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Concept: Melinda Gates


Background We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the Sustainable Development Goals of the United Nations. Methods In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice-yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses. Results A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±10.4%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5% lower overall (95% confidence interval [CI], 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P<0.001); the rate was 5.7% lower in Malawi (95% CI, -9.7 to 18.9), 18.1% lower in Niger (95% CI, 10.0 to 25.5), and 3.4% lower in Tanzania (95% CI, -21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9% lower mortality than that with placebo; 95% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection for antibiotic resistance is ongoing. Conclusions Among postneonatal, preschool children in sub-Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger. Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation; MORDOR number, NCT02047981 .).

Concepts: Africa, Sub-Saharan Africa, Sahara, Malawi, United Nations, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates


Synthetic biology has the potential to contribute breakthrough innovations to the pursuit of new global health solutions. Wishing to harness the emerging tools of synthetic biology for the goals of global health, in 2011 the Bill & Melinda Gates Foundation put out a call for grant applications to “Apply Synthetic Biology to Global Health Challenges” under its “Grand Challenges Explorations” program. A highly diverse pool of over 700 applications was received. Proposed applications of synthetic biology to global health needs included interventions such as therapeutics, vaccines, and diagnostics, as well as strategies for biomanufacturing, and the design of tools and platforms that could further global health research.

Concepts: Medicine, Research, Computer program, Innovation, Bill & Melinda Gates Foundation, The Bill, Bill Gates, Melinda Gates


The pneumonia team at the Bill & Melinda Gates Foundation congratulates the Pneumonia Etiology Research for Child Health (PERCH) study on delivering on their grant to collect high-quality data from thousands of children with World Health Organization-defined severe and very severe pneumonia and from controls in 9 diverse sites in 7 low- and middle-income countries. This supplement sets the foundation to understanding this complex study by providing an in-depth description of the study methodology, including discussion of key aspects such as antibiotic pretreatment, chest radiograph interpretation, utility of induced sputum in children, measurement of pathogen density, and use of C-reactive protein, and how these affect pneumonia etiology.

Concepts: Medicine, Bacteria, Pneumonia, Child, Bill & Melinda Gates Foundation, The Bill, Bill Gates, Melinda Gates


Background Implementation of an ivermectin-based community treatment strategy for the elimination of onchocerciasis or lymphatic filariasis has been delayed in Central Africa because of the occurrence of serious adverse events, including death, in persons with high levels of circulating Loa loa microfilariae. The LoaScope, a field-friendly diagnostic tool to quantify L. loa microfilariae in peripheral blood, enables rapid, point-of-care identification of persons at risk for serious adverse events. Methods A test-and-not-treat strategy was used in the approach to ivermectin treatment in the Okola health district in Cameroon, where the distribution of ivermectin was halted in 1999 after the occurrence of fatal events related to L. loa infection. The LoaScope was used to identify persons with an L. loa microfilarial density greater than 20,000 microfilariae per milliliter of blood, who were considered to be at risk for serious adverse events, and exclude them from ivermectin distribution. Active surveillance for posttreatment adverse events was performed daily for 6 days. Results From August through October 2015, a total of 16,259 of 22,842 persons 5 years of age or older (71.2% of the target population) were tested for L. loa microfilaremia. Among the participants who underwent testing, a total of 15,522 (95.5%) received ivermectin, 340 (2.1%) were excluded from ivermectin distribution because of an L. loa microfilarial density above the risk threshold, and 397 (2.4%) were excluded because of pregnancy or illness. No serious adverse events were observed. Nonserious adverse events were recorded in 934 participants, most of whom (67.5%) had no detectable L. loa microfilariae. Conclusions The LoaScope-based test-and-not-treat strategy enabled the reimplementation of community-wide ivermectin distribution in a heretofore “off limits” health district in Cameroon and is a potentially practical approach to larger-scale ivermectin treatment for lymphatic filariasis and onchocerciasis in areas where L. loa infection is endemic. (Funded by the Bill and Melinda Gates Foundation and others.).

Concepts: Parasitic diseases, Filariasis, Neglected diseases, Ivermectin, Loa loa filariasis, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates


Background Aerosolized vaccine can be used as a needle-free method of immunization against measles, a disease that remains a major cause of illness and death. Data on the immunogenicity of aerosolized vaccine against measles in children are inconsistent. Methods We conducted an open-label noninferiority trial involving children 9.0 to 11.9 months of age in India who were eligible to receive a first dose of measles vaccine. Children were randomly assigned to receive a single dose of vaccine by means of either aerosol inhalation or a subcutaneous injection. The primary end points were seropositivity for antibodies against measles and adverse events 91 days after vaccination. The noninferiority margin was 5 percentage points. Results A total of 1001 children were assigned to receive aerosolized vaccine, and 1003 children were assigned to receive subcutaneous vaccine; 1956 of all the children (97.6%) were followed to day 91, but outcome data were missing for 331 children because of thawed specimens. In the per-protocol population, data on 1560 of 2004 children (77.8%) could be evaluated. At day 91, a total of 662 of 775 children (85.4%; 95% confidence interval [CI], 82.5 to 88.0) in the aerosol group, as compared with 743 of 785 children (94.6%; 95% CI, 92.7 to 96.1) in the subcutaneous group, were seropositive, a difference of -9.2 percentage points (95% CI, -12.2 to -6.3). Findings were similar in the full-analysis set (673 of 788 children in the aerosol group [85.4%] and 754 of 796 children in the subcutaneous group [94.7%] were seropositive at day 91, a difference of -9.3 percentage points [95% CI, -12.3 to -6.4]) and after multiple imputation of missing results. No serious adverse events were attributable to measles vaccination. Adverse-event profiles were similar in the two groups. Conclusions Aerosolized vaccine against measles was immunogenic, but, at the prespecified margin, the aerosolized vaccine was inferior to the subcutaneous vaccine with respect to the rate of seropositivity. (Funded by the Bill and Melinda Gates Foundation; Measles Aerosol Vaccine Project Clinical Trials Registry-India number, CTRI/2009/091/000673 .).

Concepts: Clinical trial, Vaccine, Vaccination, Immunology, MMR vaccine, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates


Information generated from economic evaluation is increasingly being used to inform health resource allocation decisions globally, including in low- and middle- income countries. However, a crucial consideration for users of the information at a policy level, e.g. funding agencies, is whether the studies are comparable, provide sufficient detail to inform policy decision making, and incorporate inputs from data sources that are reliable and relevant to the context. This review was conducted to inform a methodological standardisation workstream at the Bill and Melinda Gates Foundation (BMGF) and assesses BMGF-funded cost-per-DALY economic evaluations in four programme areas (malaria, tuberculosis, HIV/AIDS and vaccines) in terms of variation in methodology, use of evidence, and quality of reporting. The findings suggest that there is room for improvement in the three areas of assessment, and support the case for the introduction of a standardised methodology or reference case by the BMGF. The findings are also instructive for all institutions that fund economic evaluations in LMICs and who have a desire to improve the ability of economic evaluations to inform resource allocation decisions.

Concepts: Decision making, Evaluation, Tuberculosis, World Health Organization, Resource allocation, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates


Vaccines are very effective in providing individual and community (herd) immunity against a range of diseases. In addition to protection against a range of diseases, vaccines also have social and economic benefits. However, for vaccines to be effective, routine immunization programmes must be undertaken regularly to ensure individual and community protection. Nonetheless, in many countries in Africa, vaccination coverage is low because governments struggle to deliver vaccines to the most remote areas, thus contributing to constant outbreaks of various vaccine-preventable diseases. African governments fail to deliver vaccines to a significant percentage of the target population due to many issues in key areas such as policy setting, programme management and financing, supply chain, global vaccine market, research and development of vaccines. This review gives an overview of the causes of these issues and what is currently being done to address them. This review will discuss the role of philanthropic organisations such as the Bill and Melinda Gates Foundation and global partnerships such as the global alliance for vaccines and immunizations in the development, purchase and delivery of vaccines.

Concepts: Immune system, Africa, Vaccine, Vaccination, Smallpox, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates


Background Taeniasis and cysticercosis are major causes of seizures and epilepsy. Infection by the causative parasite Taenia solium requires transmission between humans and pigs. The disease is considered to be eradicable, but data on attempts at regional elimination are lacking. We conducted a three-phase control program in Tumbes, Peru, to determine whether regional elimination would be feasible. Methods We systematically tested and compared elimination strategies to show the feasibility of interrupting the transmission of T. solium infection in a region of highly endemic disease in Peru. In phase 1, we assessed the effectiveness and feasibility of six intervention strategies that involved screening of humans and pigs, antiparasitic treatment, prevention education, and pig replacement in 42 villages. In phase 2, we compared mass treatment with mass screening (each either with or without vaccination of pigs) in 17 villages. In phase 3, we implemented the final strategy of mass treatment of humans along with the mass treatment and vaccination of pigs in the entire rural region of Tumbes (107 villages comprising 81,170 people and 55,638 pigs). The effect of the intervention was measured after phases 2 and 3 with the use of detailed necropsy to detect pigs with live, nondegenerated cysts capable of causing new infection. The necropsy sampling was weighted in that we preferentially included more samples from seropositive pigs than from seronegative pigs. Results Only two of the strategies implemented in phase 1 resulted in limited control over the transmission of T. solium infection, which highlighted the need to intensify the subsequent strategies. After the strategies in phase 2 were implemented, no cyst that was capable of further transmission of T. solium infection was found among 658 sampled pigs. One year later, without further intervention, 7 of 310 sampled pigs had live, nondegenerated cysts, but no infected pig was found in 11 of 17 villages, including all the villages in which mass antiparasitic treatment plus vaccination was implemented. After the final strategy was implemented in phase 3, a total of 3 of 342 pigs had live, nondegenerated cysts, but no infected pig was found in 105 of 107 villages. Conclusions We showed that the transmission of T. solium infection was interrupted on a regional scale in a highly endemic region in Peru. (Funded by the Bill and Melinda Gates Foundation and others.).

Concepts: Epidemiology, Infectious disease, Taenia solium, Cysticercosis, Taenia, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates


In 2015, an estimated 438,000 people died from malaria.(1) The overwhelming majority of these deaths occurred in young African children who were infected with Plasmodium falciparum. An effective vaccine would represent an important additional tool in the control of malaria. The most advanced of the current candidates against P. falciparum is RTS,S/AS01, a recombinant vaccine against the pre-erythrocytic stage of the parasite in which regions of P. falciparum circumsporozoite protein are fused to hepatitis B surface antigen.(2) This vaccine was developed by a public-private partnership, with support from the Bill and Melinda Gates Foundation, and investigators have completed a . . .

Concepts: Immune system, Malaria, Plasmodium falciparum, Plasmodium, Plasmodium vivax, Anopheles, Bill & Melinda Gates Foundation, Melinda Gates


In the last decade, community mobilisation (CM) interventions targeting female sex workers (FSWs) have been scaled-up in India’s national response to the HIV epidemic. This included the Bill and Melinda Gates Foundation’s Avahan programme which adopted a business approach to plan and manage implementation at scale. With the focus of evaluation efforts on measuring effectiveness and health impacts there has been little analysis thus far of the interaction of the CM interventions with the sex work industry in complex urban environments.

Concepts: Prostitution, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates, Duke University