are exacerbated by the population explosion in the region, low coverage of interventions due to funding deficits and incessant crises, and the degradation of the efficacy of existing malaria commodities. Conclusion: Sub‐Saharan Africa is at a crossroads in its fight against malaria. Promising new frontiers such as malaria vaccines, preventive monoclonal antibodies, new‐generation insecticide‐treated nets, and potentially artificial intelligence‐driven technologies offer hope in advancing malaria control and prevention in the region. Through commitment and collaboration, leveraging these opportunities can help surmount challenges and ultimately eliminate malaria in sub‐Saharan Africa. [ABSTRACT FROM AUTHOR]

While two Plasmodium falciparum circumsporozoite protein-based pre-erythrocytic vaccines (PEV), RTS,S and R21, have been approved by the WHO, no blood-stage vaccine (BSV) or transmission-blocking vaccine (TBV) has reached a phase 3 trial. One of the major obstacles that slows down malaria vaccine development is the shortage (or lack) of in vitro assays or animal models by which investigators can reasonably select the best vaccine formulation (e.g., antigen, adjuvant, or platform) and/or immunization strategy (e.g., interval of inoculation or route of immunization) before a human phase 2 trial. In the case of PEV, RTS,S and R21 have set a benchmark, and a new vaccine can be compared with (one of) the approved PEV directly in preclinical or early clinical studies. However, such an approach cannot be utilized for BSV or TBV development at this moment. The focus of this review is in vitro assays or in vivo models that can be used for P. falciparum BSV or TBV development, and I discuss important considerations during assay selection, standardization, qualification, validation, and interpretation of the assay results. Establishment of a robust assay/model with proper interpretation of the results is the one of key elements to accelerate future vaccine development. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Plasmodium falciparum malaria is a public health issue mostly seen in tropical countries. Until now, there is no effective malaria vaccine against antigens specific to the blood-stage of P. falciparum infection. Because the pathogenesis of malarial disease results from blood-stage infection, it is essential to identify the most promising blood-stage vaccine candidate antigens under natural exposure to malaria infection. Methods: A cohort of 400 pregnant women and their infants was implemented in South Benin. An active and passive protocol of malaria surveillance was established during pregnancy and infancy to precisely ascertain malaria infections during the follow-up. Twenty-eight antibody (Ab) responses specific to seven malaria candidate vaccine antigens were repeatedly quantified during pregnancy (3 time points) and infancy (6 time points) in order to study the Ab kinetics and their protective role. Abs were quantified by ELISA and logistic, linear and cox-proportional hazard model were performed to analyse the associations between Ab responses and protection against malaria in mothers and infants, taking into account socio-economic factors and for infants an environmental risk of exposure. Results: The levels of IgM against MSP1, MSP2 and MSP3 showed an early protective response against the onset of symptomatic malaria infections starting from the 18th month of life, whereas no association was found for IgG responses during infancy. In women, some IgG responses tend to be associated with a protection against malaria risk along pregnancy and at delivery, among them IgG3 against GLURP-R0 and IgG2 against MSP1. Conclusion: The main finding suggests that IgM should be considered in vaccine designs during infanthood. Investigation of the functional role played by IgM in malaria protection needs further attention. [ABSTRACT FROM AUTHOR]

Background: The newly developed malaria vaccine called "R21/Matrix-M malaria vaccine" showed a high safety and efficacy level, and Ghana is the first country to approve this new vaccine. The present study aimed to evaluate the rate of vaccine hesitancy (VH) towards the newly developed malaria vaccine among parents who currently have children who are not eligible for the vaccine but may be eligible in the near future. Additionally, the study aimed to identify the factors that could potentially influence VH. Methods: A cross-sectional survey using both online-based questionnaires and face-to-face interviews was conducted in Ghana from June to August 2023. The survey specifically targeted parents of ineligible children for vaccination, including those aged less than 5 months or between 3 and 12 years. The Parent Attitudes about Childhood Vaccination (PACV) scale was used to assess parental VH. Results: A total of 765 people participated in this study. Their median age was 36.0 years with an interquartile range of 31.0–41.0 years, 67.7% were females, 41.8% completed their tertiary education, 63.3% were married, 81.6% worked in non-healthcare sectors, and 59.7% reported that their monthly income was insufficient. About one-third (34.5%) of the parents were hesitant to give their children the R21/Matrix-M malaria vaccine. The following predictors were associated with VH: working in the healthcare sector (adjusted odds ratio (AOR) = 0.50; 95% confidence interval (CI) 0.30–0.80; p = 0.005), having the other parent working in the healthcare sector (AOR = 0.54; 95% CI 0.30–0.94; p = 0.034), and not taking scheduled routine vaccinations (AOR = 1.90; 95% CI 1.27–2.84; p = 0.002). Conclusions: Addressing VH is crucial for optimizing R21/Matrix-M vaccine coverage in Ghana's malaria control strategy. By tackling VH issues, Ghana can effectively safeguard children's health in malaria-prone areas. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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 (Pf PR 2–10) and ranges from 3% to 65% Pf PR 2–10. 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 Pf PR 2–10. Introduction of the R21/Matrix-M malaria vaccine could have a substantial public health benefit across sub-Saharan Africa. 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. [ABSTRACT FROM AUTHOR]

The Equatorial Guinea Malaria Vaccine Initiative (EGMVI) highlights how long-term African government and international energy industry investment, plus novel partnerships, can enable clinical development of vaccines in Africa, for Africa. We review achievements and challenges of this pioneering, award-winning, public–private partnership which offers a model for future Africa-centric clinical research and development (R&D). [ABSTRACT FROM AUTHOR]

Malaria is a global disease affecting a large portion of the world's population. Although vaccines have recently become available, their efficacies are suboptimal. We generated virus-like particles (VLPs) that expressed either apical membrane antigen 1 (AMA1) or microneme-associated antigen (MIC) of Plasmodium berghei and compared their efficacy in BALB/c mice. We found that immune sera acquired from AMA1 VLP-or MIC VLPimmunized mice specifically interacted with the antigen of choice and the whole P. berghei lysate antigen, indicating that the antibodies were highly parasite-specific. Both VLP vaccines significantly enhanced germinal center B cell frequencies in the inguinal lymph nodes of mice compared with the control, but only the mice that received MIC VLPs showed significantly enhanced CD4+ T cell responses in the blood following P. berghei challenge infection. AMA1 and MIC VLPs significantly suppressed TNF-α and interleukin-10 production but had a negligible effect on interferon-γ. Both VLPs prevented excessive parasitemia buildup in immunized mice, although parasite burden reduction induced by MIC VLPs was slightly more effective than that induced by AMA1. Both VLPs were equally effective at preventing body weight loss. Our findings demonstrated that the MIC VLP was an effective inducer of protection against murine experimental malaria and should be the focus of further development. [ABSTRACT FROM AUTHOR]

Malaria is caused by eukaryotic protozoan parasites of the genus Plasmodium. There are 249 million new cases and 608,000 deaths annually, and new interventions are desperately needed. Malaria vaccines can be divided into three categories: liver stage, blood stage, or transmission-blocking vaccines. Transmission-blocking vaccines prevent the transmission of disease by the mosquito vector from one human to another. Pfs230 is one of the leading transmission-blocking vaccine antigens for malaria. Here, we describe the development of a 24-copy self-assembling nanoparticle vaccine comprising domain 1 of Pfs230 genetically fused to H. pylori ferritin. The single-component Pfs230D1-ferritin construct forms a stable and homogenous 24-copy nanoparticle with good production yields. The nanoparticle is highly immunogenic, as two low-dose vaccinations of New Zealand White rabbits elicited a potent and durable antibody response with high transmission-reducing activity when formulated in two distinct adjuvants suitable for translation to human use. This single-component 24-copy Pfs230D1-ferritin nanoparticle vaccine has the potential to improve production pipelines and the cost of manufacturing a potent and durable transmission-blocking vaccine for malaria control. [ABSTRACT FROM AUTHOR]

The WHO reported an estimated 249 million malaria cases and 608,000 malaria deaths in 85 countries in 2022. A total of 94% of malaria deaths occurred in Africa, 80% of which were children under 5. In other words, one child dies every minute from malaria. The RTS,S/AS01 malaria vaccine, which uses the Plasmodium falciparum circumsporozoite protein (CSP) to target sporozoite infection of the liver, achieved modest efficacy. The Malaria Vaccine Implementation Program (MVIP), coordinated by the WHO and completed at the end of 2023, found that immunization reduced mortality by only 13%. To further reduce malaria death, the development of a more effective malaria vaccine is a high priority. Three malaria vaccine targets being considered are the sporozoite liver infection (pre-erythrocytic stage), the merozoite red blood cell infection (asexual erythrocytic stage), and the gamete/zygote mosquito infection (sexual/transmission stage). These targets involve specific ligand-receptor interactions. However, most current malaria vaccine candidates that target two major parasite population bottlenecks, liver infection, and mosquito midgut infection, do not focus on such parasite ligands. Here, we evaluate the potential of newly identified parasite ligands with a phage peptide-display technique as novel malaria vaccine antigens. [ABSTRACT FROM AUTHOR]

To improve the efficacy of Plasmodium falciparum malaria vaccine RTS,S/AS02, we conducted a study in 2001 in healthy, malaria-naïve adults administered RTS,S/AS02 in combination with FMP1, a recombinant merozoite surface-protein-1, C-terminal 42kD fragment. A double-blind Phase I/IIa study randomized N = 60 subjects 1:1:1:1 to one of four groups, N = 15/group, to evaluate safety, immunogenicity, and efficacy of intra-deltoid half-doses of RTS,S/AS02 and FMP1/AS02 administered in the contralateral (RTS,S + FMP1-separate) or same (RTS,S + FMP1-same) sites, or FMP1/AS02 alone (FMP1-alone), or RTS,S/AS02 alone (RTS,S-alone) on a 0-, 1-, 3-month schedule. Subjects receiving three doses of vaccine and non-immunized controls (N = 11) were infected with homologous P. falciparum 3D7 sporozoites by Controlled Human Malaria Infection (CHMI). Subjects in all vaccination groups experienced mostly mild or moderate local and general adverse events that resolved within eight days. Anti-circumsporozoite antibody levels were lower when FMP1 and RTS,S were co-administered at the same site (35.0 µg/mL: 95 % CI 20.3–63), versus separate arms (57.4 µg/mL: 95 % CI 32.3–102) or RTS,S alone (62.0 µg/mL: 95 % CI: 37.8–101.8). RTS,S-specific lymphoproliferative responses and ex vivo ELISpot CSP-specific interferon-gamma (IFN-γ) responses were indistinguishable among groups receiving RTS,S/AS02. There was no difference in antibody to FMP1 among groups receiving FMP1/AS02. After CHMI, groups immunized with a RTS,S-containing regimen had ∼ 30 % sterile protection against parasitemia, and equivalent delays in time-to-parasitemia. The FMP1/AS02 alone group showed no sterile immunity or delay in parasitemia. Co-administration of RTS,S and FMP1/AS02 reduced anti-RTS,S antibody, but did not affect tolerability, cellular immunity, or efficacy in a stringent CHMI model. Absence of efficacy or delay of patency in the sporozoite challenge model in the FMP1/AS02 group did not rule out efficacy of FMP1/AS02 in an endemic population. However, a Phase IIb trial of FMP1/AS02 in children in malaria-endemic Kenya did not demonstrate efficacy against natural infection. ClinicalTrials.gov identifier: NCT01556945. [ABSTRACT FROM AUTHOR]

Malaria vaccine development is hampered by extensive antigenic variation and complex life stages of Plasmodium species. Vaccine development has focused on a small number of antigens, many of which were identified without utilizing systematic genome-level approaches. In this study, we implement a machine learning-based reverse vaccinology approach to predict potential new malaria vaccine candidate antigens. We assemble and analyze P. falciparum proteomic, structural, functional, immunological, genomic, and transcriptomic data, and use positive-unlabeled learning to predict potential antigens based on the properties of known antigens and remaining proteins. We prioritize candidate antigens based on model performance on reference antigens with different genetic diversity and quantify the protein properties that contribute most to identifying top candidates. Candidate antigens are characterized by gene essentiality, gene ontology, and gene expression in different life stages to inform future vaccine development. This approach provides a framework for identifying and prioritizing candidate vaccine antigens for a broad range of pathogens. [ABSTRACT FROM AUTHOR]