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Journal articleBousema T, Okell L, Felger I, et al., 2014,
Journal articleWhite MT, Karl S, Battle K, et al., 2014,
Plasmodium vivax relapse infections occur following activation of latent liver-stagesparasites (hypnozoites) causing new blood-stage infections weeks to months after the initialinfection. We develop a within-host mathematical model of liver-stage hypnozoites, and validateit against data from tropical strains of P. vivax. The within-host model is embedded in a P. vivaxtransmission model to demonstrate the build-up of the hypnozoite reservoir following newinfections and its depletion through hypnozoite activation and death. The hypnozoite reservoiris predicted to be over-dispersed with many individuals having few or no hypnozoites, and somehaving intensely infected livers. Individuals with more hypnozoites are predicted to experiencemore relapses and contribute more to onwards P. vivax transmission. Incorporating hypnozoitekilling drugs such as primaquine into first-line treatment regimens is predicted to cause substantialreductions in P. vivax transmission as individuals with the most hypnozoites are more likely torelapse and be targeted for treatment.
Journal articleOkell 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.
Journal articleWhite MT, Griffin JT, Akpogheneta O, et al., 2014,
Journal articlePinsent A, Read JM, Griffin JT, et al., 2014,
Journal articleImai N, White MT, Ghani AC, et al., 2014,
Introduction: Plasmodium knowlesi is now recognised as a leading cause of malaria in Malaysia. As humans come intoincreasing contact with the reservoir host (long-tailed macaques) as a consequence of deforestation, assessing the potentialfor a shift from zoonotic to sustained P. knowlesi transmission between humans is critical.Methods: A multi-host, multi-site transmission model was developed, taking into account the three areas (forest, farm, andvillage) where transmission is thought to occur. Latin hypercube sampling of model parameters was used to identifyparameter sets consistent with possible prevalence in macaques and humans inferred from observed data. We then explorethe consequences of increasing human-macaque contact in the farm, the likely impact of rapid treatment, and the use oflong-lasting insecticide-treated nets (LLINs) in preventing wider spread of this emerging infection.Results: Identified model parameters were consistent with transmission being sustained by the macaques with spill over infectionsinto the human population and with high overall basic reproduction numbers (up to 2267). The extent to which macaques foragein the farms had a non-linear relationship with human infection prevalence, the highest prevalence occurring when macaquesforage in the farms but return frequently to the forest where they experience higher contact with vectors and hence sustaintransmission. Only one of 1,046 parameter sets was consistent with sustained human-to-human transmission in the absence ofmacaques, although with a low human reproduction number (R0H = 1.04). Simulations showed LLINs and rapid treatment providepersonal protection to humans with maximal estimated reductions in human prevalence of 42% and 95%, respectively.Conclusion: This model simulates conditions where P. knowlesi transmission may occur and the potential impact of controlmeasures. Predictions suggest that conventional control measures are sufficient at reducing the risk of infection in humans
Journal articleWalker PGT, ter Kuile FO, Garske T, et al., 2014,
Journal articleWhite MT, Bejon P, Olotu A, et al., 2014,
A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine, BMC Medicine, Vol: 12, ISSN: 1741-7015
Background: The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titresto the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes ofclinical malaria.Methods: Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity(anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes.We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios.Results: Vaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001),pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001).Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095).Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and asecond slower decay over the next three to four years. Antibody titres were significantly associated with protection,with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections inchildren. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculationrate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S willavert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infantswhen co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations includean absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals.Conclusions: Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observedva
Journal articleGriffin JT, Ferguson NM, Ghani AC, 2014,
Estimating the changing burden of malaria disease remains difficult owing to limitations inhealth reporting systems. Here, we use a transmission model incorporating acquisition andloss of immunity to capture age-specific patterns of disease at different transmissionintensities. The model is fitted to age-stratified data from 23 sites in Africa, and we thenproduce maps and estimates of disease burden. We estimate that in 2010 there were 252(95% credible interval: 171–353) million cases of malaria in sub-Saharan Africa that activecase finding would detect. However, only 34% (12–86%) of these cases would be observedthrough passive case detection. We estimate that the proportion of all cases of clinicalmalaria that are in under-fives varies from above 60% at high transmission to below 20% atlow transmission. The focus of some interventions towards young children may need to bereconsidered, and should be informed by the current local transmission intensity.
Journal articleMarshall JM, White MT, Ghani AC, et al., 2013,
Quantifying the mosquito's sweet tooth: modelling the effectiveness of attractive toxic sugar baits (ATSB) for malaria vector control, Malaria Journal, Vol: 12, ISSN: 1475-2875
Background: Current vector control strategies focus largely on indoor measures, such as long-lasting insecticidetreated nets (LLINs) and indoor residual spraying (IRS); however mosquitoes frequently feed on sugar sourcesoutdoors, inviting the possibility of novel control strategies. Attractive toxic sugar baits (ATSB), either sprayed onvegetation or provided in outdoor bait stations, have been shown to significantly reduce mosquito densities inthese settings.Methods: Simple models of mosquito sugar-feeding behaviour were fitted to data from an ATSB field trial in Maliand used to estimate sugar-feeding rates and the potential of ATSB to control mosquito populations. The modeland fitted parameters were then incorporated into a larger integrated vector management (IVM) model to assessthe potential contribution of ATSB to future IVM programmes.Results: In the Mali experimental setting, the model suggests that about half of female mosquitoes fed on ATSBsolution per day, dying within several hours of ingesting the toxin. Using a model incorporating the number ofgonotrophic cycles completed by female mosquitoes, a higher sugar-feeding rate was estimated for youngermosquitoes than for older mosquitoes. Extending this model to incorporate other vector control interventionssuggests that an IVM programme based on both ATSB and LLINs may substantially reduce mosquito density andsurvival rates in this setting, thereby substantially reducing parasite transmission. This is predicted to exceed theimpact of LLINs in combination with IRS provided ATSB feeding rates are 50% or more of Mali experimental levels.In addition, ATSB is predicted to be particularly effective against Anopheles arabiensis, which is relatively exophilicand therefore less affected by IRS and LLINs.Conclusions: These results suggest that high coverage with a combination of LLINs and ATSB could result insubstantial reductions in malaria transmission in this setting. Further field studies of ATSB in other settings
Journal articleWhite MT, Griffin JT, Ghani AC, 2013,
The design and statistical power of treatment re-infection studies of the association between pre-erythrocytic immunity and infection with Plasmodium falciparum, Malaria Journal, Vol: 12, ISSN: 1475-2875
Background: Understanding the role of pre-erythrocytic immune responses to Plasmodium falciparum parasites iscrucial for understanding the epidemiology of malaria. However, published studies have reported inconsistentresults on the association between markers of pre-erythrocytic immunity and protection from malaria.Methods: The design and statistical methods of studies of pre-erythrocytic immunity were reviewed, and factorsaffecting the likelihood of detecting statistically significant associations were assessed. Treatment re-infectionstudies were simulated to estimate the effects of study size, transmission intensity, and sampling frequency on thestatistical power to detect an association between markers of pre-erythrocytic immunity and protection frominfection.Results: Nine of nineteen studies reviewed reported statistically significant associations between markers ofpre-erythrocytic immunity and protection from infection. Studies with large numbers of participants inhigh-transmission settings, followed longitudinally with active detection of infection and with immune responsesanalysed as continuous variables, were most likely to detect statistically significant associations. Simulation oftreatment re-infection studies highlights that many studies are underpowered to detect statistically significantassociations, providing an explanation for the finding that only some studies report significant associations betweenpre-erythrocytic immune responses and protection from infection.Conclusions: The findings of the review and model simulations are consistent with the hypothesis thatpre-erythrocytic immune responses prevent P. falciparum infections, but that many studies are underpowered toconsistently detect this effect.
Journal articleBlagborough AM, Churcher TS, Upton LM, et al., 2013,
Transmission-blocking interventions aim to reduce the prevalence of infection in endemic communities by targeting Plasmodium within the insect host. Although many studies have reported the successful reduction of infection in the mosquito vector, direct evidence that there is an onward reduction in infection in the vertebrate host is lacking. Here we report the first experiments using a population, transmission-based study of Plasmodium berghei in Anopheles stephensi to assess the impact of a transmission-blocking drug upon both insect and host populations over multiple transmission cycles. We demonstrate that the selected transmission-blocking intervention, which inhibits transmission from vertebrate to insect by only 32%, reduces the basic reproduction number of the parasite by 20%, and in our model system can eliminate Plasmodium from mosquito and mouse populations at low transmission intensities. These findings clearly demonstrate that use of transmission-blocking interventions alone can eliminate Plasmodium from a vertebrate population, and have significant implications for the future design and implementation of transmission-blocking interventions within the field.
Journal articleBejon P, White MT, Olotu A, et al., 2013,
Journal articleRao VB, Schellenberg D, Ghani AC, 2013,
Journal articleWalker PGT, Griffin JT, Cairns M, et al., 2013,
Plasmodium falciparum placental infection during pregnancy is harmful for both mother andchild. Protection from placental infection is parity-dependent, that is, acquired over consecutivepregnancies. However, the infection status of the placenta can only be assessed atdelivery. Here, to better understand the mechanism underlying this parity-dependence, wefitted a model linking malaria dynamics within the general population to observed placentalhistology. Our results suggest that immunity resulting in less prolonged infection is a greaterdeterminant of the parity-specific patterns than immunity that prevents placental sequestration.Our results also suggest the time when maternal blood first flows into the placenta isa high-risk period. Therefore, preventative strategies implementable before or early inpregnancy, such as insecticide-treated net usage in women of child-bearing age or any futurevaccine, could substantially reduce the number of women who experience placental infection.
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