Feasibility, safety, and impact of the RTS,S/AS01E malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi.

BACKGROUND: The RTS,S/AS01E malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use. METHODS: In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. We estimated that sufficient data would have accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-male mortality ratio in age groups eligible to receive the vaccine (relative to the ratio in non-eligible children) was compared between implementation and comparison areas. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission. FINDINGS: By April 30, 2021, 652 673 children had received at least one dose of RTS,S and 494 745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 26 285 children aged 1-59 months were admitted to sentinel hospitals and 13 198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22-1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61-1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88-1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5-51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0-18%) in all-cause mortality (excluding injury). INTERPRETATION: In the first 2 years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes. There was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of four doses of RTS,S. FUNDING: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.

Measuring protective efficacy and quantifying the impact of drug resistance: A novel malaria chemoprevention trial design and methodology.

BACKGROUND: Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings. METHODS AND FINDINGS: We developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common. CONCLUSIONS: These findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance.

Making the most of malaria chemoprevention.

Against a backdrop of stalled progress in malaria control, it is surprising that the various forms of malaria chemoprevention are not more widely used. The World Health Organization (WHO) has recommended several malaria chemoprevention strategies, some of them for over a decade, and each with documented efficacy and cost effectiveness. In 2022, the WHO updated and augmented its malaria chemoprevention guidelines to facilitate their wider use. This paper considers new insights into the empirical evidence that supports the broader application of chemoprevention and encourages its application as a default strategy for young children living in moderate to high transmission settings given their high risk of severe disease and death. Chemoprevention is an effective medium-term strategy with potential benefits far outweighing costs. There is a strong argument for urgently increasing malaria chemoprevention in endemic countries.

Building momentum for malaria vaccine research and development: key considerations.

To maintain momentum towards improved malaria control and elimination, a vaccine would be a key addition to the intervention toolkit. Two approaches are recommended: (1) promote the development and short to medium term deployment of first generation vaccine candidates and (2) support innovation and discovery to identify and develop highly effective, long-lasting and affordable next generation malaria vaccines.

Averting a malaria disaster: will insecticide resistance derail malaria control?

World Malaria Day 2015 highlighted the progress made in the development of new methods of prevention (vaccines and insecticides) and treatment (single dose drugs) of the disease. However, increasing drug and insecticide resistance threatens the successes made with existing methods. Insecticide resistance has decreased the efficacy of the most commonly used insecticide class of pyrethroids. This decreased efficacy has increased mosquito survival, which is a prelude to rising incidence of malaria and fatalities. Despite intensive research efforts, new insecticides will not reach the market for at least 5 years. Elimination of malaria is not possible without effective mosquito control. Therefore, to combat the threat of resistance, key stakeholders need to rapidly embrace a multifaceted approach including a reduction in the cost of bringing new resistance management methods to market and the streamlining of associated development, policy, and implementation pathways to counter this looming public health catastrophe.

Variability of respiratory rate measurements in children suspected with non-severe pneumonia in north-east Tanzania.

OBJECTIVE: Measurement of respiratory rate is an important clinical sign in the diagnosis of pneumonia but suffers from interobserver variation. Here, we assess the use of video recordings as a quality assurance tool that could be useful both in research and in training of staff. METHODS: Respiratory rates (RR) were recorded in children aged 2-59 months presenting with cough or difficulty breathing at two busy outpatient clinics in Tanzania. Measurements were repeated at 10-min intervals in a quiet environment with simultaneous video recordings that were independently reviewed by two paediatricians. RESULTS: Eight hundred and fifty-nine videos were sent to two paediatricians; 148 (17.2%) were considered unreadable by one or both. For the 711 (82.8%) videos that were readable by both paediatricians, there was perfect agreement for the presence of raised RR with a kappa value (κ) of 0.85 (P < 0.001); and in 476 (66.9%) cases, both paediatricians agreed on the RR within 2 breaths per minute (±2 bpm). A reported illness of 5 days or more was associated with unreadable video recordings (OR = 3.44, CI: 1.5-6.08; P < 0.001). The multilevel model showed that differences between observers accounted for only 13% of the variability in RR. CONCLUSION: Video recordings are reliable tools for quality assurance of RR measurements in children with suspected pneumonia. Videos with a clear view of respiratory movements may also be useful in training primary healthcare staff.

Fake anti-malarials: start with the facts.

This meeting report presents the key findings and discussion points of a 1-day meeting entitled 'Fake anti-malarials: start with the facts' held on 28th May 2015, in Geneva, Switzerland, to disseminate the findings of the artemisinin combination therapy consortium's drug quality programme. The teams purchased over 10,000 samples, using representative sampling approaches, from six malaria endemic countries: Equatorial Guinea (Bioko Island), Cambodia, Ghana, Nigeria, Rwanda and Tanzania. Laboratory analyses of these samples showed that falsified anti-malarials (<8 %) were found in just two of the countries, whilst substandard artemisinin-based combinations were present in all six countries and, artemisinin-based monotherapy tablets are still available in some places despite the fact that the WHO has urged regulatory authorities in malaria-endemic countries to take measures to halt the production and marketing of these oral monotherapies since 2007. This report summarizes the presentations that reviewed the public health impact of falsified and substandard drugs, sampling strategies, techniques for drug quality analysis, approaches to strengthen health systems capacity for the surveillance of drug quality, and the ensuing discussion points from the dissemination meeting.

Monitoring patient care through health facility exit interviews: an assessment of the Hawthorne effect in a trial of adherence to malaria treatment guidelines in Tanzania.

BACKGROUND: Survey of patients exiting health facilities is a common way to assess consultation practices. It is, however, unclear to what extent health professionals may change their practices when they are aware of such interviews taking place, possibly paying more attention to following recommended practices. This so-called Hawthorne effect could have important consequences for interpreting research and programme monitoring, but has rarely been assessed. METHODS: A three-arm cluster-randomised trial of interventions to improve adherence to guidelines for the use of anti-malarial drugs was conducted in Tanzania. Patient interviews were conducted outside health facilities on two randomly-selected days per week. Health workers also routinely documented consultations in their ledgers. The Hawthorne effect was investigated by comparing routine data according to whether exit interviews had been conducted on three key indicators of malaria care. Adjusted logistic mixed-effects models were used, taking into account the dependencies within health facilities and calendar days. RESULTS: Routine data were collected on 19,579 consultations in 18 facilities. The odds of having a malaria rapid diagnostic test (RDT) result reported were 11 % higher on days when exit surveys were conducted (adjusted odds ratio 95 % CI: 0.98-1.26, p = 0.097), 17 % lower for prescribing an anti-malarial drug to patients with a negative RDT result (0.56-1.23, p = 0.343), and 27 % lower for prescribing an anti-malarial when no RDT result was reported (0.53-1.00, p = 0.052). The effect varied with time, with a U-shaped association over the study period (p < 0.001). We also observed a higher number of consultations recorded on days when exit-interviews were conducted (adjusted mean difference = 2.03, p < 0.001). CONCLUSIONS: Although modest, there was some suggestion of better practice by health professionals on days when exit interviews were conducted. Researchers should be aware of the potential Hawthorne effect, and take into account assessment methods when generalising findings to the 'real word' setting. This effect is, however, likely to be context dependent, and further controlled evaluation across different settings should be conducted. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01292707 . Registered on 29th January 2011.

Effectiveness of a Home-Based Counselling Strategy on Neonatal Care and Survival: A Cluster-Randomised Trial in Six Districts of Rural Southern Tanzania.

BACKGROUND: We report a cluster-randomised trial of a home-based counselling strategy, designed for large-scale implementation, in a population of 1.2 million people in rural southern Tanzania. We hypothesised that the strategy would improve neonatal survival by around 15%. METHODS AND FINDINGS: In 2010 we trained 824 female volunteers to make three home visits to women and their families during pregnancy and two visits to them in the first few days of the infant's life in 65 wards, selected randomly from all 132 wards in six districts in Mtwara and Lindi regions, constituting typical rural areas in Southern Tanzania. The remaining wards were comparison areas. Participants were not blinded to the intervention. The primary analysis was an intention-to-treat analysis comparing the neonatal mortality (day 0-27) per 1,000 live births in intervention and comparison wards based on a representative survey in 185,000 households in 2013 with a response rate of 90%. We included 24,381 and 23,307 live births between July 2010 and June 2013 and 7,823 and 7,555 live births in the last year in intervention and comparison wards, respectively. We also compared changes in neonatal mortality and newborn care practices in intervention and comparison wards using baseline census data from 2007 including 225,000 households and 22,243 births in five of the six intervention districts. Amongst the 7,823 women with a live birth in the year prior to survey in intervention wards, 59% and 41% received at least one volunteer visit during pregnancy and postpartum, respectively. Neonatal mortality reduced from 35.0 to 30.5 deaths per 1,000 live births between 2007 and 2013 in the five districts, respectively. There was no evidence of an impact of the intervention on neonatal survival (odds ratio [OR] 1.1, 95% confidence interval [CI] 0.9-1.2, p = 0.339). Newborn care practices reported by mothers were better in intervention than in comparison wards, including immediate breastfeeding (42% of 7,287 versus 35% of 7,008, OR 1.4, CI 1.3-1.6, p < 0.001), feeding only breast milk for the first 3 d (90% of 7,557 versus 79% of 7,307, OR 2.2, 95% CI 1.8-2.7, p < 0.001), and clean hands for home delivery (92% of 1,351 versus 88% of 1,799, OR 1.5, 95% CI 1.0-2.3, p = 0.033). Facility delivery improved dramatically in both groups from 41% of 22,243 in 2007 and was 82% of 7,820 versus 75% of 7,553 (OR 1.5, 95% CI 1.2-2.0, p = 0.002) in intervention and comparison wards in 2013. Methodological limitations include our inability to rule out some degree of leakage of the intervention into the comparison areas and response bias for newborn care behaviours. CONCLUSION: Neonatal mortality remained high despite better care practices and childbirth in facilities becoming common. Public health action to improve neonatal survival in this setting should include a focus on improving the quality of facility-based childbirth care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01022788.

Effect of context on respiratory rate measurement in identifying non-severe pneumonia in African children.

OBJECTIVE: Cough or difficult breathing and an increased respiratory rate for their age are the commonest indications for outpatient antibiotic treatment in African children. We aimed to determine whether respiratory rate was likely to be transiently raised by a number of contextual factors in a busy clinic leading to inaccurate diagnosis. METHODS: Respiratory rates were recorded in children aged 2-59 months presenting with cough or difficulty breathing to one of the two busy outpatient clinics and then repeated at 10-min intervals over 1 h in a quiet setting. RESULTS: One hundred and sixty-seven children were enrolled with a mean age of 7.1 (SD ± 2.9) months in infants and 27.6 (SD ± 12.8) months in children aged 12-59 months. The mean respiratory rate declined from 42.3 and 33.6 breaths per minute (bpm) in the clinic to 39.1 and 32.6 bpm after 10 min in a quiet room and to 39.2 and 30.7 bpm (P < 0.001) after 60 min in younger and older children, respectively. This resulted in 11/13 (85%) infants and 2/15 (13%) older children being misclassified with non-severe pneumonia. In a random effects linear regression model, the variability in respiratory rate within children (42%) was almost as much as the variability between children (58%). Changing the respiratory rates cut-offs to higher thresholds resulted in a small reduction in the proportion of non-severe pneumonia mis-classifications in infants. CONCLUSION: Noise and other contextual factors may cause a transient increase in respiratory rate and consequently misclassification of non-severe pneumonia. However, this effect is less pronounced in older children than infants. Respiratory rate is a difficult sign to measure as the variation is large between and within children. More studies of the accuracy and utility of respiratory rate as a proxy for non-severe pneumonia diagnosis in a busy clinic are needed.

Are Tanzanian patients attending public facilities or private retailers more likely to adhere to artemisinin-based combination therapy?

BACKGROUND: Artemisinin combination therapy (ACT) is first-line treatment for malaria in most endemic countries and is increasingly available in the private sector. Most studies on ACT adherence have been conducted in the public sector, with minimal data from private retailers. METHODS: Parallel studies were conducted in Tanzania, in which patients obtaining artemether-lumefantrine (AL) at 40 randomly selected public health facilities and 37 accredited drug dispensing outlets (ADDOs) were visited at home and questioned about doses taken. The effect of sector on adherence, controlling for potential confounders was assessed using logistic regression with a random effect for outlet. RESULTS: Of 572 health facility patients and 450 ADDO patients, 74.5% (95% CI: 69.8, 78.8) and 69.8% (95% CI: 64.6, 74.5), respectively, completed treatment and 46.0% (95% CI: 40.9, 51.2) and 34.8% (95% CI: 30.1, 39.8) took each dose at the correct time ('timely completion'). ADDO patients were wealthier, more educated, older, sought care later in the day, and were less likely to test positive for malaria than health facility patients. Controlling for patient characteristics, the adjusted odds of completed treatment and of timely completion for ADDO patients were 0.65 (95% CI: 0.43, 1.00) and 0.69 (95% CI: 0.47, 1.01) times that of health facility patients. Higher socio-economic status was associated with both adherence measures. Higher education was associated with completed treatment (adjusted OR = 1.68, 95% CI: 1.20, 2.36); obtaining AL in the evening was associated with timely completion (adjusted OR = 0.35, 95% CI: 0.19, 0.64). Factors associated with adherence in each sector were examined separately. In both sectors, recalling correct instructions was positively associated with both adherence measures. In health facility patients, but not ADDO patients, taking the first dose of AL at the outlet was associated with timely completion (adjusted OR = 2.11, 95% CI: 1.46, 3.04). CONCLUSION: When controlling for patient characteristics, there was some evidence that the adjusted odds of adherence for ADDO patients was lower than that for public health facility patients. Better understanding is needed of which patient care aspects are most important for adherence, including the role of effective provision of advice.

Malaria in school-age children in Africa: an increasingly important challenge.

School-age children have attracted relatively little attention as a group in need of special measures to protect them against malaria. However, increasing success in lowering the level of malaria transmission in many previously highly endemic areas will result in children acquiring immunity to malaria later in life than has been the case in the past. Thus, it can be anticipated that in the coming years there will be an increase in the incidence of both uncomplicated and severe malaria in school-age children in many previously highly endemic areas. In this review, which focuses primarily on Africa, recent data on the prevalence of malaria parasitaemia and on the incidence of clinical malaria in African school-age children are presented and evidence that malaria adversely effects school performance is reviewed. Long-lasting insecticide treated bednets (LLIN) are an effective method of malaria control but several studies have shown that school-age children use LLINs less frequently than other population groups. Antimalarial drugs are being used in different ways to control malaria in school-age children including screening and treatment and intermittent preventive treatment. Some studies of chemoprevention in school-age children have shown reductions in anaemia and improved school performance but this has not been the case in all trials and more research is needed to identify the situations in which chemoprevention is likely to be most effective and, in these situations, which type of intervention should be used. In the longer term, malaria vaccines may have an important role in protecting this important section of the community from malaria. Regardless of the control approach selected, it is important this is incorporated into the overall programme of measures being undertaken to enhance the health of African school-age children.

Effect of home-based counselling on newborn care practices in southern Tanzania one year after implementation: a cluster-randomised controlled trial.

BACKGROUND: In Sub-Saharan Africa over one million newborns die annually. We developed a sustainable and scalable home-based counselling intervention for delivery by community volunteers in rural southern Tanzania to improve newborn care practices and survival. Here we report the effect on newborn care practices one year after full implementation. METHODS: All 132 wards in the 6-district study area were randomised to intervention or comparison groups. Starting in 2010, in intervention areas trained volunteers made home visits during pregnancy and after childbirth to promote recommended newborn care practices including hygiene, breastfeeding and identification and extra care for low birth weight babies. In 2011, in a representative sample of 5,240 households, we asked women who had given birth in the previous year both about counselling visits and their childbirth and newborn care practices. RESULTS: Four of 14 newborn care practices were more commonly reported in intervention than comparison areas: delaying the baby's first bath by at least six hours (81% versus 68%, OR 2.0 (95% CI 1.2-3.4)), exclusive breastfeeding in the three days after birth (83% versus 71%, OR 1.9 (95% CI 1.3-2.9)), putting nothing on the cord (87% versus 70%, OR 2.8 (95% CI 1.7-4.6)), and, for home births, tying the cord with a clean thread (69% versus 39%, OR 3.4 (95% CI 1.5-7.5)). For other behaviours there was little evidence of differences in reported practices between intervention and comparison areas including childbirth in a health facility or with a skilled attendant, thermal care practices, breastfeeding within an hour of birth and, for home births, the birth attendant having clean hands, cutting the cord with a clean blade and birth preparedness activities. CONCLUSIONS: A home-based counselling strategy using volunteers and designed for scale-up can improve newborn care behaviours in rural communities of southern Tanzania. Further research is needed to evaluate if, and at what cost, these gains will lead to improved newborn survival. TRIAL REGISTRATION: Trial Registration Number NCT01022788 (http://www.clinicaltrials.gov, 2009).

A community-randomized evaluation of the effect of intermittent preventive treatment in infants on antimalarial drug resistance in southern Tanzania.

BACKGROUND: Intermittent preventive treatment in infants (IPTi) is the administration of sulfadoxine-pyrimethamine (SP) at 2, 3, and 9 months of age to prevent malaria. We investigated the influence of IPTi on drug resistance. METHODS: Twenty-four areas were randomly assigned to receive or not receive IPTi. Blood collected during representative household surveys at baseline and 15 and 27 months after implementation was tested for SP and resistance markers. RESULTS: The frequency of SP in blood was similar in the IPTi and comparison areas at baseline and at 15 months. dhfr and dhps mutations were also similar at baseline and then increased similarly in both arms after 15 months of SP-IPTi. First-line treatment was switched from SP to artemether-lumefantrine before the final survey, when SP positivity fell among infants in comparison areas but increased in IPTi areas. This was accompanied by an increase in dhfr but not dhps mutations in IPTi areas (P = .004 and P = .18, respectively). CONCLUSIONS: IPTi did not increase drug pressure or the selection on dhfr and dhps mutants, when SP was the first-line malaria treatment. Introduction of artemether-lumefantrine was followed by an increase in dhfr mutations, consistent with weak selection attributable to SP-IPTi, but not by an increase in dhps mutations, suggesting a fitness cost of this mutation.

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on the administration of sulfadoxine-pyrimethamine plus amodiaquine. However, poor regimen adherence and the increased frequency of parasite mutations conferring sulfadoxine-pyrimethamine resistance might threaten the effectiveness of SMC. Guidance is needed to de-risk the development of drug compounds for malaria prevention. We aimed to provide guidance for the early prioritisation of new and alternative SMC drugs and their target product profiles. METHODS: In this modelling study, we combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic and pharmacodynamic models. We modelled SMC drug attributes for several possible modes of action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum parasite killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions. FINDINGS: Model predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When children younger than 5 years receive four SMC cycles with high levels of coverage (ie, 69% of children receiving all cycles), drug candidates require a duration of protection half-life higher than 23 days (elimination half-life >10 days) to achieve reductions higher than 75% in clinical incidence and severe disease (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is crucial to achieve these targets, requiring more than 60% of children to receive all SMC cycles and more than 90% of children to receive at least one cycle regardless of the protection duration of the drug. INTERPRETATION: Although efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determining cycle timing. Explicitly designing or selecting drug properties to increase community uptake is paramount. FUNDING: Bill & Melinda Gates Foundation and the Swiss National Science Foundation.

Development of WHO Recommendations for the Final Phase of Elimination and Prevention of Re-Establishment of Malaria.

The WHO recommends that all affected countries work toward the elimination of malaria, even those still experiencing a high burden of disease. However, malaria programs in the final phase of elimination or those working to prevent re-establishment of transmission after elimination could benefit from specific evidence-based recommendations for these settings as part of comprehensive and quality-controlled malaria guidelines. The WHO convened an external guideline development group to formulate recommendations for interventions to reduce or prevent malaria transmission in areas with very low- to low-transmission levels and those that have eliminated malaria. In addition, several interventions that could be deployed in higher burden areas to accelerate elimination, such as mass drug administration, were reviewed. Systematic reviews were conducted that synthesized and evaluated evidence for the benefits and harms of public health interventions and summarized critical contextual factors from a health systems perspective. A total of 12 recommendations were developed, with five related to mass interventions that could be deployed at higher transmission levels and seven that would be most appropriate for programs in areas close to elimination or those working to prevent re-establishment of transmission. Four chemoprevention, two active case detection, and one vector control interventions were positively recommended, whereas two chemoprevention and three active case detection interventions were not recommended by the WHO. None of the recommendations were classified as strong given the limited and low-quality evidence base. Approaches to conducting higher quality research in very low- to low-transmission settings to improve the strength of WHO recommendations are discussed.

Public health system readiness to treat malaria in Odisha State of India.

BACKGROUND: Early diagnosis and prompt treatment is a cornerstone of malaria control. In India, artemisinin combination therapy (ACT) became the first-line treatment for falciparum malaria and rapid diagnostic test (RDTs) kits were recommended for use at the grass-root level in the new malaria treatment policy (2010). Odisha State contributes about one-fourth of the total Indian malaria burden and 40% of falciparum infection. The present study assessed the health system readiness to deploy RDTs and ACT for malaria control across the State. METHODS: Data collection was carried out from February to July 2012. Five of Odisha's 30 districts were selected through stratified random sampling, with stratification based on the phased roll-out of ACT and RDT. Two administrative 'blocks' were selected randomly in each district and data collected through health facility, auxiliary nurse midwives (ANMs) and accredited social health activist (ASHAs) assessments. Key informant interviews were conducted with individuals involved in the implementation of the malaria control programme. RESULTS: Of the 220 ANMs interviewed, 51.4% had been trained in malaria case management, including the use of ACT and RDT. A high proportion of ANM (80%) and AHSA (77%) had the necessary level of knowledge to be able to use RDT for malaria diagnosis. The proportion of ASHAs trained on malaria case management was 88.9% (209/235). However, 71% of ANM and 55% of ASHAs usually referred falciparum-positive patients to the health facility for treatment, the major reason for referral being the non-availability of drugs at the ANM and ASHA level. CONCLUSION: The relatively high level of knowledge about how to diagnose and treat malaria at the grass-root level was undermined by the poor availability of RDTs, ACT and primaquine tablets. This was associated with an unnecessarily high referral rate and potential delays in the treatment of this potentially life-threatening infection. Improvements in the supply chain for RDTs and ACT could dramatically enhance the effectiveness of malaria control in Odisha.

Seroepidemiological and parasitological evaluation of the heterogeneity of malaria infection in the Gambia.

BACKGROUND: As countries make progress in malaria control, transmission may be reduced to such an extent that few cases occur, and identification of the remaining foci of transmission may require a combination of surveillance tools. The study explored the usefulness of parasite prevalence, seroprevalence and model-estimated seroconversion rates for detecting local differences in malaria transmission in a West African country. METHODS: Age-stratified cross-sectional surveys were conducted during the wet season in 2008 and the following dry season in 2009 in The Gambia. In each season, 20 village communities were sampled from six diverse areas throughout the country. A total of 7,586 participants were surveyed, 51% (3,870) during the wet season. Parasites were detected by thick film slide microscopy, and anti-MSP1-19 antibodies were detected by ELISA using eluted dried blood from filter papers. RESULTS: Overall parasite prevalence was 12.4% in the wet season and 2.2% in the dry season, with village-specific parasite prevalence ranging from 1.4 to 45.9% in the wet season and from 0.0 to 13.2% in the dry season. Prevalence was highest in the eastern part of the country. Serological indices also varied between villages, indicating local heterogeneity in transmission, and there was a high correlation between wet and dry season estimates across the villages. The overall prevalence of anti-MSP119 antibodies was similar in the wet (19.5%) and in the dry (19.6%) seasons. CONCLUSION: The study illustrates the utility of measuring both parasite prevalence and serological indices for monitoring local variation in malaria transmission, which are more informative than single measures as control intensifies and malaria declines. Measurements of seropositivity have the logistical advantage of being relative stable seasonally so that sampling at any time of year may be conducted.

Community case management in malaria: review and perspectives after four years of operational experience in Saraya district, south-east Senegal.

BACKGROUND: Despite recent advances in malaria diagnosis and treatment, many isolated communities in rural settings continue to lack access to these life-saving tools. Community-case management of malaria (CCMm), consisting of lay health workers (LHWs) using malaria rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT) in their villages, can address this disparity. METHODS: This study examined routine reporting data from a CCMm programme between 2008 and 2011 in Saraya, a rural district in Senegal, and assessed its impact on timely access to rapid diagnostic tests and ACT. RESULTS: There was a seven-fold increase in the number of LHWs providing care and in the number of patients seen. LHW engagement in the CCM programme varied seasonally, 24,3% of all patients prescribed an ACT had a negative RDT or were never administered an RDT, and less than half of patients with absolute indications for referral (severe symptoms, age under two months and pregnancy) were referred. There were few stock-outs. DISCUSSION: This CCMm programme successfully increased the number of patients with access to RDT and ACT, but further investigation is required to identify the cause for over-prescription, and low rates of referrals for patients with absolute indications. In contrast, previous widespread stock-outs in Saraya's CCMm programme have now been resolved. CONCLUSION: This study demonstrates the potential for CCMm programmes to substantially increase access to life-saving malarial diagnostics and treatment, but also highlights important challenges in ensuring quality.

Randomized, controlled trial of the long term safety, immunogenicity and efficacy of RTS,S/AS02(D) malaria vaccine in infants living in a malaria-endemic region.

BACKGROUND: The RTS,S/AS malaria candidate vaccine is being developed with the intent to be delivered, if approved, through the Expanded Programme on Immunization (EPI) of the World Health Organization. Safety, immunogenicity and efficacy of the RTS,S/AS02(D) vaccine candidate when integrated into a standard EPI schedule for infants have been reported over a nine-month surveillance period. This paper describes results following 20 months of follow up. METHODS: This Phase IIb, single-centre, randomized controlled trial enrolled 340 infants in Tanzania to receive three doses of RTS,S/AS02(D) or hepatitis B vaccine at 8, 12, and 16 weeks of age. All infants also received DTPw/Hib (diphtheria and tetanus toxoids, whole-cell pertussis vaccine, conjugated Haemophilus influenzae type b vaccine) at the same timepoints. The study was double-blinded to month 9 and single-blinded from months 9 to 20. RESULTS: From month 0 to 20, at least one SAE was reported in 57/170 infants who received RTS,S/AS02(D) (33.5%; 95% confidence interval [CI]: 26.5, 41.2) and 62/170 infants who received hepatitis B vaccine (36.5%; 95% CI: 29.2, 44.2). The SAE profile was similar in both vaccine groups; none were considered to be related to vaccination. At month 20, 18 months after completion of vaccination, 71.8% of recipients of RTS,S/AS02(D) and 3.8% of recipients of hepatitis B vaccine had seropositive titres for anti-CS antibodies; seroprotective levels of anti-HBs antibodies remained in 100% of recipients of RTS,S/AS02(D) and 97.7% recipients of hepatitis B vaccine. Anti-HBs antibody GMTs were higher in the RTS,S/AS02(D) group at all post-vaccination time points compared to control. According to protocol population, vaccine efficacy against multiple episodes of malaria disease was 50.7% (95% CI: -6.5 to 77.1, p = 0.072) and 26.7% (95% CI: -33.1 to 59.6, p = 0.307) over 12 and 18 months post vaccination, respectively. In the Intention to Treat population, over the 20-month follow up, vaccine efficacy against multiple episodes of malaria disease was 14.4% (95% CI: -41.9 to 48.4, p = 0.545). CONCLUSIONS: The acceptable safety profile and good tolerability of RTS,S/AS02(D) in combination with EPI vaccines previously reported from month 0 to 9 was confirmed over a 20 month surveillance period in this infant population. Antibodies against both CS and HBsAg in the RTS,S/AS02(D) group remained significantly higher compared to control for the study duration. Over 18 months follow up, RTS,S/AS02(D) prevented approximately a quarter of malaria cases in the study population. CLINICAL TRIALS: Gov identifier: NCT00289185.