Imperial College London

DrMichaelWhite

Faculty of MedicineSchool of Public Health

Visiting Researcher
 
 
 
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m.white08

 
 
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Praed StreetSt Mary's Campus

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Summary

 

Publications

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33 results found

White MT, Amino R, Mueller I, 2017, Theoretical implications of a pre-erythrocytic Plasmodium vivax vaccine for preventing relapses, Trends in Parasitology, Vol: 33, Pages: 260-263, ISSN: 1471-5007

Preventing malaria infection through vaccination requires preventing every sporozoite inoculated by mosquito bite: a major challengefor Plasmodium falciparum. Plasmodium vivax sporozoites consist of tachysporozoites causing primary infection and bradysporozoites leading to relapses.We hypothesise that a candidate P. vivax vaccine with low efficacy against primary infection may substantially reduce transmission by preventing relapses.

Journal article

White MT, Yeung S, Patouillard E, Cibulskis Ret al., 2016, Costs and Cost-Effectiveness of Plasmodium vivax Control., Am J Trop Med Hyg, Vol: 95, Pages: 52-61

The continued success of efforts to reduce the global malaria burden will require sustained funding for interventions specifically targeting Plasmodium vivax The optimal use of limited financial resources necessitates cost and cost-effectiveness analyses of strategies for diagnosing and treating P. vivax and vector control tools. Herein, we review the existing published evidence on the costs and cost-effectiveness of interventions for controlling P. vivax, identifying nine studies focused on diagnosis and treatment and seven studies focused on vector control. Although many of the results from the much more extensive P. falciparum literature can be applied to P. vivax, it is not always possible to extrapolate results from P. falciparum-specific cost-effectiveness analyses. Notably, there is a need for additional studies to evaluate the potential cost-effectiveness of radical cure with primaquine for the prevention of P. vivax relapses with glucose-6-phosphate dehydrogenase testing.

Journal article

White MT, Shirreff G, Karl S, Ghani A, Mueller Iet al., 2016, Variation in relapse frequency and the transmission potential of Plasmodium vivax malaria, Proceedings of the Royal Society of London. Series B, Biological Sciences, Vol: 283, ISSN: 0080-4649

There is substantial variation in the relapse frequency of Plasmodium vivax malaria, with fast-relapsing strains in tropical areas, and slow-relapsing strains in temperate areas with seasonal transmission. We hypothesize that much of the phenotypic diversity in P. vivax relapses arises from selection of relapse frequency to optimize transmission potential in a given environment, in a process similar to the virulence trade-off hypothesis. We develop mathematical models of P. vivax transmission and calculate the basic reproduction number R0 to investigate how transmission potential varies with relapse frequency and seasonality. In tropical zones with year-round transmission, transmission potential is optimized at intermediate relapse frequencies of two to three months: slower-relapsing strains increase the opportunity for onward transmission to mosquitoes, but also increase the risk of being outcompeted by faster-relapsing strains. Seasonality is an important driver of relapse frequency for temperate strains, with the time to first relapse predicted to be six to nine months, coinciding with the duration between seasonal transmission peaks. We predict that there is a threshold degree of seasonality, below which fast-relapsing tropical strains are selected for, and above which slow-relapsing temperate strains dominate, providing an explanation for the observed global distribution of relapse phenotypes.

Journal article

Penny MA, Verity RV, Bever C, Sauboin C, Galactionova K, Flasche S, White MT, Wenger EA, Van de Velde N, Pemberton-Ross P, Griffin JT, Smith TA, Eckhoff PA, Muhib F, Jit M, Ghani ACet 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

Journal article

Robinson LJ, Wampfler R, Betuela I, Karl S, White MT, Li Wai Suen C, Hofmann NE, Kinboro B, Waltmann A, Brewster J, Lorry L, Tarongka N, Samol L, Silkey M, Bassat Q, Siba PM, Schofield L, Felger I, Mueller Iet al., 2015, Strategies for Understanding and Reducing the Plasmodium vivax and Plasmodium ovale Hypnozoite Reservoir in Papua New Guinean Children: A Randomised Placebo-Controlled Trial and Mathematical Model, PLOS Medicine, Vol: 12, ISSN: 1549-1277

BackgroundThe undetectable hypnozoite reservoir for relapsing Plasmodium vivax and P. ovale malarias presents a major challenge for malaria control and elimination in endemic countries. This study aims to directly determine the contribution of relapses to the burden of P. vivax and P. ovale infection, illness, and transmission in Papua New Guinean children.Methods and FindingsFrom 17 August 2009 to 20 May 2010, 524 children aged 5–10 y from East Sepik Province in Papua New Guinea (PNG) participated in a randomised double-blind placebo-controlled trial of blood- plus liver-stage drugs (chloroquine [CQ], 3 d; artemether-lumefantrine [AL], 3 d; and primaquine [PQ], 20 d, 10 mg/kg total dose) (261 children) or blood-stage drugs only (CQ, 3 d; AL, 3 d; and placebo [PL], 20 d) (263 children). Participants, study staff, and investigators were blinded to the treatment allocation. Twenty children were excluded during the treatment phase (PQ arm: 14, PL arm: 6), and 504 were followed actively for 9 mo. During the follow-up time, 18 children (PQ arm: 7, PL arm: 11) were lost to follow-up. Main primary and secondary outcome measures were time to first P. vivax infection (by qPCR), time to first clinical episode, force of infection, gametocyte positivity, and time to first P. ovale infection (by PCR). A basic stochastic transmission model was developed to estimate the potential effect of mass drug administration (MDA) for the prevention of recurrent P. vivax infections. Targeting hypnozoites through PQ treatment reduced the risk of having at least one qPCR-detectable P. vivax or P. ovale infection during 8 mo of follow-up (P. vivax: PQ arm 0.63/y versus PL arm 2.62/y, HR = 0.18 [95% CI 0.14, 0.25], p < 0.001; P. ovale: 0.06 versus 0.14, HR = 0.31 [95% CI 0.13, 0.77], p = 0.011) and the risk of having at least one clinical P. vivax episode (HR = 0.25 [95% CI 0.11, 0.61], p = 0.002). PQ also reduced the molecular force of P. vivax blood-stage infection in the first 3 mo o

Journal article

White MT, Verity R, Churcher TS, Ghani ACet al., 2015, Vaccine approaches to malaria control and elimination: Insights from mathematical models, Vaccine, Vol: 33, Pages: 7544-7550, ISSN: 1873-2518

A licensed malaria vaccine would provide a valuable new tool for malaria control and elimination efforts.Several candidate vaccines targeting different stages ofthe malaria parasite’s lifecycle are currently underdevelopment, with one candidate, RTS,S/AS01 for the prevention of Plasmodium falciparum infection,having recently completed Phase III trials. Predicting the public health impact of a candidate malariavaccine requires using clinical trial data to estimate the vaccine’s efficacy profile—the initial efficacyfollowing vaccination and the pattern of waning of efficacy over time. With an estimated vaccine efficacyprofile, the effects of vaccination on malaria transmission can be simulated with the aid of mathematicalmodels.Here, we provide an overview of methods for estimating the vaccine efficacy profiles of pre-erythrocyticvaccines and transmission-blocking vaccines from clinicaltrial data. In the case of RTS,S/AS01, model estimatesfrom Phase II clinical trial data indicate a bi-phasic exponential profile of efficacy against infection,with efficacy waning rapidly in the first 6 months after vaccination followed by a slower rate of waningover the next 4 years. Transmission-blocking vaccines have yet to be tested in large-scale Phase II orPhase III clinical trials so we review ongoing work investigating how a clinical trial might be designed toensure that vaccine efficacy can be estimated with sufficient statistical power. Finally, we demonstratehow parameters estimated from clinical trials can be used to predict the impact of vaccination campaignson malaria using a mathematical model of malaria transmission

Journal article

White MT, Verity R, Griffin JT, Asante KP, Owusu-Agyei S, Greenwood B, Drakeley C, Gesase S, Lusingu J, Ansong D, Adjei S, Agbenyega T, Ogutu B, Otieno L, Otieno W, Agnandji ST, Lell B, Kremsner P, Hoffman I, Martinson F, Kamthunzu P, Tinto H, Valea I, Sorgho H, Oneko M, Otieno K, Hamel MJ, Salim N, Mtoro A, Abdulla S, Aide P, Sacarlal J, Aponte JJ, Njuguna P, Marsh K, Bejon P, Riley EM, Ghani ACet 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

Journal article

Walker PGT, White MT, Griffin JT, Reynolds A, Ferguson NM, Ghani ACet al., 2015, Malaria morbidity and mortality in Ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis, Lancet Infectious Diseases, Vol: 15, Pages: 825-832, ISSN: 1473-3099

BackgroundThe ongoing Ebola epidemic in parts of west Africa largely overwhelmed health-care systems in 2014, making adequate care for malaria impossible and threatening the gains in malaria control achieved over the past decade. We quantified this additional indirect burden of Ebola virus disease.MethodsWe estimated the number of cases and deaths from malaria in Guinea, Liberia, and Sierra Leone from Demographic and Health Surveys data for malaria prevalence and coverage of malaria interventions before the Ebola outbreak. We then removed the effect of treatment and hospital care to estimate additional cases and deaths from malaria caused by reduced health-care capacity and potential disruption of delivery of insecticide-treated bednets. We modelled the potential effect of emergency mass drug administration in affected areas on malaria cases and health-care demand.FindingsIf malaria care ceased as a result of the Ebola epidemic, untreated cases of malaria would have increased by 45% (95% credible interval 43–49) in Guinea, 88% (83–93) in Sierra Leone, and 140% (135–147) in Liberia in 2014. This increase is equivalent to 3·5 million (95% credible interval 2·6 million to 4·9 million) additional untreated cases, with 10 900 (5700–21 400) additional malaria-attributable deaths. Mass drug administration and distribution of insecticide-treated bednets timed to coincide with the 2015 malaria transmission season could largely mitigate the effect of Ebola virus disease on malaria.InterpretationThese findings suggest that untreated malaria cases as a result of reduced health-care capacity probably contributed substantially to the morbidity caused by the Ebola crisis. Mass drug administration can be an effective means to mitigate this burden and reduce the number of non-Ebola fever cases within health systems.

Journal article

Cheke RA, Basanez MG, Perry M, White MT, Garms R, Obuobie E, Lamberton PH, Young S, Osei-Atweneboana M, Intsiful J, Shen M, Boakye DA, Wilson Met al., 2015, Potential effects of warmer worms and vectors on onchocerciasis transmission in West Africa, Philosophical Transactions of the Royal Society B: Biological Sciences, ISSN: 1471-2970

Journal article

White MT, Karl S, Battle K, Hay SI, Mueller I, Ghani ACet al., 2014, Modelling the contribution of the hypnozoite reservoir to Plasmodium vivax transmission, eLife, Vol: 3, ISSN: 2050-084X

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 article

Ismail HA, Tijani MK, Langer C, Reiling L, White MT, Beeson JG, Wahlgren M, Nwuba R, Persson KEMet al., 2014, Subclass responses and their half-lives for antibodies against EBA175 and PfRh2 in naturally acquired immunity against Plasmodium falciparum malaria, MALARIA JOURNAL, Vol: 13, ISSN: 1475-2875

Journal article

White MT, Griffin JT, Akpogheneta O, Conway DJ, Koram KA, Riley EM, Ghani ACet 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

Journal article

Pinsent A, Blake IM, White MT, Riley Set al., 2014, Surveillance of low pathogenic novel H7N9 avian influenza in commercial poultry barns: detection of outbreaks and estimation of virus introduction time, BMC INFECTIOUS DISEASES, Vol: 14, ISSN: 1471-2334

BackgroundBoth high and low pathogenic subtype A avian influenza remain ongoing threats to the commercial poultry industry globally. The emergence of a novel low pathogenic H7N9 lineage in China presents itself as a new concern to both human and animal health and may necessitate additional surveillance in commercial poultry operations in affected regions.MethodsSampling data was simulated using a mechanistic model of H7N9 influenza transmission within commercial poultry barns together with a stochastic observation process. Parameters were estimated using maximum likelihood. We assessed the probability of detecting an outbreak at time of slaughter using both real-time polymerase chain reaction (rt-PCR) and a hemagglutinin inhibition assay (HI assay) before considering more intense sampling prior to slaughter. The day of virus introduction and R 0 were estimated jointly from weekly flock sampling data. For scenarios where R 0 was known, we estimated the day of virus introduction into a barn under different sampling frequencies.ResultsIf birds were tested at time of slaughter, there was a higher probability of detecting evidence of an outbreak using an HI assay compared to rt-PCR, except when the virus was introduced <2 weeks before time of slaughter. Prior to the initial detection of infection N s a m p l e = 50 (1%) of birds were sampled on a weekly basis once, but after infection was detected, N s a m p l e = 2000 birds (40%) were sampled to estimate both parameters. We accurately estimated the day of virus introduction in isolation with weekly and 2-weekly sampling.ConclusionsA strong sampling effort would be required to infer both the day of virus introduction and R 0. Such a sampling effort would not be required to estimate the day of virus introduction alone once R 0 was known, and sampling N s a m p l e = 50 of birds in the flock on a weekly or 2 weekly basis would be sufficient.

Journal article

Imai N, White MT, Ghani AC, Drakeley CJet al., 2014, Transmission and Control of Plasmodium knowlesi: A Mathematical Modelling Study, PLOS Neglected Tropical Diseases, Vol: 8, ISSN: 1935-2735

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 article

White MT, Bejon P, Olotu A, Griffin JT, Bojang K, Lusingu J, Salim N, Abdulla S, Otsyula N, Agnandji ST, Lell B, Asante KP, Owusu-Agyei S, Mahama E, Agbenyega T, Ansong D, Sacarlal J, Aponte JJ, Ghani ACet 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 article

White MT, Lwetoijera D, Marshall J, Caron-Lormier G, Bohan DA, Denholm I, Devine GJet al., 2014, Negative Cross Resistance Mediated by Co-Treated Bed Nets: A Potential Means of Restoring Pyrethroid-Susceptibility to Malaria Vectors, PLOS ONE, Vol: 9, ISSN: 1932-6203

Journal article

Marshall JM, White MT, Ghani AC, Schlein Y, Muller GC, Beier JCet 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 article

White MT, Smith DL, 2013, Synergism from combinations of infection-blocking malaria vaccines, MALARIA JOURNAL, Vol: 12, ISSN: 1475-2875

Journal article

White 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 article

Killeen GF, Seyoum A, Sikaala C, Zomboko AS, Gimnig JE, Govella NJ, White MTet al., 2013, Eliminating malaria vectors, PARASITES & VECTORS, Vol: 6, ISSN: 1756-3305

Journal article

White MT, Bejon P, Olotu A, Griffin JT, Riley EM, Kester KE, Ockenhouse CF, Ghani ACet al., 2013, The Relationship between RTS,S Vaccine-Induced Antibodies, CD4(+) T Cell Responses and Protection against Plasmodium falciparum Infection, PLOS ONE, Vol: 8, ISSN: 1932-6203

Journal article

Bejon P, White MT, Olotu A, Bojang K, Lusingu JPA, Salim N, Otsyula NN, Agnandji ST, Asante KP, Owusu-Agyei S, Abdulla S, Ghani ACet al., 2013, Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data, LANCET INFECTIOUS DISEASES, Vol: 13, Pages: 319-327, ISSN: 1473-3099

Journal article

White MT, Conteh L, Cibulskis R, Ghani ACet al., 2011, Costs and cost-effectiveness of malaria control interventions - a systematic review, MALARIA JOURNAL, Vol: 10

Journal article

White MT, Conteh L, Cibulskis R, Ghani ACet al., 2011, Costs and cost-effectiveness of malaria control interventions - a systematic review, Malaria Journal

BACKGROUND:The control and elimination of malaria requires expanded coverage of and access to effective malaria control interventions such as insecticide-treated nets (ITNs), indoor residual spraying (IRS), intermittent preventive treatment (IPT), diagnostic testing and appropriate treatment. Decisions on how to scale up the coverage of these interventions need to be based on evidence of programme effectiveness, equity and cost-effectiveness.METHODS:A systematic review of the published literature on the costs and cost-effectiveness of malaria interventions was undertaken. All costs and cost-effectiveness ratios were inflated to 2009 USD to allow comparison of the costs and benefits of several different interventions through various delivery channels, across different geographical regions and from varying costing perspectives.RESULTS:Fifty-five studies of the costs and forty three studies of the cost-effectiveness of malaria interventions were identified, 78% of which were undertaken in sub-Saharan Africa, 18% in Asia and 4% in South America. The median financial cost per ITN distributed was $7.03 (range $2.97-$19.20), $3.91 (range $1.11-$12.87) per household for IRS, $0.10 (range $0.08-$0.18) for IPT in infants, $4.03 (range $1.25-$11.80) for IPT in children, and $2.06 (range $0.47-$3.36) for IPT in pregnant women. The median financial cost of diagnosing a case of malaria was $4.32 (range $0.34-$9.34). The median financial cost of treating an episode of uncomplicated malaria was $5.84 (range $2.36-$23.65) and the median financial cost of treating an episode of severe malaria was $30.26 (range $15.64-$137.87). Economies of scale were observed in the implementation of ITNs, IRS and IPT, with lower unit costs reported in studies with larger numbers of beneficiaries. From a provider perspective, the median incremental cost effectiveness ratio per disability adjusted life year averted was $27 (range $8.15-$110) for ITNs, $143 (range $135-$150) for IRS, and $24 (range $1.

Journal article

White MT, Griffin JT, Churcher TS, Ferguson NM, Basanez MG, Ghani ACet al., 2011, Modelling the impact of vector control interventions on Anopheles gambiae population dynamics, Parasites & Vectors, Vol: 4, ISSN: 1756-3305

BACKGROUND:Intensive anti-malaria campaigns targeting the Anopheles population have demonstrated substantial reductions in adult mosquito density. Understanding the population dynamics of Anopheles mosquitoes throughout their whole lifecycle is important to assess the likely impact of vector control interventions alone and in combination as well as to aid the design of novel interventions.METHODS:An ecological model of Anopheles gambiae sensu lato populations incorporating a rainfall-dependent carrying capacity and density-dependent regulation of mosquito larvae in breeding sites is developed. The model is fitted to adult mosquito catch and rainfall data from 8 villages in the Garki District of Nigeria (the 'Garki Project') using Bayesian Markov Chain Monte Carlo methods and prior estimates of parameters derived from the literature. The model is used to compare the impact of vector control interventions directed against adult mosquito stages--long-lasting insecticide treated nets (LLIN), indoor residual spraying (IRS)-- and directed against aquatic mosquito stages, alone and in combination on adult mosquito density.RESULTS:A model in which density-dependent regulation occurs in the larval stages via a linear association between larval density and larval death rates provided a good fit to seasonal adult mosquito catches. The effective mosquito reproduction number in the presence of density-dependent regulation is dependent on seasonal rainfall patterns and peaks at the start of the rainy season. In addition to killing adult mosquitoes during the extrinsic incubation period, LLINs and IRS also result in less eggs being oviposited in breeding sites leading to further reductions in adult mosquito density. Combining interventions such as the application of larvicidal or pupacidal agents that target the aquatic stages of the mosquito lifecycle with LLINs or IRS can lead to substantial reductions in adult mosquito density.CONCLUSIONS:Density-dependent regulation of anophel

Journal article

Okell LC, Griffin JT, Kleinschmidt I, Hollingsworth TD, Churcher TS, White MT, Bousema T, Drakeley CJ, Ghani ACet al., 2011, The potential contribution of mass treatment to the control of Plasmodium falciparum malaria., PLoS One

Mass treatment as a means to reducing P. falciparum malaria transmission was used during the first global malaria eradication campaign and is increasingly being considered for current control programmes. We used a previously developed mathematical transmission model to explore both the short and long-term impact of possible mass treatment strategies in different scenarios of endemic transmission. Mass treatment is predicted to provide a longer-term benefit in areas with lower malaria transmission, with reduced transmission levels for at least 2 years after mass treatment is ended in a scenario where the baseline slide-prevalence is 5%, compared to less than one year in a scenario with baseline slide-prevalence at 50%. However, repeated annual mass treatment at 80% coverage could achieve around 25% reduction in infectious bites in moderate-to-high transmission settings if sustained. Using vector control could reduce transmission to levels at which mass treatment has a longer-term impact. In a limited number of settings (which have isolated transmission in small populations of 1000-10,000 with low-to-medium levels of baseline transmission) we find that five closely spaced rounds of mass treatment combined with vector control could make at least temporary elimination a feasible goal. We also estimate the effects of using gametocytocidal treatments such as primaquine and of restricting treatment to parasite-positive individuals. In conclusion, mass treatment needs to be repeated or combined with other interventions for long-term impact in many endemic settings. The benefits of mass treatment need to be carefully weighed against the risks of increasing drug selection pressure.

Journal article

White MT, Griffin JT, Riley EM, Drakeley CJ, Moorman AM, Sumba PO, Kazura JW, Ghani AC, John CCet al., 2011, Efficacy model for antibody-mediated pre-erythrocytic malaria vaccines, PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 278, Pages: 1298-1305, ISSN: 0962-8452

Journal article

White M, Griffin JT, Riley EM, Drakeley CJ, Moormann AM, Sumba PO, Kazura JW, Ghani AC, John CCet al., 2010, Efficacy model for antibody-mediated pre-erythrocytic malaria vaccines, Proc Biol Sci., Pages: 1298-1305

Antibodies to the pre-erythrocytic antigens, circumsporozoite protein (CSP), thrombospondin-related adhesive protein (TRAP) and liver-stage antigen 1, have been measured in field studies of semi-immune adults and shown to correlate with protection from Plasmodium falciparum infection. A mathematical model is formulated to estimate the probability of sporozoite infection as a function of antibody titres to multiple pre-erythrocytic antigens. The variation in antibody titres from field data was used to estimate the relationship between the probability of P. falciparum infection per infectious mosquito bite and antibody titre. Using this relationship, we predict the effect of vaccinations that boost baseline CSP or TRAP antibody titres. Assuming the estimated relationship applies to vaccine-induced antibody titres, then single-component CSP or TRAP antibody-mediated pre-erythrocytic vaccines are likely to provide partial protection from infection, with vaccine efficacy of approximately 50 per cent depending on the magnitude of the vaccine-induced boost to antibody titres. It is possible that the addition of a TRAP component to a CSP-based vaccine such as RTS,S would provide an increase in infection-blocking efficacy of approximately 25 per cent should the problem of immunological interference between antigens be overcome.

Journal article

Griffin JT, Hollingsworth TD, Okell LC, Churcher TS, White MT, Hinsley W, Bousema T, Drakeley CJ, Ferguson NM, Basanez MG, Ghani ACet al., 2010, Reducing Plasmodium falciparum malaria transmission in Africa: a model-based evaluation of intervention strategies, PLoS Medicine

BACKGROUND:Over the past decade malaria intervention coverage has been scaled up across Africa. However, it remains unclear what overall reduction in transmission is achievable using currently available tools.METHODS AND FINDINGS:We developed an individual-based simulation model for Plasmodium falciparum transmission in an African context incorporating the three major vector species (Anopheles gambiae s.s., An. arabiensis, and An. funestus) with parameters obtained by fitting to parasite prevalence data from 34 transmission settings across Africa. We incorporated the effect of the switch to artemisinin-combination therapy (ACT) and increasing coverage of long-lasting insecticide treated nets (LLINs) from the year 2000 onwards. We then explored the impact on transmission of continued roll-out of LLINs, additional rounds of indoor residual spraying (IRS), mass screening and treatment (MSAT), and a future RTS,S/AS01 vaccine in six representative settings with varying transmission intensity (as summarized by the annual entomological inoculation rate, EIR: 1 setting with low, 3 with moderate, and 2 with high EIRs), vector-species combinations, and patterns of seasonality. In all settings we considered a realistic target of 80% coverage of interventions. In the low-transmission setting (EIR approximately 3 ibppy [infectious bites per person per year]), LLINs have the potential to reduce malaria transmission to low levels (<1% parasite prevalence in all age-groups) provided usage levels are high and sustained. In two of the moderate-transmission settings (EIR approximately 43 and 81 ibppy), additional rounds of IRS with DDT coupled with MSAT could drive parasite prevalence below a 1% threshold. However, in the third (EIR = 46) with An. arabiensis prevailing, these interventions are insufficient to reach this threshold. In both high-transmission settings (EIR approximately 586 and 675 ibppy), either unrealistically high coverage levels (>90%) or novel tools and/or sub

Journal article

White MT, Griffin JT, Drakeley CJ, Ghani ACet al., 2010, Heterogeneity in malaria exposure and vaccine response: implications for the interpretation of vaccine efficacy trials, Malaria Journal

BACKGROUND:Phase III trials of the malaria vaccine, RTS, S, are now underway across multiple sites of varying transmission intensity in Africa. Heterogeneity in exposure, vaccine response and waning of efficacy may bias estimates of vaccine efficacy.METHODS:Theoretical arguments are used to identify the expected effects of a) heterogeneity in exposure to infectious bites; b) heterogeneity in individual's response to the vaccine; and c) waning efficacy on measures of vaccine efficacy from clinical trials for an infection-blocking vaccine.RESULTS:Heterogeneity in exposure and vaccine response leads to a smaller proportion of trial participants becoming infected than one would expect in a homogeneous setting. This causes estimates of vaccine efficacy from clinical trials to be underestimated if transmission heterogeneity is ignored, and overestimated if heterogeneity in vaccine response is ignored. Waning of vaccine efficacy can bias estimates of vaccine efficacy in both directions.CONCLUSIONS:Failure to account for heterogeneities in exposure and response, and waning of efficacy in clinical trials can lead to biased estimates of malaria vaccine efficacy. Appropriate methods to reduce these biases need to be used to ensure accurate interpretation and comparability between trial sites of results from the upcoming Phase III clinical trials of RTS, S.

Journal article

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