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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]

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]

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]

Abstract 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 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

Abstract 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.

Introduction: The uptake trend of a new vaccine is unpredictable and may reflect the quality of introduction process and community acceptance. The objective of this study was to conduct a trend analysis of RTS,S malaria vaccine uptake in the seven pilot regions of Ghana from 2019 to 2022. The findings are envisaged to strengthen malaria vaccine introductions in the future. Methods: A retrospective analysis was conducted on routine childhood immunisation data for 2019–2022. Coverages for the first (RTS,S1), second (RTS,S2), third (RTS,S3) and fourth (RTS,S4) doses of malaria vaccine; third dose of diphtheria, tetanus, pertussis-containing vaccine (DTP3/Penta3); first dose measles-rubella (MR1) and second dose measles-rubella (MR2) vaccines were calculated. Dropout rates and uptake gaps were estimated to assess variations in the uptake of consecutive RTS,S schedules; and the differences in the uptake of RTS,S and the comparator vaccines, respectively. Results: Nationally, the coverages of the first three doses of the RTS,S malaria vaccine rose sharply from 2019 (RTS,S1 = 54.9 %; RTS,S2 = 54.6 %; RTS,S3 = 38.6 %) through 2020 (RTS,S1 = 70.7 %; RTS,S2 = 67.4 %; RTS,S3 = 66.3 %) to peaks in 2021 (RTS,S1 = 76.0 %; RTS,S2 = 73.1 %; RTS,S3 = 74.2 %), and declined marginally in 2022 (RTS,S1 = 74.0 %; RTS,S2 = 69.9 %; RTS,S3 = 71.3 %). For the fourth dose, the low uptake in 2020 (7.5 %) was followed by a steep rise in 2021 (46.9 %) that continued, but at a reduced rate to 50.6% in 2022. The dropout rates and uptake gaps were initially high but declined consistently over the study period. Generally, the trends in vaccination coverages, and dropout rates and uptake gaps at the national level were reflected in the respective regions. Conclusion: The coverage of RTS,S malaria vaccine improved consistently over the study period despite the low uptake in the early phase of the pilot. While the decreasing dropout rates and uptake gaps may indicate improved community acceptance, strengthening immunisation service delivery is crucial in sustaining the observed trajectory.

Abstract Background Malaria remains a significant global health burden affecting millions of people, children under 5 years and pregnant women being most vulnerable. In 2019, the World Health Organization (WHO) endorsed the introduction of RTS,S/AS01 malaria vaccine as Phase IV implementation evaluation in three countries: Malawi, Kenya and Ghana. Acceptability and factors influencing vaccination coverage in implementing areas is relatively unknown. In Malawi, only 60% of children were fully immunized with malaria vaccine in Nsanje district in 2021, which is below 80% WHO target. This study aimed at exploring factors influencing uptake of malaria vaccine and identify approaches to increase vaccination. Methods In a cross-sectional study conducted in April–May, 2023, 410 mothers/caregivers with children aged 24–36 months were selected by stratified random sampling and interviewed using a structured questionnaire. Vaccination data was collected from health passports, for those without health passports, data was collected using recall history. Regression analyses were used to test association between independent variables and full uptake of malaria vaccine. Results Uptake of malaria vaccine was 90.5% for dose 1, but reduced to 87.6%, 69.5% and 41.2% for dose 2, 3, and 4 respectively. Children of caregivers with secondary or upper education and those who attended antenatal clinic four times or more had increased odds of full uptake of malaria vaccine [OR: 2.43, 95%CI 1.08–6.51 and OR: 1.89, 95%CI 1.18–3.02], respectively. Children who ever suffered side-effects following immunization and those who travelled long distances to reach the vaccination centre had reduced odds of full uptake of malaria vaccine [OR: 0.35, 95%CI 0.06–0.25 and OR: 0.30, 95%CI 0.03–0.39] respectively. Only 17% (n = 65) of mothers/caregivers knew the correct schedule for vaccination and 38.5% (n = 158) knew the correct number of doses a child was to receive. Conclusion Only RTS,S dose 1 and 2 uptake met WHO coverage targets. Mothers/caregivers had low level of information regarding malaria vaccine, especially on numbers of doses to be received and dosing schedule. The primary modifiable factor influencing vaccine uptake was mother/caregiver knowledge about the vaccine. Thus, to increase the uptake Nsanje District Health Directorate should strengthen communities’ education about malaria vaccine. Programmes to strengthen mother/caregiver knowledge should be included in scale-up of the vaccine in Malawi and across sub-Saharan Africa.

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]

Background: Malaria remains a significant global health burden affecting millions of people, children under 5 years and pregnant women being most vulnerable. In 2019, the World Health Organization (WHO) endorsed the introduction of RTS,S/AS01 malaria vaccine as Phase IV implementation evaluation in three countries: Malawi, Kenya and Ghana. Acceptability and factors influencing vaccination coverage in implementing areas is relatively unknown. In Malawi, only 60% of children were fully immunized with malaria vaccine in Nsanje district in 2021, which is below 80% WHO target. This study aimed at exploring factors influencing uptake of malaria vaccine and identify approaches to increase vaccination. Methods: In a cross-sectional study conducted in April–May, 2023, 410 mothers/caregivers with children aged 24–36 months were selected by stratified random sampling and interviewed using a structured questionnaire. Vaccination data was collected from health passports, for those without health passports, data was collected using recall history. Regression analyses were used to test association between independent variables and full uptake of malaria vaccine. Results: Uptake of malaria vaccine was 90.5% for dose 1, but reduced to 87.6%, 69.5% and 41.2% for dose 2, 3, and 4 respectively. Children of caregivers with secondary or upper education and those who attended antenatal clinic four times or more had increased odds of full uptake of malaria vaccine [OR: 2.43, 95%CI 1.08–6.51 and OR: 1.89, 95%CI 1.18–3.02], respectively. Children who ever suffered side-effects following immunization and those who travelled long distances to reach the vaccination centre had reduced odds of full uptake of malaria vaccine [OR: 0.35, 95%CI 0.06–0.25 and OR: 0.30, 95%CI 0.03–0.39] respectively. Only 17% (n = 65) of mothers/caregivers knew the correct schedule for vaccination and 38.5% (n = 158) knew the correct number of doses a child was to receive. Conclusion: Only RTS,S dose 1 and 2 uptake met WHO coverage targets. Mothers/caregivers had low level of information regarding malaria vaccine, especially on numbers of doses to be received and dosing schedule. The primary modifiable factor influencing vaccine uptake was mother/caregiver knowledge about the vaccine. Thus, to increase the uptake Nsanje District Health Directorate should strengthen communities' education about malaria vaccine. Programmes to strengthen mother/caregiver knowledge should be included in scale-up of the vaccine in Malawi and across sub-Saharan Africa. [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 Background A recent WHO recommendation for perennial malaria chemoprevention (PMC) encourages countries to adapt dose timing and number to local conditions. However, knowledge gaps on the epidemiological impact of PMC and possible combination with the malaria vaccine RTS,S hinder informed policy decisions in countries where malaria burden in young children remains high. Methods The EMOD malaria model was used to predict the impact of PMC with and without RTS,S on clinical and severe malaria cases in children under the age of two years (U2). PMC and RTS,S effect sizes were fit to trial data. PMC was simulated with three to seven doses (PMC-3-7) before the age of eighteen months and RTS,S with three doses, shown to be effective at nine months. Simulations were run for transmission intensities of one to 128 infectious bites per person per year, corresponding to incidences of

Abstract Malaria is a vector-borne parasitic disease caused by the apicomplexan protozoan parasite Plasmodium. Malaria is a significant health problem and the leading cause of socioeconomic losses in developing countries. WHO approved several antimalarials in the last 2 decades, but the growing resistance against the available drugs has worsened the scenario. Drug resistance and diversity among Plasmodium strains hinder the path of eradicating malaria leading to the use of new technologies and strategies to develop effective vaccines and drugs. A timely and accurate diagnosis is crucial for any disease, including malaria. The available diagnostic methods for malaria include microscopy, RDT, PCR, and non-invasive diagnosis. Recently, there have been several developments in detecting malaria, with improvements leading to achieving an accurate, quick, cost-effective, and non-invasive diagnostic tool for malaria. Several vaccine candidates with new methods and antigens are under investigation and moving forward to be considered for clinical trials. This article concisely reviews basic malaria biology, the parasite's life cycle, approved drugs, vaccine candidates, and available diagnostic approaches. It emphasizes new avenues of therapeutics for malaria. Graphical Abstract

Background: The world has made great strides towards beating malaria, although about half of the world population is still exposed to the risk of contracting malaria. Developing an effective malaria vaccine was a huge challenge for medical science. In 2021 the World Health Organization (WHO) approved the first malaria vaccine, RTS,S/AS01 vaccine (Mosquirix™), for widespread use. This review highlights the history of development, and the different approaches and types of malaria vaccines, and the literature to date. It covers the developmental stages of RTS,S/AS01 and recommends steps for its deployment. The review explores other potential vaccine candidates and their status, and suggests options for their further development. It also recommends future roles for vaccines in eradicating malaria. Questions remain on how RTS,S vaccine will work in widespread use and how it can best be utilized to benefit vulnerable communities. Conclusion: Malaria vaccines have been in development for almost 60 years. The RTS,S/AS01 vaccine has now been approved, but cannot be a stand-alone solution. Development should continue on promising candidates such as R21, PfSPZ and P. vivax vaccines. Multi-component vaccines may be a useful addition to other malaria control techniques in achieving eradication of malaria. [ABSTRACT FROM AUTHOR]

• The majority of RTS,S cost-effective estimates fall below the published $9.30 USD per dose price point. • RTS,S is more cost-effective in high transmission areas which have maximized bed net coverage. • Country-level costs and limitations will be influential in subsequent sub-national analyses. The World Health Organization has recommended a 4-dose schedule of the RTS,S/AS01 (RTS,S) vaccine for children in regions of moderate to high P. falciparum transmission. Faced with limited supply and finite resources, global funders and domestic malaria control programs will need to examine the relative cost-effectiveness of RTS,S and identify target areas for vaccine implementation relative to scale-up of existing interventions. Using an individual-based mathematical model of P. falciparum , we modelled the cost-effectiveness of RTS,S across a range of settings in sub-Saharan Africa, incorporating various rainfall patterns, insecticide-treated net (ITN) use, treatment coverage, and parasite prevalence bands. We compare age-based and seasonal RTS,S administration to increasing ITN usage, switching to next generation ITNs in settings experiencing insecticide-resistance, and introduction of seasonal malaria chemoprevention (SMC) in areas of seasonal transmission. For RTS,S to be the most cost-effective intervention option considered, the maximum cost per dose was less than $9.30 USD in 90.9% of scenarios. Nearly all (89.8%) values at or above $9.30 USD per dose were in settings with 60% established bed net use and / or with established SMC, and 76.3% were in the highest Pf PR 2-10 band modelled (40%). Addition of RTS,S to strategies involving 60% ITN use, increased ITN usage or a switch to PBO nets, and SMC, if eligible, still led to significant marginal case reductions, with a median of 2,653 (IQR: 1,741 to 3,966) cases averted per 100,000 people annually, and 82,270 (IQR: 54,034 to 123,105) cases averted per 100,000 fully vaccinated children (receiving at least three doses). Use of RTS,S results in reductions in malaria cases and deaths even when layered upon existing interventions. When comparing relative cost-effectiveness, scale up of ITNs, introduction of SMC, and switching to new technology nets should be prioritized in eligible settings. [ABSTRACT FROM AUTHOR]

Background: A recent WHO recommendation for perennial malaria chemoprevention (PMC) encourages countries to adapt dose timing and number to local conditions. However, knowledge gaps on the epidemiological impact of PMC and possible combination with the malaria vaccine RTS,S hinder informed policy decisions in countries where malaria burden in young children remains high. Methods: The EMOD malaria model was used to predict the impact of PMC with and without RTS,S on clinical and severe malaria cases in children under the age of two years (U2). PMC and RTS,S effect sizes were fit to trial data. PMC was simulated with three to seven doses (PMC-3-7) before the age of eighteen months and RTS,S with three doses, shown to be effective at nine months. Simulations were run for transmission intensities of one to 128 infectious bites per person per year, corresponding to incidences of < 1 to 5500 cases per 1000 population U2. Intervention coverage was either set to 80% or based on 2018 household survey data for Southern Nigeria as a sample use case. The protective efficacy (PE) for clinical and severe cases in children U2 was calculated in comparison to no PMC and no RTS,S. Results: The projected impact of PMC or RTS,S was greater at moderate to high transmission than at low or very high transmission. Across the simulated transmission levels, PE estimates of PMC-3 at 80% coverage ranged from 5.7 to 8.8% for clinical, and from 6.1 to 13.6% for severe malaria (PE of RTS,S 10–32% and 24.6–27.5% for clinical and severe malaria, respectively. In children U2, PMC with seven doses nearly averted as many cases as RTS,S, while the combination of both was more impactful than either intervention alone. When operational coverage, as seen in Southern Nigeria, increased to a hypothetical target of 80%, cases were reduced beyond the relative increase in coverage. Conclusions: PMC can substantially reduce clinical and severe cases in the first two years of life in areas with high malaria burden and perennial transmission. A better understanding of the malaria risk profile by age in early childhood and on feasible coverage by age, is needed for selecting an appropriate PMC schedule in a given setting. [ABSTRACT FROM AUTHOR]

Malaria is a vector-borne parasitic disease caused by the apicomplexan protozoan parasite Plasmodium. Malaria is a significant health problem and the leading cause of socioeconomic losses in developing countries. WHO approved several antimalarials in the last 2 decades, but the growing resistance against the available drugs has worsened the scenario. Drug resistance and diversity among Plasmodium strains hinder the path of eradicating malaria leading to the use of new technologies and strategies to develop effective vaccines and drugs. A timely and accurate diagnosis is crucial for any disease, including malaria. The available diagnostic methods for malaria include microscopy, RDT, PCR, and non-invasive diagnosis. Recently, there have been several developments in detecting malaria, with improvements leading to achieving an accurate, quick, cost-effective, and non-invasive diagnostic tool for malaria. Several vaccine candidates with new methods and antigens are under investigation and moving forward to be considered for clinical trials. This article concisely reviews basic malaria biology, the parasite's life cycle, approved drugs, vaccine candidates, and available diagnostic approaches. It emphasizes new avenues of therapeutics for malaria. [ABSTRACT FROM AUTHOR]

Abstract Background In 2019, the RTS,S/AS01E malaria vaccine was introduced on a pilot basis in six regions of Ghana by the Ministry of Health/Ghana Health Service as part of the WHO-coordinated Malaria Vaccine Implementation Programme (MVIP). This is the first time a malaria vaccination programme has been implemented in any country. This paper describes the challenges faced, and lessons learned, during the planning and early implementation of the RTS,S/AS01E vaccine in three out of the six regions that implemented the programme in Ghana. Methods Twenty-one in-depth interviews were conducted with regional and district health service managers and frontline health workers three months after the start of MVIP in May 2019. Data were coded using NVivo software version 12 and a coding framework was developed to support thematic analysis to identify the challenges and lessons learned during the RTS,S/AS01E implementation pilot, which were also categorized into the Consolidated Framework for Implementation Research (CFIR). Results Participants reported challenges related to the characteristics of the intervention, such as issues with the vaccine schedule and eligibility criteria, and challenges related to how it was implemented as a pilot programme. Additionally, major challenges were faced due to the spread of rumours leading to vaccine refusals; thus, the outer setting of the CFIR was adapted to accommodate rumours within the community context. Health service managers and frontline health workers also experienced challenges with the process of implementing RTS,S/AS01E, including inadequate sensitization and training, as well as issues with the timeline. They also experienced challenges associated with the features of the systems within which the vaccine was being implemented, including inadequate resources for cold-chain at the health facility level and transportation at the district and health facility levels. This study identified the need for a longer, more intensive and sustained delivery of contextually-appropriate sensitization prior to implementation of a programme such as MVIP. Conclusions This study identified 12 main challenges and lessons learned by health service managers and health workers during the planning and early implementation phases of the RTS,S/AS01E pilot introduction in Ghana. These findings are highly relevant to the likely scale-up of RTS,S/AS01E within Ghana and possible implementation in other African countries, as well as to other future introductions of novel vaccines.

The RTS,S malaria vaccine was recently recommended for use among children at risk in malaria endemic regions. Although significant efforts have been made to minimise malaria cases, the results of these innovations have not been totally satisfactory due to specific limitations. However, this revolutionary vaccine has a great tendency to put an end to malaria. Being the first vaccine against malaria, this commentary examines its journey from the idealisation and conception to the recommendation by the World Health Organization. The commentary also examines some of the challenges that might affect the execution of the vaccination programme in sub-Saharan Africa and other malaria endemic regions and suggest recommendations to overcome the possible them.

Background: Following the successful pilot of RTS,S malaria vaccine, it has been recommended by the WHO for prevention of Plasmodium falciparum malaria in children living in endemic areas. Despite the proven benefits of the malaria vaccine, uptake especially of the fourth dose, remains relatively low. We assessed complete uptake of RTS,S malaria vaccine among children 24-59 months and associated factors in the Sunyani Municipality of Ghana., Methods: A cross-sectional study was conducted among 361 caregivers of children aged 24-59 months in the Sunyani Municipality, who had received at least one dose of RTS,S malaria vaccine. Structured questionnaires were administered to caregivers and relevant vaccination information was extracted from the maternal and child health record books. Binary logistic regression analysis was used to determine factors associated with complete uptake of the vaccine at 95 % confidence interval (CI)., Results: Approximately 45 % (164/361) of the children had completed the RTS,S malaria vaccination schedule. Children aged 48-59 months (AOR:0.26, 95 %CI:0.09-0.76), those with caregivers who believed that children were being used for experiment (AOR:0.29, 95 %CI:0.16-0.54) or doubted the safety of the vaccine (AOR:0.27, 95 %CI:0.14-0.52) were less likely to complete the four doses. On the other hand, children of caregivers who reported vaccine shortages and travelled long distances to access immunization services (AOR:3.15, 95 %CI:1.17-8.47), and those with adequate knowledge on the malaria vaccine (AOR:1.89, 95 %CI:1.08-3.29) were more likely to complete the vaccination schedule., Conclusion: Less than half of the children who started RTS,S malaria vaccination completed the full schedule. Age of child, caregiver knowledge and perception of the malaria vaccine, and access to immunization service were associated with complete uptake of the RTS,S malaria vaccine. Strengthening caregiver education and access to immunization services could improve uptake of the subsequent doses and coverage of the fourth dose., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: The uptake trend of a new vaccine is unpredictable and may reflect the quality of introduction process and community acceptance. The objective of this study was to conduct a trend analysis of RTS,S malaria vaccine uptake in the seven pilot regions of Ghana from 2019 to 2022. The findings are envisaged to strengthen malaria vaccine introductions in the future., Methods: A retrospective analysis was conducted on routine childhood immunisation data for 2019-2022. Coverages for the first (RTS,S1), second (RTS,S2), third (RTS,S3) and fourth (RTS,S4) doses of malaria vaccine; third dose of diphtheria, tetanus, pertussis-containing vaccine (DTP3/Penta3); first dose measles-rubella (MR1) and second dose measles-rubella (MR2) vaccines were calculated. Dropout rates and uptake gaps were estimated to assess variations in the uptake of consecutive RTS,S schedules; and the differences in the uptake of RTS,S and the comparator vaccines, respectively., Results: Nationally, the coverages of the first three doses of the RTS,S malaria vaccine rose sharply from 2019 (RTS,S1 = 54.9 %; RTS,S2 = 54.6 %; RTS,S3 = 38.6 %) through 2020 (RTS,S1 = 70.7 %; RTS,S2 = 67.4 %; RTS,S3 = 66.3 %) to peaks in 2021 (RTS,S1 = 76.0 %; RTS,S2 = 73.1 %; RTS,S3 = 74.2 %), and declined marginally in 2022 (RTS,S1 = 74.0 %; RTS,S2 = 69.9 %; RTS,S3 = 71.3 %). For the fourth dose, the low uptake in 2020 (7.5 %) was followed by a steep rise in 2021 (46.9 %) that continued, but at a reduced rate to 50.6% in 2022. The dropout rates and uptake gaps were initially high but declined consistently over the study period. Generally, the trends in vaccination coverages, and dropout rates and uptake gaps at the national level were reflected in the respective regions., Conclusion: The coverage of RTS,S malaria vaccine improved consistently over the study period despite the low uptake in the early phase of the pilot. While the decreasing dropout rates and uptake gaps may indicate improved community acceptance, strengthening immunisation service delivery is crucial in sustaining the observed trajectory., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Abstract Background The currently used malaria vaccine, RTS,S, is designed based on the Plasmodium falciparum circumsporozoite protein (PfCSP). The pfcsp gene, besides having different polymorphic patterns, can vary between P. falciparum isolates due to geographical origin and host immune response. Such aspects are essential when considering the deployment of the RTS,S vaccine in a certain region. Therefore, this study assessed the genetic diversity of P. falciparum in Sudan based on the pfcsp gene by investigating the diversity at the N-terminal, central repeat, and the C-terminal regions. Methods A cross-sectional molecular study was conducted; P. falciparum isolates were collected from different health centres in Khartoum State between January and December 2019. During the study period, a total of 261 febrile patients were recruited. Malaria diagnosis was made by expert microscopists using Giemsa-stained thick and thin blood films. DNA samples were examined by the semi-nested polymerase chain reaction (PCR). Single clonal infection of the confirmed P. falciparum cases, were used to amplify the pfcsp gene. The amplified amplicons of pfcsp have been sequenced using the Sanger dideoxy method. The obtained sequences of pfcsp nucleotide diversity parameters including the numbers of haplotypes (Hap), haplotypes diversity (Hapd), the average number of nucleotide differences between two sequences (p), and the numbers of segregating sites (S) were obtained. The haplotype networks were constructed using the online tcsBU software. Natural selection theory was also tested on pfcsp using Fuand Li’s D, Fuand Li’s F statistics, and Tajima’s D test using DnaSP. Results In comparison with the different pfcsp reference strains, the Sudanese isolates showed high similarity with other African isolates. The results of the N-terminal region showed the presence of 2 different haplotypes with a Hapd of 0.425 ± 0.00727. The presence of the unique insertion of NNNGDNGREGKDEDKRDGNN was reported. The KLKQP motif was conserved in all the studied isolates. At the central repeat region, 11 haplotypes were seen with a Hapd of 0.779 ± 0.00097. The analysis of the genetic diversity in the C-terminal region showed the presence of 10 haplotypes with a Hapd of 0.457 ± 0.073. Several non-synonymous amino acids changes were also seen at the Th2R and the Th3R T-cell epitope regions including T317K, E317K, Q318E, K321N, I322K, T322K, R322K, K324Q, I327L, G352N, S354P, R355K, N356D, Q357E, and E361A. Conclusions In this study, the results indicated a high conservation at the pfcsp gene. This may further contribute in understanding the genetic polymorphisms of P. falciparum prior to the deployment of the RTS,S vaccine in Sudan.

Background: In 2019, the RTS,S/AS01E malaria vaccine was introduced on a pilot basis in six regions of Ghana by the Ministry of Health/Ghana Health Service as part of the WHO-coordinated Malaria Vaccine Implementation Programme (MVIP). This is the first time a malaria vaccination programme has been implemented in any country. This paper describes the challenges faced, and lessons learned, during the planning and early implementation of the RTS,S/AS01E vaccine in three out of the six regions that implemented the programme in Ghana. Methods: Twenty-one in-depth interviews were conducted with regional and district health service managers and frontline health workers three months after the start of MVIP in May 2019. Data were coded using NVivo software version 12 and a coding framework was developed to support thematic analysis to identify the challenges and lessons learned during the RTS,S/AS01E implementation pilot, which were also categorized into the Consolidated Framework for Implementation Research (CFIR). Results: Participants reported challenges related to the characteristics of the intervention, such as issues with the vaccine schedule and eligibility criteria, and challenges related to how it was implemented as a pilot programme. Additionally, major challenges were faced due to the spread of rumours leading to vaccine refusals; thus, the outer setting of the CFIR was adapted to accommodate rumours within the community context. Health service managers and frontline health workers also experienced challenges with the process of implementing RTS,S/AS01E, including inadequate sensitization and training, as well as issues with the timeline. They also experienced challenges associated with the features of the systems within which the vaccine was being implemented, including inadequate resources for cold-chain at the health facility level and transportation at the district and health facility levels. This study identified the need for a longer, more intensive and sustained delivery of contextually-appropriate sensitization prior to implementation of a programme such as MVIP. Conclusions: This study identified 12 main challenges and lessons learned by health service managers and health workers during the planning and early implementation phases of the RTS,S/AS01E pilot introduction in Ghana. These findings are highly relevant to the likely scale-up of RTS,S/AS01E within Ghana and possible implementation in other African countries, as well as to other future introductions of novel vaccines. [ABSTRACT FROM AUTHOR]

Abstract Background Developing thermostable vaccines is a challenge for pharmaceutical companies due to the inherent instability of biological molecules in aqueous solution. The problem is even more stringent in regions subjected to high temperatures in which protective cold chain is difficult to maintain due to a lack of infrastructure. Here, a simple, cost-effective solution to increase the thermostability of the malaria candidate vaccine RTS,S/AS01 is described. This vaccine currently needs to be stored between 2 and 8 °C due to the sensitivity of liquid AS01 to higher temperatures. The strategy was to increase thermostability by co-lyophilizing the RTS,S antigen and AS01. Methods Co-lyophilization was achieved in a solution containing 5% sucrose, 10 mM potassium phosphate and 0.0312% polysorbate 80 at pH 6.1. The physicho-chemical characteristics and immunogenic properties of the resulting solid product, called CL-vac, fresh or stored at high temperature, were compared to those of the candidate RTS,S/AS01. Results CL-vac proved to be acceptable in terms of visual appearance and physico-chemical characteristics. The structural integrity of both RTS,S and AS01 within CL-vac and its equivalence to the RTS,S/AS01 candidate vaccine were shown. Further, the stability of CL-vac was demonstrated for storage periods including 1 year at 4 °C, 1 year at 30 °C, and up to 6 months at 37 °C. In addition, CL-vac could withstand a heat excursion consisting of 1 month at 45 °C after storage for 1 year at 30 °C. Equivalence and stability were demonstrated by the various analytical tools and the immunogenicity of the samples after storage was also demonstrated in mice. Conclusions In conclusion, the co-lyophilization process appeared as a promising approach to increase RTS/AS01 vaccine thermostability.

Malaria is an illness caused by Plasmodium parasites transmitted to humans by infected mosquitoes. Of the five species that infect humans, P. falciparum exacts the highest toll in terms of human morbidity and mortality, and therefore represents a major public health threat in endemic areas. Recent advances in control efforts have reduced malaria incidence and prevalence, including rapid diagnostic testing, highly effective artemisinin combination therapy, use of insecticide-treated bednets, and indoor residual spraying. But, reductions in numbers of cases have stalled over the last few years, and incidence may have increased. As this concerning trend calls for new tools to combat the disease, the RTS,S vaccine has arrived just in time. The vaccine was created in 1987 and began pilot implementation in endemic countries in 2019. This first-generation malaria vaccine demonstrates modest efficacy against malaria illness and holds promise as a public health tool, especially for children in high-transmission areas where mortality is high.

SUMMARYMalaria remains one of the biggest health problems in the world. While significant reductions in malaria morbidity and mortality had been achieved from 2000 to 2015, the favorable trend has stalled, rather significant increases in malaria cases are seen in multiple areas. In 2022, there were 249 million estimated cases, and 608,000 malaria-related deaths, mostly in infants and children aged under 5 years, globally. Therefore, in addition to the expansion of existing anti-malarial control measures, it is critical to develop new tools, such as vaccines and monoclonal antibodies (mAbs), to fight malaria. In the last 2 years, the first and second malaria vaccines, both targeting Plasmodium falciparum circumsporozoite proteins (PfCSP), have been recommended by the World Health Organization to prevent P. falciparum malaria in children living in moderate to high transmission areas. While the approval of the two malaria vaccines is a considerable milestone in vaccine development, they have much room for improvement in efficacy and durability. In addition to the two approved vaccines, recent clinical trials with mAbs against PfCSP, blood-stage vaccines against P. falciparum or P. vivax , and transmission-blocking vaccine or mAb against P. falciparum have shown promising results. This review summarizes the development of the anti-PfCSP vaccines and mAbs, and recent topics in the blood- and transmission-blocking-stage vaccine candidates and mAbs. We further discuss issues of the current vaccines and the directions for the development of next-generation vaccines., Competing Interests: The authors declare no conflict of interest.

Background: The currently used malaria vaccine, RTS,S, is designed based on the Plasmodium falciparum circumsporozoite protein (PfCSP). The pfcsp gene, besides having different polymorphic patterns, can vary between P. falciparum isolates due to geographical origin and host immune response. Such aspects are essential when considering the deployment of the RTS,S vaccine in a certain region. Therefore, this study assessed the genetic diversity of P. falciparum in Sudan based on the pfcsp gene by investigating the diversity at the N-terminal, central repeat, and the C-terminal regions. Methods: A cross-sectional molecular study was conducted; P. falciparum isolates were collected from different health centres in Khartoum State between January and December 2019. During the study period, a total of 261 febrile patients were recruited. Malaria diagnosis was made by expert microscopists using Giemsa-stained thick and thin blood films. DNA samples were examined by the semi-nested polymerase chain reaction (PCR). Single clonal infection of the confirmed P. falciparum cases, were used to amplify the pfcsp gene. The amplified amplicons of pfcsp have been sequenced using the Sanger dideoxy method. The obtained sequences of pfcsp nucleotide diversity parameters including the numbers of haplotypes (Hap), haplotypes diversity (Hapd), the average number of nucleotide differences between two sequences (p), and the numbers of segregating sites (S) were obtained. The haplotype networks were constructed using the online tcsBU software. Natural selection theory was also tested on pfcsp using Fuand Li's D, Fuand Li's F statistics, and Tajima's D test using DnaSP. Results: In comparison with the different pfcsp reference strains, the Sudanese isolates showed high similarity with other African isolates. The results of the N-terminal region showed the presence of 2 different haplotypes with a Hapd of 0.425 ± 0.00727. The presence of the unique insertion of NNNGDNGREGKDEDKRDGNN was reported. The KLKQP motif was conserved in all the studied isolates. At the central repeat region, 11 haplotypes were seen with a Hapd of 0.779 ± 0.00097. The analysis of the genetic diversity in the C-terminal region showed the presence of 10 haplotypes with a Hapd of 0.457 ± 0.073. Several non-synonymous amino acids changes were also seen at the Th2R and the Th3R T-cell epitope regions including T317K, E317K, Q318E, K321N, I322K, T322K, R322K, K324Q, I327L, G352N, S354P, R355K, N356D, Q357E, and E361A. Conclusions: In this study, the results indicated a high conservation at the pfcsp gene. This may further contribute in understanding the genetic polymorphisms of P. falciparum prior to the deployment of the RTS,S vaccine in Sudan. [ABSTRACT FROM AUTHOR]

Abstract Background Vaccination and naturally acquired immunity against microbial pathogens may have complex interactions that influence disease outcomes. To date, only vaccine-specific immune responses have routinely been investigated in malaria vaccine trials conducted in endemic areas. We hypothesized that RTS,S/A01E immunization affects acquisition of antibodies to Plasmodium falciparum antigens not included in the vaccine and that such responses have an impact on overall malaria protective immunity. Methods We evaluated IgM and IgG responses to 38 P. falciparum proteins putatively involved in naturally acquired immunity to malaria in 195 young children participating in a case-control study nested within the African phase 3 clinical trial of RTS,S/AS01E (MAL055 NCT00866619) in two sites of different transmission intensity (Kintampo high and Manhiça moderate/low). We measured antibody levels by quantitative suspension array technology and applied regression models, multimarker analysis, and machine learning techniques to analyze factors affecting their levels and correlates of protection. Results RTS,S/AS01E immunization decreased antibody responses to parasite antigens considered as markers of exposure (MSP142, AMA1) and levels correlated with risk of clinical malaria over 1-year follow-up. In addition, we show for the first time that RTS,S vaccination increased IgG levels to a specific group of pre-erythrocytic and blood-stage antigens (MSP5, MSP1 block 2, RH4.2, EBA140, and SSP2/TRAP) which levels correlated with protection against clinical malaria (odds ratio [95% confidence interval] 0.53 [0.3–0.93], p = 0.03, for MSP1; 0.52 [0.26–0.98], p = 0.05, for SSP2) in multivariable logistic regression analyses. Conclusions Increased antibody responses to specific P. falciparum antigens in subjects immunized with this partially efficacious vaccine upon natural infection may contribute to overall protective immunity against malaria. Inclusion of such antigens in multivalent constructs could result in more efficacious second-generation multistage vaccines.

Abstract Background Leading malaria vaccine, RTS,S, is based on the circumsporozoite protein (CSP) of sporozoites. RTS,S confers partial protection against malaria in children, but efficacy wanes relatively quickly after primary immunization. Vaccine efficacy has some association with anti-CSP IgG; however, it is unclear how these antibodies function, and how functional antibodies are induced and maintained over time. Recent studies identified antibody-complement interactions as a potentially important immune mechanism against sporozoites. Here, we investigated whether RTS,S vaccine-induced antibodies could function by interacting with complement. Methods Serum samples were selected from children in a phase IIb trial of RTS,S/AS02A conducted at two study sites of high and low malaria transmission intensity in Manhiça, Mozambique. Samples following primary immunization and 5-year post-immunization follow-up time points were included. Vaccine-induced antibodies were characterized by isotype, subclass, and epitope specificity, and tested for the ability to fix and activate complement. We additionally developed statistical methods to model the decay and determinants of functional antibodies after vaccination. Results RTS,S vaccination induced anti-CSP antibodies that were mostly IgG1, with some IgG3, IgG2, and IgM. Complement-fixing antibodies were effectively induced by vaccination, and targeted the central repeat and C-terminal regions of CSP. Higher levels of complement-fixing antibodies were associated with IgG that equally recognized both the central repeat and C-terminal regions of CSP. Older age and higher malaria exposure were significantly associated with a poorer induction of functional antibodies. There was a marked decay in functional complement-fixing antibodies within months after vaccination, as well as decays in IgG subclasses and IgM. Statistical modeling suggested the decay in complement-fixing antibodies was mostly attributed to the waning of anti-CSP IgG1, and to a lesser extent IgG3. Conclusions We demonstrate for the first time that RTS,S can induce complement-fixing antibodies in young malaria-exposed children. The short-lived nature of functional responses mirrors the declining vaccine efficacy of RTS,S over time. The negative influence of age and malaria exposure on functional antibodies has implications for understanding vaccine efficacy in different settings. These findings provide insights into the mechanisms and longevity of vaccine-induced immunity that will help inform the future development of highly efficacious and long-lasting malaria vaccines.

RTS,S is the leading malaria vaccine in development, but has demonstrated only moderate protective efficacy in clinical trials. RTS,S is a virus-like particle (VLP) that uses the human hepatitis B virus as scaffold to display the malaria sporozoite antigen, circumsporozoite protein (CSP). Particle formation requires four-fold excess scaffold antigen, and as a result, CSP represents only a small portion of the final vaccine construct. Alternative VLP or nanoparticle platforms that reduce the amount of scaffold antigen and increase the amount of the target CSP antigen present in particles may enhance vaccine immunogenicity and efficacy. Here, we describe the production and characterization of a novel VLP that uses the small surface antigen (dS) of duck hepatitis B virus to display CSP. The CSP-dS fusion protein successfully formed VLPs without the need for excess scaffold antigen, and thus CSP represented a larger portion of the vaccine construct. CSP-dS formed large particles approximately 31-74 nm in size and were confirmed to display CSP on the surface. CSP-dS VLPs were highly immunogenic in mice and induced antibodies to multiple regions of CSP, even when administered at a lower vaccine dosage. Vaccine-induced antibodies demonstrated relevant functional activities, including Fc-dependent interactions with complement and Fcγ-receptors, previously identified as important in malaria immunity. Further, vaccine-induced antibodies had similar properties (epitope-specificity and avidity) to monoclonal antibodies that are protective in mouse models. Our novel platform to produce VLPs without excess scaffold protein has wide implications for the future development of vaccines for malaria and other infectious diseases.

RTS,S is the leading malaria vaccine in development, but has demonstrated only moderate protective efficacy in clinical trials. RTS,S is a virus-like particle (VLP) that uses the human hepatitis B virus as scaffold to display the malaria sporozoite antigen, circumsporozoite protein (CSP). Particle formation requires four-fold excess scaffold antigen, and as a result, CSP represents only a small portion of the final vaccine construct. Alternative VLP or nanoparticle platforms that reduce the amount of scaffold antigen and increase the amount of the target CSP antigen present in particles may enhance vaccine immunogenicity and efficacy. Here, we describe the production and characterization of a novel VLP that uses the small surface antigen (dS) of duck hepatitis B virus to display CSP. The CSP-dS fusion protein successfully formed VLPs without the need for excess scaffold antigen, and thus CSP represented a larger portion of the vaccine construct. CSP-dS formed large particles approximately 31-74 nm in size and were confirmed to display CSP on the surface. CSP-dS VLPs were highly immunogenic in mice and induced antibodies to multiple regions of CSP, even when administered at a lower vaccine dosage. Vaccine-induced antibodies demonstrated relevant functional activities, including Fc-dependent interactions with complement and Fcγ-receptors, previously identified as important in malaria immunity. Further, vaccine-induced antibodies had similar properties (epitope-specificity and avidity) to monoclonal antibodies that are protective in mouse models. Our novel platform to produce VLPs without excess scaffold protein has wide implications for the future development of vaccines for malaria and other infectious diseases. [ABSTRACT FROM AUTHOR]

Radiation‐attenuated sporozoites induce sterilizing immunity and remain the 'gold standard' for malaria vaccine development. Despite practical challenges in translating these whole sporozoite vaccines to large‐scale intervention programmes, they have provided an excellent platform to dissect the immune responses to malaria pre‐erythrocytic (PE) stages, comprising both sporozoites and exoerythrocytic forms. Investigations in rodent models have provided insights that led to the clinical translation of various vaccine candidates—including RTS,S/AS01, the most advanced candidate currently in a trial implementation programme in three African countries. With advances in immunology, transcriptomics and proteomics, and application of lessons from past failures, an effective, long‐lasting and wide‐scale malaria PE vaccine remains feasible. This review underscores the progress in PE vaccine development, focusing on our understanding of host‐parasite immunological crosstalk in the tissue environments of the skin and the liver. We highlight possible gaps in the current knowledge of PE immunity that can impact future malaria vaccine development efforts. [ABSTRACT FROM AUTHOR]

Introduction: An effective vaccine against malaria forms a global health priority. Both naturally acquired immunity and sterile protection induced by irradiated sporozoite immunization were described decades ago. Still no vaccine exists that sufficiently protects children in endemic areas. Identifying immunological correlates of vaccine efficacy can inform rational vaccine design and potentially accelerate clinical development. Areas covered: We discuss recent research on immunological correlates of malaria vaccine efficacy, including: insights from state-of-the-art omics platforms and systems vaccinology analyses; functional anti-parasitic assays; pre-immunization predictors of vaccine efficacy; and comparison of correlates of vaccine efficacy against controlled human malaria infections (CHMI) and against naturally acquired infections. Expert Opinion: Effective vaccination may be achievable without necessarily understanding immunological correlates, but the relatively disappointing efficacy of malaria vaccine candidates in target populations is concerning. Hypothesis-generating omics and systems vaccinology analyses, alongside assessment of pre-immunization correlates, have the potential to bring about paradigm-shifts in malaria vaccinology. Functional assays may represent in vivo effector mechanisms, but have scarcely been formally assessed as correlates. Crucially, evidence is still meager that correlates of vaccine efficacy against CHMI correspond with those against naturally acquired infections in target populations. Finally, the diversity of immunological assays and efficacy endpoints across malaria vaccine trials remains a major confounder. [ABSTRACT FROM AUTHOR]

A safe and effective vaccine will likely be necessary for the control or eradication of malaria which kills 400,000 annually. Our most advanced vaccine candidate to date is RTS,S which is based on the Plasmodium falciparum circumsporozoite protein (PfCSP) of the malaria parasite. However, protection by RTS,S is incomplete and short-lived. Here we summarize results from recent clinical trials of RTS,S and critically evaluate recent studies that aim to understand the correlates of protective immunity and why vaccine-induced protection is short-lived. In particular, recent systems serology studies have highlighted a key role for the necessity of inducing functional antibodies. In-depth analyses of immune responses to CSP in both mouse models and vaccinated humans have also highlighted difficulties in generating the maintaining high-quality antibody responses. Finally, in recent years biophysical and structural studies of antibody binding to PfCSP have led to a better understanding of how highly potent antibodies can block infection, which can inform vaccine design. We highlight how both structure-guided vaccine design and a better understanding of the immune response to PfCSP can inform a second generation of PfCSP-based vaccines stimulating a broader range of protective targets within PfCSP. [ABSTRACT FROM AUTHOR]

The RTS,S/AS02A malaria vaccine is based on the Plasmodium falciparum circumsporozoite protein (PfCSP), which is O-fucosylated on the sporozoite surface. We determined whether RTS,S/AS02A-induced immunoglobulin G (IgG) antibodies recognize vaccine-like nonfucosylated PfCSP better than native-like fucosylated PfCSP. Similar to previous vaccine trials, RTS,S/AS02A vaccination induced high anti-PfCSP IgG levels associated with malaria protection. IgG recognition of nonfucosylated and fucosylated PfCSP was equivalent, suggesting that PfCSP fucosylation does not affect antibody recognition. Clinical Trials Registration. NCT00197041., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract Background The RTS,S/AS01E vaccine provides partial protection against malaria in African children, but immune responses have only been partially characterized and do not reliably predict protective efficacy. We aimed to evaluate comprehensively the immunogenicity of the vaccine at peak response, the factors affecting it, and the antibodies associated with protection against clinical malaria in young African children participating in the multicenter phase 3 trial for licensure. Methods We measured total IgM, IgG, and IgG1–4 subclass antibodies to three constructs of the Plasmodium falciparum circumsporozoite protein (CSP) and hepatitis B surface antigen (HBsAg) that are part of the RTS,S vaccine, by quantitative suspension array technology. Plasma and serum samples were analyzed in 195 infants and children from two sites in Ghana (Kintampo) and Mozambique (Manhiça) with different transmission intensities using a case-control study design. We applied regression models and machine learning techniques to analyze immunogenicity, correlates of protection, and factors affecting them. Results RTS,S/AS01E induced IgM and IgG, predominantly IgG1 and IgG3, but also IgG2 and IgG4, subclass responses. Age, site, previous malaria episodes, and baseline characteristics including antibodies to CSP and other antigens reflecting malaria exposure and maternal IgGs, nutritional status, and hemoglobin concentration, significantly affected vaccine immunogenicity. We identified distinct signatures of malaria protection and risk in RTS,S/AS01E but not in comparator vaccinees. IgG2 and IgG4 responses to RTS,S antigens post-vaccination, and anti-CSP and anti-P. falciparum antibody levels pre-vaccination, were associated with malaria risk over 1-year follow-up. In contrast, antibody responses to HBsAg (all isotypes, subclasses, and timepoints) and post-vaccination IgG1 and IgG3 to CSP C-terminus and NANP were associated with protection. Age and site affected the relative contribution of responses in the correlates identified. Conclusions Cytophilic IgG responses to the C-terminal and NANP repeat regions of CSP and anti-HBsAg antibodies induced by RTS,S/AS01E vaccination were associated with malaria protection. In contrast, higher malaria exposure at baseline and non-cytophilic IgG responses to CSP were associated with disease risk. Data provide new correlates of vaccine success and failure in African children and reveal key insights into the mode of action that can guide development of more efficacious next-generation vaccines.

The RTS,S/AS01 malaria vaccine (Mosquirix) reduces the incidence of Plasmodium falciparum malaria and is intended for routine administration to infants in Sub-Saharan Africa. We evaluated the immunogenicity and safety of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix) and human rotavirus vaccine (HRV; Rotarix) when co-administered with RTS,S/AS01 (www.clinicaltrials.gov NCT01345240) in African infants. 705 healthy infants aged 8–12 weeks were randomized to receive three doses of either RTS,S/AS01 or licensed hepatitis B (HBV; Engerix B) vaccine (control) co-administered with diphtheria-tetanus-acellular pertussis-Haemophilus influenzae type-b-conjugate vaccine (DTaP/Hib) and trivalent oral poliovirus vaccine at 8–12-16 weeks of age, because DTaP/Hib was not indicated before 8 weeks of age. The vaccination schedule can still be considered broadly applicable because it was within the age range recommended for EPI vaccination. PHiD-CV or HRV were either administered together with the study vaccines, or after a 2-week interval. Booster doses of PHiD-CV and DTaP/Hib were administered at age 18 months. Non-inferiority of anti-HBV surface antigen antibody seroprotection rates following co-administration with RTS,S/AS01 was demonstrated compared to the control group (primary objective). Pre-specified non-inferiority criteria were reached for PHiD-CV (for 9/10 vaccine serotypes), HRV, and aP antigens co-administered with RTS,S/AS01 as compared to HBV co-administration (secondary objectives). RTS,S/AS01 induced a response to circumsporozoite protein in all groups. Pain and low grade fever were reported more frequently in the PHiD-CV group co-administered with RTS,S/AS01 than PHiD-CV co-administered with HBV. No serious adverse events were considered to be vaccine-related. RTS,S/AS01 co-administered with pediatric vaccines had an acceptable safety profile. Immune responses to RTS,S/AS01 and to co-administered PHiD-CV, pertussis antigens and HRV were satisfactory.

Background: Developing thermostable vaccines is a challenge for pharmaceutical companies due to the inherent instability of biological molecules in aqueous solution. The problem is even more stringent in regions subjected to high temperatures in which protective cold chain is difficult to maintain due to a lack of infrastructure. Here, a simple, cost-effective solution to increase the thermostability of the malaria candidate vaccine RTS,S/AS01 is described. This vaccine currently needs to be stored between 2 and 8 °C due to the sensitivity of liquid AS01 to higher temperatures. The strategy was to increase thermostability by co-lyophilizing the RTS,S antigen and AS01. Methods: Co-lyophilization was achieved in a solution containing 5% sucrose, 10 mM potassium phosphate and 0.0312% polysorbate 80 at pH 6.1. The physicho-chemical characteristics and immunogenic properties of the resulting solid product, called CL-vac, fresh or stored at high temperature, were compared to those of the candidate RTS,S/AS01. Results: CL-vac proved to be acceptable in terms of visual appearance and physico-chemical characteristics. The structural integrity of both RTS,S and AS01 within CL-vac and its equivalence to the RTS,S/AS01 candidate vaccine were shown. Further, the stability of CL-vac was demonstrated for storage periods including 1 year at 4 °C, 1 year at 30 °C, and up to 6 months at 37 °C. In addition, CL-vac could withstand a heat excursion consisting of 1 month at 45 °C after storage for 1 year at 30 °C. Equivalence and stability were demonstrated by the various analytical tools and the immunogenicity of the samples after storage was also demonstrated in mice. Conclusions: In conclusion, the co-lyophilization process appeared as a promising approach to increase RTS/AS01 vaccine thermostability. [ABSTRACT FROM AUTHOR]

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Malaria, caused by Plasmodium species, remains a major global health concern, causing millions of deaths annually. While the introduction of the RTS,S vaccine has shown promise, there is a pressing need for more effective vaccines due to the emergence of drug-resistant parasites and insecticide-resistant vectors. However, the complex life cycle and genetic diversity of the parasite, technical obstacles, limited funding, and the impact of the 2019 pandemic have hindered progress in malaria vaccine development. This review focuses on advancements in malaria vaccine development, particularly the ongoing clinical trials targeting antigens from different stages of the Plasmodium life cycle. Additionally, we discuss the rationale, strategies, and challenges associated with vaccine design, aiming to enhance the immune response and protective efficacy of vaccine candidates. A cost-effective and multistage vaccine could hold the key to controlling and eradicating malaria.

Although RTS,S remains the most advanced malaria vaccine, the factors influencing differences in vaccine immunogenicity or efficacy between individuals or populations are still poorly characterised. The analyses of genetic determinants of immunogenicity have previously been restricted by relatively small sample sizes from individual trials. Here we combine data from six Phase II RTS,S trials and evaluate the relationship between HLA allele groups and RTS,S-mediated protection in controlled human malaria infections (CHMI), using multivariate logistic or linear regression. We observed significant associations between three allele groups (HLA-A ∗ 01, HLA-B ∗ 08, and HLA-DRB1 ∗ 15/ ∗ 16) and protection, while another three allele groups (HLA-A ∗ 03, HLA-B ∗ 53, and HLA-DRB1 ∗ 07) were significantly associated with lack of protection. It is noteworthy that these ‘protective’ allele groups are thought to be at a lower prevalence in sub-Saharan African populations than in the UK or USA where these Phase II trials occurred. Taken together, the analyses presented here give an indication that HLA genotype may influence RTS,S-mediated protective efficacy against malaria infection. [ABSTRACT FROM AUTHOR]

The RTS,S candidate malaria vaccine can protect against controlled human malaria infection (CHMI), but how protection is achieved remains unclear. Here, we have analyzed longitudinal peripheral blood transcriptome and immunogenicity data from a clinical efficacy trial in which healthy adults received three RTS,S doses 4 weeks apart followed by CHMI 2 weeks later. Multiway partial least squares discriminant analysis (N-PLS-DA) of transcriptome data identified 110 genes that could be used in predictive models of protection. Among the 110 genes, 42 had known immune-related functions, including 29 that were related to the NF-κB-signaling pathway and 14 to the IFN-γ-signaling pathway. Post-dose 3 serum IFN-γ concentrations were also correlated with protection; and N-PLS-DA of IFN-γ-signaling pathway transcriptome data selected almost all (44/45) of the representative genes for predictive models of protection. Hence, the identification of the NF-κB and IFN-γ pathways provides further insight into how vaccine-mediated protection may be achieved. [ABSTRACT FROM AUTHOR]

Background RTS,S/AS01 is a safe and moderately efficacious vaccine considered for implementation in endemic Africa. Model predictions of impact and cost-effectiveness of this new intervention could aid in country adoption decisions. Methods The impact of RTS,S was assessed in 43 countries using an ensemble of models of Plasmodium falciparum epidemiology. Informed by the 32 months follow-up data from the phase 3 trial, vaccine effectiveness was evaluated at country levels of malaria parasite prevalence, coverage of control interventions and immunization. Benefits and costs of the program incremental to routine malaria control were evaluated for a four dose schedule: first dose administered at six months, second and third - before 9 months, and fourth dose at 27 months of age. Sensitivity analyses around vaccine properties, transmission, and economic inputs were conducted. Results If implemented in all 43 countries the vaccine has the potential to avert 123 (117; 129) million malaria episodes over the first 10 years. Burden averted averages 18,413 (range of country median estimates 156–40,054) DALYs per 100,000 fully vaccinated children with much variation across settings primarily driven by differences in transmission intensity. At a price of $5 per dose program costs average $39.8 per fully vaccinated child with a median cost-effectiveness ratio of $188 (range $78–$22,448) per DALY averted; the ratio is lower by one third - $136 (range $116–$220) - in settings where parasite prevalence in children aged 2–10 years is at or above 10%. Conclusion RTS,S/AS01 has the potential to substantially reduce malaria burden in children across Africa. Conditional on assumptions on price, coverage, and vaccine properties, adding RTS,S to routine malaria control interventions would be highly cost-effective. Implementation decisions will need to further consider feasibility of scaling up existing control programs, and operational constraints in reaching children at risk with the schedule. [ABSTRACT FROM AUTHOR]