68 results found
Walker P, Cairns M, Slater H, et al., 2020, Modelling the incremental benefit of introducing malaria screening strategies to antenatal care in Africa, Nature Communications, Vol: 11, Pages: 1-12, ISSN: 2041-1723
Plasmodium falciparum in pregnancy is a major cause of adverse pregnancy outcomes. We combine performance estimates of standard rapid diagnostic tests (RDT) from trials of intermittent screening and treatment in pregnancy (ISTp) with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy with sulphadoxine-pyrimethamine (IPTp-SP). We estimate that RDTs in primigravidae at first antenatal visit are substantially more sensitive than in non-pregnant adults (OR = 17.2, 95% Cr.I. 13.8-21.6), and that sensitivity declines in subsequent visits and with gravidity, likely driven by declining susceptibility to placental infection. Monthly ISTp with standard RDTs, even with highly effective drugs, is not superior to monthly IPTp-SP. However, a hybrid strategy, recently adopted in Tanzania, combining testing and treatment at first visit with IPTp-SP may offer benefit, especially in areas with high-grade SP resistance. Screening and treatment in the first trimester, when IPTp-SP is contraindicated, could substantially improve pregnancy outcomes.
Verity R, Okell LC, Dorigatti I, et al., 2020, Estimates of the severity of coronavirus disease 2019: a model-based analysis., Lancet Infectious Diseases, Vol: 20, Pages: 669-677, ISSN: 1473-3099
BACKGROUND: In the face of rapidly changing data, a range of case fatality ratio estimates for coronavirus disease 2019 (COVID-19) have been produced that differ substantially in magnitude. We aimed to provide robust estimates, accounting for censoring and ascertainment biases. METHODS: We collected individual-case data for patients who died from COVID-19 in Hubei, mainland China (reported by national and provincial health commissions to Feb 8, 2020), and for cases outside of mainland China (from government or ministry of health websites and media reports for 37 countries, as well as Hong Kong and Macau, until Feb 25, 2020). These individual-case data were used to estimate the time between onset of symptoms and outcome (death or discharge from hospital). We next obtained age-stratified estimates of the case fatality ratio by relating the aggregate distribution of cases to the observed cumulative deaths in China, assuming a constant attack rate by age and adjusting for demography and age-based and location-based under-ascertainment. We also estimated the case fatality ratio from individual line-list data on 1334 cases identified outside of mainland China. Using data on the prevalence of PCR-confirmed cases in international residents repatriated from China, we obtained age-stratified estimates of the infection fatality ratio. Furthermore, data on age-stratified severity in a subset of 3665 cases from China were used to estimate the proportion of infected individuals who are likely to require hospitalisation. FINDINGS: Using data on 24 deaths that occurred in mainland China and 165 recoveries outside of China, we estimated the mean duration from onset of symptoms to death to be 17·8 days (95% credible interval [CrI] 16·9-19·2) and to hospital discharge to be 24·7 days (22·9-28·1). In all laboratory confirmed and clinically diagnosed cases from mainland China (n=70 117), we estimated a crude case fatality ratio (adjusted for cen
Okell L, Bretscher MT, Dahal P, et al., 2020, The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data, BMC Medicine, Vol: 18, Pages: 1-17, ISSN: 1741-7015
Background: The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programmes combined with sulfadoxine-pyrimethamine. Whilst artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas. Methods: We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n=4214 individuals). The time to PCR-confirmed re-infection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to re-infection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment. Results: We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to re-infection in multivariate models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~2-fold longer protection than AL. Conversely at a higher prevalence of 86Y and 76T mutant parasites (>80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protec
Sherrard-Smith E, Skarp JE, Beale AD, et al., 2019, Mosquito feeding behavior and how it influences residual malaria transmission across Africa, Proceedings of the National Academy of Sciences, Vol: 116, Pages: 15086-15095, ISSN: 0027-8424
The antimalarial efficacy of the most important vector control interventions—long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS)—primarily protect against mosquitoes’ biting people when they are in bed and indoors. Mosquito bites taken outside of these times contribute to residual transmission which determines the maximum effectiveness of current malaria prevention. The likelihood mosquitoes feed outside the time of day when LLINs and IRS can protect people is poorly understood, and the proportion of bites received outdoors may be higher after prolonged vector control. A systematic review of mosquito and human behavior is used to quantify and estimate the public health impact of outdoor biting across Africa. On average 79% of bites by the major malaria vectors occur during the time when people are in bed. This estimate is substantially lower than previous predictions, with results suggesting a nearly 10% lower proportion of bites taken at the time when people are beneath LLINs since the year 2000. Across Africa, this higher outdoor transmission is predicted to result in an estimated 10.6 million additional malaria cases annually if universal LLIN and IRS coverage was achieved. Higher outdoor biting diminishes the cases of malaria averted by vector control. This reduction in LLIN effectiveness appears to be exacerbated in areas where mosquito populations are resistant to insecticides used in bed nets, but no association was found between physiological resistance and outdoor biting. Substantial spatial heterogeneity in mosquito biting behavior between communities could contribute to differences in effectiveness of malaria control across Africa.
Mousa A, Challenger JD, Cunnington AJ, et al., 2019, THE EFFECT OF DELAYED TREATMENT ON PROGRESSION TO SEVERE PLASMODIUM FALCIPARUM MALARIA: A POOLED MULTICENTRE INDIVIDUAL-PATIENT ANALYSIS, 68th Annual Meeting of the American-Society-for-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 215-215, ISSN: 0002-9637
Sherrard-Smith E, Griffin J, Winskill P, et al., 2018, Systematic review of indoor residual spray efficacy and effectiveness against Plasmodium falciparum in Africa, Nature Communications, Vol: 9, ISSN: 2041-1723
Indoor residual spraying (IRS) is an important part of malaria control. There is a growing list of insecticide classes; pyrethroids remain the principal insecticide used in bednets but recently, novel non-pyrethroid IRS products, with contrasting impacts, have been introduced. There is an urgent need to better assess product efficacy to help decision makers choose effective and relevant tools for mosquito control. Here we use experimental hut trial data to characterise the entomological efficacy of widely-used, novel IRS insecticides. We quantify their impact against pyrethroid-resistant mosquitoes and use a Plasmodium falciparum transmission model to predict the public health impact of different IRS insecticides. We report that long-lasting IRS formulations substantially reduce malaria, though their benefit over cheaper, shorter-lived formulations depends on local factors including bednet use, seasonality, endemicity and pyrethroid resistance status of local mosquito populations. We provide a framework to help decision makers evaluate IRS product effectiveness.
Hogan AB, Winskill P, Verity R, et al., 2018, Modelling population-level impact to inform target product profiles for childhood malaria vaccines, BMC Medicine, Vol: 16, ISSN: 1741-7015
BackgroundThe RTS,S/AS01 vaccine for Plasmodium falciparum malaria demonstrated moderate efficacy in 5–17-month-old children in phase 3 trials, and from 2018, the vaccine will be evaluated through a large-scale pilot implementation program. Work is ongoing to optimise this vaccine, with higher efficacy for a different schedule demonstrated in a phase 2a challenge study. The objective of our study was to investigate the population-level impact of a modified RTS,S/AS01 schedule and dose amount in order to inform the target product profile for a second-generation malaria vaccine.MethodsWe used a mathematical modelling approach as the basis for our study. We simulated the changing anti-circumsporozoite antibody titre following vaccination and related the titre to vaccine efficacy. We then implemented this efficacy profile within an individual-based model of malaria transmission. We compared initial efficacy, duration and dose timing, and evaluated the potential public health impact of a modified vaccine in children aged 5–17 months, measuring clinical cases averted in children younger than 5 years.ResultsIn the first decade of delivery, initial efficacy was associated with a higher reduction in childhood clinical cases compared to vaccine duration. This effect was more pronounced in high transmission settings and was due to the efficacy benefit occurring in younger ages where disease burden is highest. However, the low initial efficacy and long duration schedule averted more cases across all age cohorts if a longer time horizon was considered. We observed an age-shifting effect due to the changing immunological profile in higher transmission settings, in scenarios where initial efficacy was higher, and the fourth dose administered earlier.ConclusionsOur findings indicate that, for an imperfect childhood malaria vaccine with suboptimal efficacy, it may be advantageous to prioritise initial efficacy over duration. We predict that a modified vaccine could outpe
Winskill P, Slater H, Griffin J, et al., 2017, The US President's Malaria Initiative, Plasmodium falciparum transmission and mortality: A modelling study, PLoS Medicine, Vol: 14, ISSN: 1549-1277
BackgroundAlthough significant progress has been made in reducing malaria transmission globally inrecent years, a large number of people remain at risk and hence the gains made are fragile.Funding lags well behind amounts needed to protect all those at risk and ongoing contributionsfrom major donors, such as the President’s Malaria Initiative (PMI), are vital to maintainprogress and pursue further reductions in burden. We use a mathematical modellingapproach to estimate the impact of PMI investments to date in reducing malaria burden andto explore the potential negative impact on malaria burden should a proposed 44% reductionin PMI funding occur.Methods and findingsWe combined an established mathematical model of Plasmodium falciparum transmissiondynamics with epidemiological, intervention, and PMI-financing data to estimate the contributionPMI has made to malaria control via funding for long-lasting insecticide treated nets(LLINs), indoor residual spraying (IRS), and artemisinin combination therapies (ACTs). Weestimate that PMI has prevented 185 million (95% CrI: 138 million, 230 million) malariacases and saved 940,049 (95% CrI: 545,228, 1.4 million) lives since 2005. If funding is maintained,PMI-funded interventions are estimated to avert a further 162 million cases (95%CrI: 116 million, 194 million) cases, saving a further 692,589 (95% CrI: 392,694, 955,653)lives between 2017 and 2020. With an estimate of US$94 (95% CrI: US$51, US$166) perDisability Adjusted Life Year (DALY) averted, PMI-funded interventions are highly costeffective.We also demonstrate the further impact of this investment by reducing caseloadson health systems. If a 44% reduction in PMI funding were to occur, we predict that this lossof direct aid could result in an additional 67 million (95% CrI: 49 million, 82 million) cases and290,649 deaths (95% CrI: 167,208, 395,263) deaths between 2017 and 2020. We have notmodelled indirect impacts of PMI funding (such as health systems strengthening
Bretscher MT, Griffin JT, Ghani AC, et al., 2017, Modelling the benefits of long-acting or transmission-blocking drugs for reducing Plasmodium falciparum transmission by case management or by mass treatment, MALARIA JOURNAL, Vol: 16, ISSN: 1475-2875
BackgroundAnti-malarial drugs are an important tool for malaria control and elimination. Alongside their direct benefit in the treatment of disease, drug use has a community-level effect, clearing the reservoir of infection and reducing onward transmission of the parasite. Different compounds potentially have different impacts on transmission—with some providing periods of prolonged chemoprophylaxis whilst others have greater transmission-blocking potential. The aim was to quantify the relative benefit of such properties for transmission reduction to inform target product profiles in the drug development process and choice of first-line anti-malarial treatment in different endemic settings.MethodsA mathematical model of Plasmodium falciparum epidemiology was used to estimate the transmission reduction that can be achieved by using drugs of varying chemoprophylactic (protection for 3, 30 or 60 days) or transmission-blocking activity (blocking 79, 92 or 100% of total onward transmission). Simulations were conducted at low, medium or high transmission intensity (slide-prevalence in 2–10 year olds being 1, 10 or 40%, respectively), with drugs administered either via case management or mass drug administration (MDA).ResultsTransmission reductions depend strongly on deployment strategy, treatment coverage and endemicity level. Transmission-blocking was most effective at low endemicity, whereas chemoprophylaxis was most useful at high endemicity levels. Increasing the duration of protection as much as possible was beneficial. Increasing transmission-blocking activity from the level of ACT to a 100% transmission-blocking drug (close to the effect estimated for ACT combined with primaquine) produced moderate impact but was not as effective as increasing the duration of protection in medium-to-high transmission settings (slide prevalence 10–40%). Combining both good transmission-blocking activity (e.g. as achieved by ACT or ACT + primaquine) and a long durat
Okell L, Griffin JT, Roper C, 2017, Mapping sulphadoxine-pyrimethamine-resistant Plasmodium falciparum malaria in infected humans and in parasite populations in Africa, Scientific Reports, Vol: 7, ISSN: 2045-2322
Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We update a systematic review to map the prevalence of K540E and A581G mutations in 294 surveys of infected humans across Africa from 2004-present. Interpreting these data is complicated by multiclonal infections in humans, especially in high transmission areas. We extend statistical methods to estimate the frequency, i.e. the proportion of resistant clones in the parasite population at each location, and so standardise for varying transmission levels. Both K540E and A581G mutations increased in prevalence and frequency in 60% of areas after 2008, highlighting the need for ongoing surveillance. Resistance measures within countries were similar within 300 km, suggesting an appropriate spatial scale for surveillance. Spread of the mutations tended to accelerate once their prevalence exceeded 10% (prior to fixation). Frequencies of resistance in parasite populations are the same or lower than prevalence in humans, so more areas would be classified as likely to benefit from IPT if similar frequency thresholds were applied. We propose that the use of resistance frequencies as well as prevalence measures for policy decisions should be evaluated.
Patouillard E, Ghani ACH, Bhatt S, et al., 2017, Global investment targets for malaria control and elimination between 2016 and 2030, BMJ Global Health, Vol: 2, ISSN: 2059-7908
Background Access to malaria control interventions falls short of universal health coverage. The Global Technical Strategy for malaria targets at least 90% reduction in case incidence and mortality rates, and elimination in 35 countries by 2030. The potential to reach these targets will be determined in part by investments in malaria. This study estimates the financing required for malaria control and elimination over the 2016–2030 period.Methods A mathematical transmission model was used to explore the impact of increasing intervention coverage on burden and costs. The cost analysis took a public provider perspective covering all 97 malaria endemic countries and territories in 2015. All control interventions currently recommended by the WHO were considered. Cost data were sourced from procurement databases, the peer-reviewed literature, national malaria strategic plans, the WHO-CHOICE project and key informant interviews.Results Annual investments of $6.4 billion (95% uncertainty interval (UI $4.5–$9.0 billion)) by 2020, $7.7 billion (95% UI $5.4–$10.9 billion) by 2025 and $8.7 billion (95% UI $6.0–$12.3 billion) by 2030 will be required to reach the targets set in the Global Technical Strategy. These are equivalent to annual investment per person at risk of malaria of US$3.90 by 2020, US$4.30 by 2025 and US$4.40 by 2030, compared with US$2.30 if interventions were sustained at current coverage levels. The 20 countries with the highest burden in 2015 will require 88% of the total investment.Conclusions Given the challenges in increasing domestic and international funding, the efficient use of currently available resources should be a priority
Churcher TS, Sinden RE, Edwards NJ, et al., 2017, Probability of transmission of malaria from mosquito to human Is regulated by mosquito parasite density in naïve and vaccinated hosts, PLOS Pathogens, Vol: 13, ISSN: 1553-7366
Over a century since Ronald Ross discovered that malaria is caused by the bite of an infectious mosquito it is still unclear how the number of parasites injected influences disease transmission. Currently it is assumed that all mosquitoes with salivary gland sporozoites are equally infectious irrespective of the number of parasites they harbour, though this has never been rigorously tested. Here we analyse >1000 experimental infections of humans and mice and demonstrate a dose-dependency for probability of infection and the length of the host pre-patent period. Mosquitoes with a higher numbers of sporozoites in their salivary glands following blood-feeding are more likely to have caused infection (and have done so quicker) than mosquitoes with fewer parasites. A similar dose response for the probability of infection was seen for humans given a pre-erythrocytic vaccine candidate targeting circumsporozoite protein (CSP), and in mice with and without transfusion of anti-CSP antibodies. These interventions prevented infection more efficiently from bites made by mosquitoes with fewer parasites. The importance of parasite number has widespread implications across malariology, ranging from our basic understanding of the parasite, how vaccines are evaluated and the way in which transmission should be measured in the field. It also provides direct evidence for why the only registered malaria vaccine RTS,S was partially effective in recent clinical trials.
Winskill P, Walker P, Griffin J, et al., 2017, Modelling the cost-effectiveness of introducing the RTS,S malaria vaccine relative to scaling up other malaria interventions in sub-Saharan Africa, BMJ Global Health, Vol: 2, ISSN: 2059-7908
Objectives: To evaluate the relative cost-effectiveness of introducing the RTS,S malaria vaccine in sub-Saharan Africa compared with further scale-up of existing interventions.Design: A mathematical modelling and cost-effectiveness study.Setting: Sub-Saharan Africa.Participants: People of all ages.Interventions: The analysis considers the introduction and scale-up of the RTS,S malaria vaccine and the scale-up of long lasting insecticide treated bed nets (LLINs), indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC).Main outcome measure: The number of Plasmodium falciparum cases averted in all age groups over a ten year period.Results: Assuming access to treatment remains constant, increasing coverage of LLINs was consistently the most cost-effective intervention across a range of transmission settings and was found to occur early in the cost-effectiveness scale-up pathway. IRS, RTS,S and SMC entered the cost-effective pathway once LLIN coverage had been maximised. If non-linear production functions are included to capture the cost of reaching very high coverage, the resulting pathways become more complex and result in selection of multiple interventions.Conclusions: RTS,S was consistently implemented later in the cost-effectiveness pathway than the LLINs, IRS and SMC but was still of value as a fourth intervention in many settings to reduce burden to the levels set out in the international goals.
Griffin JT, 2016, Is a reproduction number of one a threshold for Plasmodium falciparum malaria elimination?, Malaria Journal, Vol: 15
Churcher TS, Lissenden N, Griffin JT, et al., 2016, The impact of pyrethroid resistance on the efficacy and effectiveness of bednets for malaria control in Africa, eLife, Vol: 5, ISSN: 2050-084X
Long lasting pyrethroid treated bednets are the most important tool for preventing malaria. Pyrethroid resistant Anopheline mosquitoes are now ubiquitous in Africa though the public health impact remains unclear, impeding the deployment of more expensive nets. Meta-analyses of bioassay studies and experimental hut trials are used to characterise how pyrethroid resistance changes the efficacy of standard bednets, and those containing the synergist piperonyl butoxide (PBO), and assess its impact on malaria control. New bednets provide substantial personal protection until high levels of resistance though protection may wane faster against more resistant mosquito populations as nets age. Transmission dynamics models indicate that even low levels of resistance would increase the incidence of malaria due to reduced mosquito mortality and lower overall community protection over the life-time of the net. Switching to PBO bednets could avert up to 0.5 clinical cases per person per year in some resistance scenarios.
Walker PG, Griffin JT, Ferguson NM, et al., 2016, Estimating the most efficient allocation of interventions to achieve reductions in Plasmodium falciparum malaria burden and transmission in Africa: a modelling study, Lancet Global Health, Vol: 4, Pages: e474-e484, ISSN: 2214-109X
BACKGROUND: Reducing the burden of malaria is a global priority, but financial constraints mean that available resources must be allocated rationally to maximise their effect. We aimed to develop a model to estimate the most efficient (ie, minimum cost) ordering of interventions to reduce malaria burden and transmission. We also aimed to estimate the efficiency of different spatial scales of implementation. METHODS: We combined a dynamic model capturing heterogeneity in malaria transmission across Africa with financial unit cost data for key malaria interventions. We combined estimates of patterns of malaria endemicity, seasonality in rainfall, and mosquito composition to map optimum packages of these interventions across Africa. Using non-linear optimisation methods, we examined how these optimum packages vary when control measures are deployed and assessed at national, subnational first administrative (provincial), or fine-scale (5 km(2) pixel) spatial scales. FINDINGS: The most efficient package in a given setting varies depending on whether disease reduction or elimination is the target. Long-lasting insecticide-treated nets are generally the most cost-effective first intervention to achieve either goal, with seasonal malaria chemoprevention or indoor residual spraying added second depending on seasonality and vector species. These interventions are estimated to reduce malaria transmission to less than one case per 1000 people per year in 43·4% (95% CI 40·0-49·0) of the population at risk in Africa. Adding three rounds of mass drug administration per year is estimated to increase this proportion to 90·9% (95% CI 86·9-94·6). Further optimisation can be achieved by targeting policies at the provincial level, achieving an estimated 32·1% (95% CI 29·6-34·5) cost saving relative to adopting country-wide policies. Nevertheless, we predict that only 26 (95% CI 22-29) of 41 countries could reduce transmissio
Marshall JM, Touré M, Ouédraogo AL, et al., 2016, Key traveller groups of relevance to spatial malaria transmission: a survey of movement patterns in four sub-Saharan African countries, Malaria Journal, Vol: 15, ISSN: 1475-2875
Griffi JT, Bhatt S, Sinka ME, et al., 2016, Potential for reduction of burden and local elimination of malaria by reducing Plasmodium falciparum malaria transmission: a mathematical modelling study, Lancet Infectious Diseases, Vol: 16, Pages: 465-472, ISSN: 1473-3099
Slater HC, Griffin JT, Ghani AC, et al., 2016, Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa., Malaria Journal, Vol: 15, ISSN: 1475-2875
BACKGROUND: Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia. If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality. This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge. METHODS: Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized. An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa. Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure. RESULTS: Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance. Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7 % increase in cases compared to a scenario with no resistance. A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period. CONCLUSION: Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives. However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only.
Penny MA, Verity RV, Bever C, et al., 2015, Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models, The Lancet, Vol: 387, Pages: 367-375, ISSN: 0140-6736
BackgroundThe phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings.MethodsWe compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5–17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2–10 year olds (PfPR2–10; range 3–65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2–10 per dose.FindingsIn regions with a PfPR2–10 of 10–65%, RTS,S/AS01 is predicted to avert a median of 93 940 (range 20 490–126 540) clinical cases and 394 (127–708) deaths for the three-dose schedule, or 116 480 (31 450–160 410) clinical cases and 484 (189–859) deaths for the four-dose schedule, per 100 000 fully vaccinated children. A positive impact is also predicted at a PfPR2–10 of 5–10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2–10 of 10–65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18–2
van den Hoogen LL, Griffin JT, Cook J, et al., 2015, Serology describes a profile of declining malaria transmission in Farafenni, The Gambia, Malaria Journal, Vol: 14, ISSN: 1475-2875
BACKGROUND: Malaria morbidity and mortality has declined in recent years in a number of settings. The ability to describe changes in malaria transmission associated with these declines is important in terms of assessing the potential effects of control interventions, and for monitoring and evaluation purposes. METHODS: Data from five cross-sectional surveys conducted in Farafenni and surrounding villages on the north bank of River Gambia between 1988 and 2011 were compiled. Antibody responses to MSP-119 were measured in samples from all surveys, data were normalized and expressed as seroprevalence and seroconversion rates (SCR) using different mathematical models. RESULTS: Results showed declines in serological metrics with seroprevalence in children aged one to 5 years dropping from 19 % (95 % CI 15-23 %) in 1988 to 1 % (0-2 %) in 2011 (p value for trend in proportions < 0.001) and the SCR dropping from 0.069 year(-1) (0.059-0.080) to 0.022 year(-1) (0.017-0.028; p = 0.004). The serological data were consistent with previously described drops in both parasite prevalence in children aged 1-5 years (62 %, 57-66 %, in 1988 to 2 %, 0-4 %, in 2011; p < 0.001), and all-cause under five mortality rates (37 per 1000 person-years, 34-41, in 1990 to 17, 15-19, in 2006; p = 0.059). CONCLUSIONS: This analysis shows accurate reconstruction of historical malaria transmission patterns in the Farafenni area using anti-malarial antibody responses. Demonstrating congruence between serological measures, and conventional clinical and parasitological measures suggests broader utility for serology in monitoring and evaluation of malaria transmission.
Bhatt S, Weiss DJ, Cameron E, et al., 2015, The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015, Nature, Vol: 526, Pages: 207-211, ISSN: 0028-0836
Since the year 2000, a concerted campaign against malaria has led to unprecedented levels of intervention coverage across sub-Saharan Africa. Understanding the effect of this control effort is vital to inform future control planning. However, the effect of malaria interventions across the varied epidemiological settings of Africa remains poorly understood owing to the absence of reliable surveillance data and the simplistic approaches underlying current disease estimates. Here we link a large database of malaria field surveys with detailed reconstructions of changing intervention coverage to directly evaluate trends from 2000 to 2015, and quantify the attributable effect of malaria disease control efforts. We found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015. We estimate that interventions have averted 663 (542–753 credible interval) million clinical cases since 2000. Insecticide-treated nets, the most widespread intervention, were by far the largest contributor (68% of cases averted). Although still below target levels, current malaria interventions have substantially reduced malaria disease incidence across the continent. Increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance, should form a cornerstone of post-2015 control strategies.
Winskill P, Walker PG, Griffin JT, et al., 2015, COST-EFFECTIVE SCALE-UP OF CURRENT INTERVENTIONS AND RTS,S IN SUB-SAHARAN AFRICAN SETTINGS, Publisher: AMER SOC TROP MED & HYGIENE, Pages: 477-477, ISSN: 0002-9637
Cameron E, Battle KE, Bhatt S, et al., 2015, Defining the relationship between infection prevalence and clinical incidence of Plasmodium falciparum malaria, Nature Communications, Vol: 6, ISSN: 2041-1723
In many countries health system data remain too weak to accurately enumerate Plasmodium falciparum malaria cases. In response, cartographic approaches have been developed that link maps of infection prevalence with mathematical relationships to predict the incidence rate of clinical malaria. Microsimulation (or ‘agent-based’) models represent a powerful new paradigm for defining such relationships; however, differences in model structure and calibration data mean that no consensus yet exists on the optimal form for use in disease-burden estimation. Here we develop a Bayesian statistical procedure combining functional regression-based model emulation with Markov Chain Monte Carlo sampling to calibrate three selected microsimulation models against a purpose-built data set of age-structured prevalence and incidence counts. This allows the generation of ensemble forecasts of the prevalence–incidence relationship stratified by age, transmission seasonality, treatment level and exposure history, from which we predict accelerating returns on investments in large-scale intervention campaigns as transmission and prevalence are progressively reduced.
White MT, Verity R, Griffin JT, et al., 2015, Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial, Lancet Infectious Diseases, Vol: 15, Pages: 1450-1458, ISSN: 1473-3099
BackgroundThe RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014.MethodsUsing data from 8922 African children aged 5–17 months and 6537 African infants aged 6–12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time.FindingsRTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5–17 months than in those aged 6–12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6–12 weeks and higher immunogenicity in those aged 5–17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5–17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42–48) and that of the long-lived component was 591 days (557–632). After primary vaccination 12% (11–13) of the response was estimated to be long-lived, rising to 30% (28–32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98–153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and effi
Cairns ME, Walker PGT, Okell LC, et al., 2015, Seasonality in malaria transmission: implications for case-management with long-acting artemisinin combination therapy in sub-Saharan Africa, Malaria Journal, Vol: 14, ISSN: 1475-2875
Background: Long-acting artemisinin-based combination therapy (LACT) offers the potential to prevent recurrentmalaria attacks in highly exposed children. However, it is not clear where this advantage will be most important, anddeployment of these drugs is not rationalized on this basis.Methods: To understand where post-treatment prophylaxis would be most beneficial, the relationship betweenseasonality, transmission intensity and the interval between malaria episodes was explored using data from six cohortstudies in West Africa and an individual-based malaria transmission model. The total number of recurrent malariacases per 1000 child-years at risk, and the fraction of the total annual burden that this represents were estimated forsub-Saharan Africa.Results: In settings where prevalence is less than 10 %, repeat malaria episodes constitute a small fraction of thetotal burden, and few repeat episodes occur within the window of protection provided by currently available drugs.However, in higher transmission settings, and particularly in high transmission settings with highly seasonal transmis‑sion, repeat malaria becomes increasingly important, with up to 20 % of the total clinical burden in children estimatedto be due to repeat episodes within 4 weeks of a prior attack.Conclusion: At a given level of transmission intensity and annual incidence, the concentration of repeat malariaepisodes in time, and consequently the protection from LACT is highest in the most seasonal areas. As a result, thedegree of seasonality, in addition to the overall intensity of transmission, should be considered by policy makers whendeciding between ACT that differ in their duration of post-treatment prophylaxis.
Griffin JT, 2015, The Interaction between Seasonality and Pulsed Interventions against Malaria in Their Effects on the Reproduction Number, Plos Computational Biology, Vol: 11, ISSN: 1553-7358
© 2015 Jamie T. Griffin. The basic reproduction number (R0) is an important quantity summarising the dynamics of an infectious disease, as it quantifies how much effort is needed to control transmission. The relative change in R0 due to an intervention is referred to as the effect size. However malaria and other diseases are often highly seasonal and some interventions have time-varying effects, meaning that simple reproduction number formulae cannot be used. Methods have recently been developed for calculating R0 for diseases with seasonally varying transmission. I extend those methods to calculate the effect size of repeated rounds of mass drug administration, indoor residual spraying and other interventions against Plasmodium falciparum malaria in seasonal settings in Africa. I show that if an intervention reduces transmission from one host to another by a constant factor, then its effect size is the same in a seasonal as in a non-seasonal setting. The optimal time of year for drug administration is in the low season, whereas the best time for indoor residual spraying or a vaccine which reduces infection rates is just before the high season. In general, the impact of time-varying interventions increases with increasing seasonality, if carried out at the optimal time of year. The effect of combinations of interventions that act at different stages of the transmission cycle is roughly the product of the separate effects. However for individual time-varying interventions, it is necessary to use methods such as those developed here rather than inserting the average efficacy into a simple formula.
Griffin JT, Hollingsworth TD, Reyburn H, et al., 2015, Gradual acquisition of immunity to severe malaria with increasing exposure, Proceedings of the Royal Society B: Biological Sciences, Vol: 282, ISSN: 0962-8452
Okell LC, Cairns M, Griffin JT, et al., 2014, Contrasting benefits of different artemisinin combination therapies as first-line malaria treatments using model-based cost-effectiveness analysis, Nature Communications, Vol: 5, ISSN: 2041-1723
There are currently several recommended drug regimens for uncomplicated falciparummalaria in Africa. Each has different properties that determine its impact on diseaseburden. Two major antimalarial policy options are artemether–lumefantrine (AL) anddihydroartemisinin–piperaquine (DHA–PQP). Clinical trial data show that DHA–PQP provideslonger protection against reinfection, while AL is better at reducing patient infectiousness.Here we incorporate pharmacokinetic-pharmacodynamic factors, transmission-reducingeffects and cost into a mathematical model and simulate malaria transmission and treatmentin Africa, using geographically explicit data on transmission intensity and seasonality,population density, treatment access and outpatient costs. DHA–PQP has a modestly higherestimated impact than AL in 64% of the population at risk. Given current higher costestimates for DHA–PQP, there is a slightly greater cost per case averted, except in areas withhigh, seasonally varying transmission where the impact is particularly large. We find that alocally optimized treatment policy can be highly cost effective for reducing clinical malariaburden.
White MT, Griffin JT, Akpogheneta O, et al., 2014, Dynamics of the Antibody Response to Plasmodium falciparum Infection in African Children, JOURNAL OF INFECTIOUS DISEASES, Vol: 210, Pages: 1115-1122, ISSN: 0022-1899
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