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Vaccination against malariaVaccination against malaria is an old dream that reemerged in 2015 with the European Medicines Agency’s favourable opinion on a first antimalarial vaccine, RTS,S/AS01. Six years later, the World Health Organization (WHO) is advising a wide deployment of this vaccine in sub-Saharan Africa and in regions with high and moderate transmission where Plasmodium falciparum circulates. This follows favourable results from the pilot programme in Ghana, Kenya and Malawi involving over 800,000 children since 2019. This article addresses the objectives and main vaccine candidates targeting the different stages of parasite development, highlighting the progress and limitations of these different approaches. The RTS,S saga has been a milestone in vaccine development, with a first-generation vaccine recommended by the WHO for use in children over 5 months of age in sub-Saharan Africa and other areas of moderate to high transmission of P. falciparum malaria, in combination with other prevention measures. Research efforts continue to better understand the correlates of protection. With advances in vaccine platforms, new multi-antigen, multi-stage, and even multi-species ap-proaches might emerge and brighten the horizon for malaria control.Vaccination contre le paludismeL’espoir d’une vaccination contre le paludisme commence à se dessiner concrètement depuis 2015 avec l’avis favorable de l’Agence européenne du médicament sur un premier vaccin antipaludique, RTS,S/AS01. Six ans plus tard, l’Organisation mondiale de la santé (OMS) conseille un large déploiement de ce vaccin en Afrique subsaharienne et dans les régions à transmission forte et modérée où circule Plasmodium falciparum. Cette décision fait suite aux résultats favorables du programme pilote réalisé au Ghana, au Kenya et au Malawi sur plus de 800 000 enfants depuis 2019. Cet article décrit les objectifs et les principaux candidats vaccinaux ciblant les différents stades de développement du parasite, en soulignant les progrès et les limites de ces différentes approches. L’épopée RTS,S a été une étape clé dans le développement vaccinal, avec un vaccin de première génération recommandé par l’OMS chez les enfants de plus de 5 mois en Afrique subsaharienne et dans d’autres régions où la transmission du paludisme à P. falciparum est modérée ou forte, en association avec les autres mesures de prévention. Les efforts de recherche continuent pour mieux comprendre les corrélats de protection. Grâce aux progrès des plateformes vaccinales, de nouvelles approches multi-antigéniques, multistades, voire multi-espèces pourraient voir le jour et éclaircir l’horizon de la lutte contre le paludisme.

Le vaccin antipaludique RTS,S/AS01 a reçu un avis scientifique favorable de l’Agence Européenne des Médicaments (EMA) en Juillet 2015. L’Organisation Mondiale de la Santé (OMS) a recommandé l’introduction pilote de ce vaccin chez des enfants âgés d’au moins 5 mois en utilisant un schéma de vaccination comprenant 3 doses initiales espacées d’au moins un mois et une 4ème dose administrée 15 à 18 mois après la 3ème dose. Des essais cliniques et des modèles mathématiques ont montré que la protection partielle contre le paludisme conférée par le vaccin RTS,S/AS01 pourrait avoir un impact substantiel sur la santé publique si le vaccin est utilisé en association avec d’autres mesures de lutte antipaludique, en particulier dans les zones hautement endémiques. L’impact le plus important a été observé chez les enfants âgés de 5 mois ou plus ayant reçu 4 doses de RTS,S/AS01. Le vaccin sera ensuite évalué en situation réelle afin de déterminer son impact sur la mortalité, son innocuité dans le cadre d’une vaccination de routine, et la faisabilité opérationnelle d’administrer 4 doses du vaccin dont certaines nécessitant de nouveaux contacts dans le calendrier de vaccination. En cas de succès, cela permettra une mise en œuvre à plus grande échelle.

Recent advances in mosquito eradication and antimalarial treatments have reduced the malaria burden only modestly. An effective malaria vaccine remains a high priority, but its development has several challenges. Among many potential candidates, the RTS,S/AS01 vaccine (Mosquirix ) remains the leading candidate. This review aims to understand the advances in the RTS,S/AS01 vaccine, and future comments regarding the vaccine's effectiveness in malaria eradication. Literature review for the past five decades was performed searching PubMed, EMBASE Ovid, and Cochrane Library, with using the following search items: (\"malaria\" OR \"WHO's malaria\" OR \"Plasmodium falciparum\" OR \"RTS,S\" OR \"RTS,S/AS01\" OR \"RTS,S/AS02\" OR \"pre-erythrocytic malaria\" OR \"circumsporozoite\" OR \"Mosquirix\") AND (\"vaccine\" OR \"vaccination\"). RTS,S/AS01, a recombinant pre-erythrocytic vaccine containing surface-protein (circumsporozoite) antigen, is safe, well-tolerated, and immunogenic in children. Three doses, along with a booster, have a modest efficacy of about 36% in children (age 5-17 months) and about 26% in infants (age 6-12 weeks) against clinical malaria during a 48-month follow-up. However, the efficacy varies among population subgroups and with the parasite strain, it reduces without a booster and offers protection for a limited duration. Because of its potential cost-effectiveness and positive public health effect, the vaccine is being investigated in a pilot program for mortality benefits and broader deployment. The RTS,S/AS01 vaccine prevents malaria; however, it should be considered another addition to the malaria-control program and not as an eradication tool because of its relatively low to modest efficacy.

Background While Ghana has a good track record in the Expanded Programme on Immunization, there are substantial challenges with regards to subsequent vaccinations, particularly after the first year of life of the child. Given that the last dose of the RTS, S/AS01 E vaccine against malaria is administered at 24 months, there is a high likelihood of default. Hence, it is imperative to understand the dynamics and reasons for the defaults to enable the development of effective implementation strategies. This study explored why caregivers default on the RTS, S/AS01 E vaccine from the perspective of health service providers and caregivers. Methods This study employed an exploratory, descriptive approach. Using a purposive sampling technique, caregivers who defaulted and health service providers directly involved in the planning and delivery of the RTS, S/AS01 E vaccine at the district level were recruited. A total of five health service providers and 30 mothers (six per FGD) participated in this study. Data analysis was done using NVivo-12 following Collaizi’s thematic framework for qualitative analysis. The study relies on the Standards for Reporting Qualitative Research. Results Reasons for defaulting included the overlap of timing of the last dose and the child starting school, disrespectful attitudes of some health service providers, concerns about adverse side effects and discomforts, travel out of the implementing district, the perception that the vaccines are too many, and lack of support from partners. Conclusion To reduce the occurrence of defaulting on the RTS, S/AS01 E  vaccine programme, stakeholders must reconsider the timing of the last dose of the vaccine. The schedule of the RTS, S/AS01 E vaccine should be aligned with the established EPI schedule of Ghana. This will significantly limit the potential of defaults, particularly for the last dose. Also, the findings from this study underscore a need to encourage male partner involvement in the RTS, S/AS01 E vaccine programme. Health promotion programmes could be implemented to raise caregivers’ awareness of potential adverse reactions and discomforts—this is necessary to prepare the caregiver for the vaccine process psychologically.

The international GNSS service (IGS) real-time service (RTS) provides orbit and clock corrections for the global navigation satellite system (GNSS) via the internet. RTS is widely used for real-time, precise positioning and its data is transmitted via the internet. Intermittent data loss can occur and cause positioning accuracy degradation. RTS data has a discontinuity when the issue of data (IOD) changes every two hours. If the signal loss occurs immediately after the IOD change, then the performance of the RTS prediction degrades significantly. We propose an adjustment method to make the RTS data across the IOD change, which makes it possible to use long RTS data for building a prediction model. The proposed adjustment method is combined with a long-short-term memory (LSTM) network to improve long-period prediction accuracy. Experiments with GPS and RTS were performed to evaluate the RTS orbit prediction accuracy. The LSTM with the IOD adjustment outperforms other polynomial prediction methods, and the positioning accuracy with the predicted RTS orbit correction shows a significant improvement.

High−precision and robust localization is critical for intelligent vehicle and transportation systems, while the sensor signal loss or variance could dramatically affect the localization performance. The vehicle localization problem in an environment with Global Navigation Satellite System (GNSS) signal errors is investigated in this study. The error state Kalman filtering (ESKF) and Rauch–Tung–Striebel (RTS) smoother are integrated using the data from Inertial Measurement Unit (IMU) and GNSS sensors. A segmented RTS smoothing algorithm is proposed in order to estimate the error state, which is typically close to zero and mostly linear, which allows more accurate linearization and improved state estimation accuracy. The proposed algorithm is evaluated using simulated GNSS signals with and without signal errors. The simulation results demonstrate its superior accuracy and stability for state estimation. The designed ESKF algorithm yielded an approximate 3% improvement in long straight line and turning scenarios compared to classical EKF algorithm. Additionally, the ESKF−RTS algorithm exhibited a 10% increase in the localization accuracy compared to the ESKF algorithm. In the double turning scenarios, the ESKF algorithm resulted in an improvement of about 50% in comparison to the EKF algorithm, while the ESKF−RTS algorithm improved by about 50% compared to the ESKF algorithm. These results indicated that the proposed ESKF−RTS algorithm is more robust and provides more accurate localization.

Background Following a 30-year development process, RTS,S/AS01 E (GSK, Belgium) is the first malaria vaccine to reach Phase IV assessments. The World Health Organization-commissioned Malaria Vaccine Implementation Programme (MVIP) is coordinating the delivery of RTS,S/AS01 E through routine national immunization programmes in areas of 3 countries in sub-Saharan Africa. The first doses were given in the participating MVIP areas in Malawi on 23 April, Ghana on 30 April, and Kenya on 13 September 2019. The countries participating in the MVIP have little or no baseline incidence data on rare diseases, some of which may be associated with immunization, a deficit that could compromise the interpretation of possible adverse events reported following the introduction of a new vaccine in the paediatric population. Further, effects of vaccination on malaria transmission, existing malaria control strategies, and possible vaccine-mediated selective pressure on Plasmodium falciparum variants, could also impact long-term malaria control. To address this data gap and as part of its post-approval commitments, GSK has developed a post-approval plan comprising of 4 complementary Phase IV studies that will evaluate safety, effectiveness and impact of RTS,S/AS01 E through active participant follow-up in the context of its real-life implementation. Methods EPI-MAL-002 (NCT02374450) is a pre-implementation safety surveillance study that is establishing the background incidence rates of protocol-defined adverse events of special interest. EPI-MAL-003 (NCT03855995) is an identically designed post-implementation safety and vaccine impact study. EPI-MAL-005 (NCT02251704) is a cross-sectional pre- and post-implementation study to measure malaria transmission intensity and monitor the use of other malaria control interventions in the study areas, and EPI-MAL-010 (EUPAS42948) will evaluate the P. falciparum genetic diversity in the periods before and after vaccine implementation. Conclusion GSK’s post-approval plan has been designed to address important knowledge gaps in RTS,S/AS01 E vaccine safety, effectiveness and impact. The studies are currently being conducted in the MVIP areas. Their implementation has provided opportunities and posed challenges linked to conducting large studies in regions where healthcare infrastructure is limited. The results from these studies will support ongoing evaluation of RTS,S/AS01 E ’s benefit-risk and inform decision-making for its potential wider implementation across sub-Saharan Africa. Graphic abstract

Background A recent trial of 5920 children in Burkina Faso and Mali showed that the combination of seasonal vaccination with the RTS,S/AS01 E malaria vaccine (primary series and two seasonal boosters) and seasonal malaria chemoprevention (four monthly cycles per year) was markedly more effective than either intervention given alone in preventing clinical malaria, severe malaria, and deaths from malaria. Methods In order to help optimise the timing of these two interventions, trial data were reanalysed to estimate the duration of protection against clinical malaria provided by RTS,S/AS01 E when deployed seasonally, by comparing the group who received the combination of SMC and RTS,S/AS01 E with the group who received SMC alone. The duration of protection from SMC was also estimated comparing the combined intervention group with the group who received RTS,S/AS01 E alone. Three methods were used: Piecewise Cox regression, Flexible parametric survival models and Smoothed Schoenfeld residuals from Cox models, stratifying on the study area and using robust standard errors to control for within-child clustering of multiple episodes. Results The overall protective efficacy from RTS,S/AS01 E over 6 months was at least 60% following the primary series and the two seasonal booster doses and remained at a high level over the full malaria transmission season. Beyond 6 months, protective efficacy appeared to wane more rapidly, but the uncertainty around the estimates increases due to the lower number of cases during this period (coinciding with the onset of the dry season). Protection from SMC exceeded 90% in the first 2–3 weeks post-administration after several cycles, but was not 100%, even immediately post-administration. Efficacy begins to decline from approximately day 21 and then declines more sharply after day 28, indicating the importance of preserving the delivery interval for SMC cycles at a maximum of four weeks. Conclusions The efficacy of both interventions was highest immediately post-administration. Understanding differences between these interventions in their peak efficacy and how rapidly efficacy declines over time will help to optimise the scheduling of SMC, malaria vaccination and the combination in areas of seasonal transmission with differing epidemiology, and using different vaccine delivery systems. Trial registration The RTS,S-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT03143218