Spatiotemporal Dynamic of the RTS,S/AS01 Malaria Vaccine Target Antigens in Senegal.
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SUBMITTER: Diallo MA
PROVIDER: S-EPMC8641351 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
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Spatiotemporal Dynamic of the RTS,S/AS01 Malaria Vaccine Target Antigens in Senegal.
Diallo Mamadou Alpha MA L'Ollivier Coralie C Diongue Khadim K Badiane Aida Sadikh AS Kodio Aly A Tall Mamadou Lamine ML Sy Mouhamad M Seck Mame Cheikh MC Sene Doudou D Ndiaye Mouhamadou M Fall Fatou Ba FB Ranque Stéphane S Ndiaye Daouda D
The American journal of tropical medicine and hygiene 20211011 6
The RTS,S/AS01 malaria vaccine confers only moderate protection against malaria. Evidence suggests that the effectiveness of the RTS,S/AS01 vaccine depends upon the parasite population genetics, specifically regarding the circumsporozoite protein haplotypes in the population. We investigated Plasmodium falciparum circumsporozoite protein (PfCSP) gene sequences from two endemic sites in 2018 in Senegal. The PfCSP sequences were compared with those retrieved from the Pf3k genome database. In the c ...[more]
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Project description:BackgroundThe World Health Organization (WHO) recommended widespread use of the RTS,S/AS01 (RTS,S) malaria vaccine among children residing in regions of moderate to high malaria transmission. This recommendation is informed by RTS,S evidence, including findings from the pilot rollout of the vaccine in Ghana, Kenya, and Malawi. This study estimates the incremental costs of introducing and delivering the malaria vaccine within routine immunization programs in the context of malaria vaccine pilot introduction, to help inform decision-making.MethodsAn activity-based, retrospective costing was conducted from the governments' perspective. Vaccine introduction and delivery costs supported by the donors during the pilot introduction were attributed as costs to the governments under routine implementation. Detailed resource use data were extracted from the pilot program expenditure and activity reports for 2019-2021. Primary data from representative health facilities were collected to inform recurrent operational and service delivery costs.Costs were categorized as introduction or recurrent costs. Both financial and economic costs were estimated and reported in 2020 USD. The cost of donated vaccine doses was evaluated at $2, $5 and $10 per dose and included in the economic cost estimates. Financial costs include the procurement add on costs for the donated vaccines and immunization supplies, along with other direct expenses.FindingsAt a vaccine price of $5 per dose, the incremental cost per dose administered across countries ranges from $2.30 to $3.01 (financial), and $8.28 to $10.29 (economic). The non-vaccine cost of delivery ranges between $1.04 and $2.46 (financial) and $1.52 and $4.62 (economic), by country. Considering only recurrent costs, the non-vaccine cost of delivery per dose ranges between $0.29 and $0.89 (financial) and $0.59 and $2.29 (economic), by country. Introduction costs constitute between 33% and 71% of total financial costs. Commodity and procurement add-on costs are the main cost drivers of total cost across countries. Incremental resource needs for implementation are dependent on country's baseline immunization program capacity constraints.InterpretationThe financial costs of introducing RTS,S are comparable with costs of introducing other new vaccines. Country resource requirements for malaria vaccine introduction are most influenced by vaccine price and potential donor funding for vaccine purchases and introduction support.
| S-EPMC9946791 | biostudies-literature
Project description:BackgroundRTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009-2014 phase III trial (MALARIA-055, NCT00866619), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted.MethodsWe implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6-12 weeks) and children (5-17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation.ResultsVaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner.ConclusionsVegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called "dambos" which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context.Trial registrationEfficacy of GSK Biologicals' Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009.
| S-EPMC7291743 | biostudies-literature
Project description:BackgroundThe RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus.MethodsWe used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination.ResultsIn the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy.ConclusionsThese results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).
| S-EPMC4762279 | biostudies-literature
Project description:BackgroundThe candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial.MethodsWe administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed.ResultsThe incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222).ConclusionsThe RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).
| S-EPMC10915853 | biostudies-literature
Project description:BackgroundThe candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules.MethodsWe conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 vaccine or a rabies (control) vaccine. The end point was clinical malaria (temperature of ≥37.5°C and infection with Plasmodium falciparum of >2500 parasites per cubic millimeter). In an analysis that was not prespecified, the malaria exposure of each child was estimated with the use of information on the prevalence of malaria among residents within a 1-km radius of the child's home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group.ResultsOver 7 years of follow-up, we identified 1002 episodes of clinical malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes among 224 children randomly assigned to the control group. The vaccine efficacy, as assessed by negative binomial regression, was 4.4% (95% confidence interval [CI], -17.0 to 21.9; P=0.66) in the intention-to-treat analysis and 7.0% (95% CI, -14.5 to 24.6; P=0.52) in the per-protocol analysis. Vaccine efficacy waned over time (P=0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children with higher-than-average exposure to malaria parasites (intention-to-treat analysis: -43.5%; 95% CI, -100.3 to -2.8 [P=0.03]; per-protocol analysis: -56.8%; 95% CI, -118.7 to -12.3 [P=0.008]).ConclusionsA three-dose vaccination with RTS,S/AS01 was initially protective against clinical malaria, but this result was offset by rebound in later years in areas with higher-than-average exposure to malaria parasites. (Funded by the PATH Malaria Vaccine Initiative and others; ClinicalTrials.gov number, NCT00872963.).
| S-EPMC4962898 | biostudies-literature
Project description:RTS,S/AS01 (Mosquirix®) is a vaccine against malaria caused by Plasmodium falciparum. In a phase 3 trial, RTS,S/AS01 showed vaccine efficacy against clinical malaria, severe malaria and malaria hospitalization, with an acceptable safety and tolerability profile, in children aged 6 weeks to 17 months; the vaccine efficacy was greater in children than in infants and waned over time. In another phase 3 trial, RTS,S/AS01 was noninferior to seasonal malaria chemoprevention in children. WHO recommends a 4-dose schedule of RTS,S/AS01 for the prevention of P. falciparum malaria in children from 5 months of age living in regions with moderate to high malaria transmission, with an optional 5-dose schedule for areas with highly seasonal malaria transmission. First results from large pilot implementation in Africa show that RTS,S/AS01 has a favourable safety profile, increases equity in access to malaria prevention, is highly cost effective, can be delivered through routine national immunization programmes and substantially reduces severe malaria burden.Supplementary informationThe online version contains supplementary material available at 10.1007/s40267-022-00937-3.
| S-EPMC9449949 | biostudies-literature
Project description:BackgroundIn the phase III RTS,S /AS01 trial, significant heterogeneity in efficacy of the vaccine across study sites was seen. Question on whether variations in socio - economic status (SES) of participant contributed to the heterogeinity of the vaccine efficacy (VE) remains unknown.MethodsData from the Phase III RTS,S /AS01 trial in children aged 5-17 months in Kintampo were re-analysed. SES of each child was derived from the Kintampo Health and Demographic Surveillance System, using principal component analysis of household assets. Extended Cox regression was used to estimate the interaction between RTS,S/AS01 VE and household SES.ResultsProtective efficacy of the RTS,S/AS0 vaccine significantly varied by participant's household SES, thus increase in household SES was associated with an increase in protective efficacy (P-value = 0.0041). Effect modification persisted after adjusting for age at first vaccination, gender, distance from community to the health facility, child's haemoglobin level, household size, place of residence and mothers' educational level.ConclusionHousehold SES may be a proxy for malaria transmission intensity. The study showed a significant modification of the RTS,S/AS01 malaria vaccine efficacy by the different levels of child's household socio - economic status.Trial registrationEfficacy of GSK Biologicals' candidate malaria vaccine (25049) against malaria disease in infants and children in Africa. NCT00866619 prospectively registered on 20 March 2009.
| S-EPMC7845116 | biostudies-literature
Project description:RTS,S/AS01 malaria vaccine received a favorable scientific opinion from the European Medicines Agency (EMA) in July 2015. The World Health Organization (WHO) recommended the pilot introduction of this vaccine in children aged 5 months or older using a vaccination schedule which included 3 initial doses separated by at least 1 month and a 4th dose administered 15-18 months after the 3rd dose. Clinical trials and mathematical models showed that the partial protection against malaria conferred by vaccine RTS,S/AS01 Malaria Vaccine could have a substantial impact on public health if the vaccine was used in association with other control measures for malaria, in particular in highly endemic areas. The most significant impact was observed in children aged 5 months or older who received 4 doses of RTS,S/AS01. Vaccine effectiveness will then be evaluated under real-life conditions in order to determine its impact on mortality, its safety in the context of routine immunization and the feasibility of implementing the 4-dose vaccination schedule requiring new immunization contacts. If successful, this would pave the way for larger-scale implementation.
| S-EPMC6201624 | biostudies-literature
Project description:Mouse models are useful for the early down-selection of malaria vaccine candidates. The Walter Reed Army Institute of Research has optimized a transgenic Plasmodium berghei sporozoite challenge model to compare the efficacy of Plasmodium falciparum circumsporozoite protein (CSP) vaccines. GSK's RTS,S vaccine formulated in the adjuvant AS01 can protect malaria-naïve individuals against malaria. We report that the RTS,S/AS01 vaccine induces high level sterile protection in our mouse model. Down titration of the antigen at a constant AS01 dose revealed a potent antigen dose-sparing effect and the superiority of RTS,S/AS01 over a soluble CSP antigen. RTS,S-mediated protective immunity was associated with a threshold of major repeat antibody titer. Combined titration of the antigen and adjuvant showed that reducing the adjuvant could improve antibody boosting post-3rd vaccination and reduce the threshold antibody concentration required for protection. Mouse models can provide a pathway for preclinical assessment of strategies to improve CSP vaccines against malaria.
| S-EPMC10415390 | biostudies-literature
Project description:BackgroundThe RTS,S/AS01 vaccine against Plasmodium falciparum malaria infection completed phase III trials in 2014 and demonstrated efficacy against clinical malaria of approximately 36% over 4 years for a 4-dose schedule in children aged 5-17 months. Pilot vaccine implementation has recently begun in 3 African countries. If the pilots demonstrate both a positive health impact and resolve remaining safety concerns, wider roll-out could be recommended from 2021 onwards. Vaccine demand may, however, outstrip initial supply. We sought to identify where vaccine introduction should be prioritised to maximise public health impact under a range of supply constraints using mathematical modelling.Methods and findingsUsing a mathematical model of P. falciparum malaria transmission and RTS,S vaccine impact, we estimated the clinical cases and deaths averted in children aged 0-5 years in sub-Saharan Africa under 2 scenarios for vaccine coverage (100% and realistic) and 2 scenarios for other interventions (current coverage and World Health Organization [WHO] Global Technical Strategy targets). We used a prioritisation algorithm to identify potential allocative efficiency gains from prioritising vaccine allocation among countries or administrative units to maximise cases or deaths averted. If malaria burden at introduction is similar to current levels-assuming realistic vaccine coverage and country-level prioritisation in areas with parasite prevalence >10%-we estimate that 4.3 million malaria cases (95% credible interval [CrI] 2.8-6.8 million) and 22,000 deaths (95% CrI 11,000-35,000) in children younger than 5 years could be averted annually at a dose constraint of 30 million. This decreases to 3.0 million cases (95% CrI 2.0-4.7 million) and 14,000 deaths (95% CrI 7,000-23,000) at a dose constraint of 20 million, and increases to 6.6 million cases (95% CrI 4.2-10.8 million) and 38,000 deaths (95% CrI 18,000-61,000) at a dose constraint of 60 million. At 100% vaccine coverage, these impact estimates increase to 5.2 million cases (95% CrI 3.5-8.2 million) and 27,000 deaths (95% CrI 14,000-43,000), 3.9 million cases (95% CrI 2.7-6.0 million) and 19,000 deaths (95% CrI 10,000-30,000), and 10.0 million cases (95% CrI 6.7-15.7 million) and 51,000 deaths (95% CrI 25,000-82,000), respectively. Under realistic vaccine coverage, if the vaccine is prioritised sub-nationally, 5.3 million cases (95% CrI 3.5-8.2 million) and 24,000 deaths (95% CrI 12,000-38,000) could be averted at a dose constraint of 30 million. Furthermore, sub-national prioritisation would allow introduction in almost double the number of countries compared to national prioritisation (21 versus 11). If vaccine introduction is prioritised in the 3 pilot countries (Ghana, Kenya, and Malawi), health impact would be reduced, but this effect becomes less substantial (change of <5%) if 50 million or more doses are available. We did not account for within-country variation in vaccine coverage, and the optimisation was based on a single outcome measure, therefore this study should be used to understand overall trends rather than guide country-specific allocation.ConclusionsThese results suggest that the impact of constraints in vaccine supply on the public health impact of the RTS,S malaria vaccine could be reduced by introducing the vaccine at the sub-national level and prioritising countries with the highest malaria incidence.
| S-EPMC7703928 | biostudies-literature