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Grand Challenges is a family of initiatives fostering innovation to solve key global health and development problems. Each initiative is an experiment in the use of challenges to focus innovation on making an impact. Individual challenges address some of the same problems, but from differing perspectives.

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S. Typhi in Water and Role of Microbial Partners

France DaigleUniversité de MontréalMontreal, Quebec, Canada
Grand Challenges Explorations
Salmonella Typhi
1 Nov 2019

France Daigle of the University of Montreal in Canada will identify the microorganisms that enable the survival of the typhoid fever-causing bacterium, Salmonella enterica serovar Typhi, at low levels in water, and thereby enhances disease spread. Typhoid fever spreads through contaminated food and water, and results in over 125,000 deaths annually worldwide. S. Typhi are so-called auxotrophic bacteria because they rely on an external source of the essential amino acids that they need to grow. Microbial interactions may provide nutrients and also increase bacterial fitness and support persistence by protecting them from the environment, thereby increasing the rate of disease transmission. They will assemble a microbial community in water consisting of three components: one protozoan (from a group known to promote bacterial survival); a defined consortium of bacteria representative of the human fecal microbiota; and fluorescently-tagged S. Typhi. They will evaluate the ability of S. Typhi to grow in these microcosms, and how they grow, such as in biofilms or inside the protozoa. They will also determine whether these persistent S. Typhi are better able to infect and survive in human cells. Finally, water samples from an endemic region in East Africa will be analyzed for the presence of S. Typhi and identified beneficial microbial partners using quantitative PCR.

Genome Sequencing of S. Typhi in Protistan Reservoirs

Andrew JacksonUniversity of LiverpoolLiverpool, United Kingdom
Grand Challenges Explorations
Salmonella Typhi
1 Nov 2019

Andrew Jackson of the University of Liverpool in the United Kingdom will determine whether the amoeba, Acanthamoeba, which is commonly found in water and soil, acts as a host for Salmonella Typhi bacteria, which cause typhoid fever, to support growth and disease spread in Malawi. Typhoid fever is a systemic, potentially fatal illness, usually contracted by consuming contaminated drinking water. An estimated 11-21 million cases occur worldwide each year. Acanthamoeba is known as the 'Trojan Horse' of the microbial world for its ability to host a number of human pathogens, including S. Typhi. It is speculated that Acanthamoeba acts as an environmental reservoir to facilitate the survival of S. Typhi, and perhaps other human pathogens. They will prove the widespread presence of Acanthamoeba-Salmonella associations directly by using single-cell DNA sequencing. Individual amoeba will be isolated from water and soil samples from typhoid hotspots in Malawi using fluorescence-activated cell sorting. Total DNA in each amoeba will be sequenced in order to identify carriage of S. Typhi strains. Single nucleotide polymorphism analysis will be used to compare these with bacteria in local clinical isolates to determine the role of Acanthamoeba in disease transmission.

On-Demand, Cell-Free Biomanufacturing of Conjugate Vaccines

Matthew DeLisaCornell UniversityIthaca, New York, United States
Grand Challenges Explorations
EmergingTechnologies
1 Nov 2019

Matthew DeLisa of Cornell University in the U.S. will create a cell-free synthetic biology platform for low-income settings that produces thermostable polysaccharide-based conjugate vaccines against diarrheal pathogens upon the addition of water to a single tube. Half-a-million children under age five die each year from diarrhea and dysentery, the majority in low- and middle-income countries. Two major causes of bacterial diarrhea are enterotoxigenic E. coli (ETEC) and Shigella strains. Conjugate vaccines combine multiple antigens into one vaccine to increase its activity. However, they require a complex manufacturing process, living cells, and refrigerated storage, which limit their application in developing countries. They will develop the materials and methods for manufacturing thermostable anti-diarrheal vaccines in single tubes that only require the addition of water just ahead of administration. The tubes will contain a plasmid that can express an FDA-approved carrier protein, along with selected O-antigen-polysaccharides from ETEC or Shigella strains, and an enzyme that can conjugate the two via glycosylation, all within a freeze-dried pellet. Following development, they will test the safety, scalability and portability of the vaccines, and characterize their ability to generate effective antibodies that can kill the bacteria. The system is expected to reduce conjugate vaccine costs, and its modular nature will facilitate expansion to other vaccine-preventable diseases.

Overcome Hysteresis Effect by Social Network Targeting

Feng FuDartmouth CollegeHanover, New Hampshire, United States
Grand Challenges Explorations
Immunization Demand
1 Nov 2019

Feng Fu of Dartmouth College in the U.S. will use social networks to promote positive attitudes and overcome negative views of vaccinations and thereby increase demand. The success of vaccinations has led to steep declines in the incidence of many serious diseases. However, this has decreased the perception of disease risk and thereby lowered vaccination coverage as parents concerns switch to other factors, such as cost and the perceived risk of the vaccination itself, which are fueled via social media channels. These current low vaccination rates exhibit so-called hysteresis whereby the past concerns about safety or necessity prevent the rates from increasing even when the concerns have been disproven. To overcome this, they will use computer modeling approaches to test the ability of targeting social networks to leverage social "contagion" (i.e., spread) of positive attitudes to vaccine knowledge. They will use a healthcare intervention dataset from a network of rural villages in Honduras to model how one or more health-related behaviors or beliefs of an individual affects the group to simulate the social contagion process related to vaccines. They will also evaluate the potential positive impact of influential individuals who publicly support vaccination. The results will be used to develop social network targeting algorithms to increase the demand for vaccination. Their modeling results will be validated using the real data from the village networks.

Leveraging Food Distribution Networks to Increase Knowledge

Jessica CraigCenter for Disease Dynamics, Economics & PolicyWashington, District of Columbia, United States
Grand Challenges Explorations
Immunization Demand
1 Nov 2019

Jessica Craig of the Center for Disease Dynamics, Economics and Policy in the U.S. will use existing food distribution networks in low-income countries to publicize the importance of vaccination and inform caregivers when, where, and how to access local vaccine services by printing them on food labels, food and water carrying tools, and receipts. They will test whether their approach can improve vaccination rates using one rural and one urban area each in Kenya and in the Central African Republic. They will map their food distribution systems and health service clinics and consult local healthcare workers on the design of vaccine information materials to reach both literate and illiterate populations. They will evaluate the number of caregivers interacting with the materials using surveys in clinics, as well as the change in vaccination rate before and after a six-month period with materials in circulation. The approach is relatively simple and cost-effective because it leverages an existing network with a wide audience, and requires no additional work from frontline healthcare workers. It is also adaptable to any setting with a food distribution network, and can be expanded to deliver other types of health information.

Improving Frontline Worker and Caregiver Skills in Vaccination Pain Management

Caroline AuraUniversity of NairobiNairobi, Kenya
Grand Challenges Explorations
Immunization Demand
1 Nov 2019

Caroline Aura from the University of Nairobi in Kenya will teach frontline health workers and caregivers new skills so they can apply simple techniques such as swaddling and rocking to lessen the pain and distress of infants during injections to improve vaccination rates. Vaccination rates are still too low in many low-resource settings, which may be due in part to the discomfort they cause infants. This in turn makes caregivers reluctant to obtain all the recommended vaccinations for their children. Methods exist to reduce the associated pain of injections, but health workers lack the knowledge and skills to implement them. To test their approach, they will recruit vaccinators and community health workers at four rural immunization centers and use seminars and workshops to teach them pain-relieving techniques, including using specific positions and making soothing sounds. They will also develop audio-visual training tools and illustrative guides to help teach the techniques to parents for them to use at home as well. All healthy children under 12 months old visiting the centers for a vaccination will also receive one of the pain relief techniques. They will evaluate the ability of the health workers to manage pain, the level of distress of the infants, and the experience of the caregivers.

Sediment Biofilm Ecology in High-Typhoid-Incidence Rivers

Aaron JenkinsUniversity of SydneySydney, New South Wales, Australia
Grand Challenges Explorations
Salmonella Typhi
1 Nov 2019

Aaron Jenkins of the University of Sydney in Australia will combine genomics approaches with physical chemistry to identify the organisms and environmental factors in riverbeds that support the survival and spread of the bacterium, Salmonella enterica serovar Typhi, which causes typhoid. Aquatic environments are a major reservoir of typhoid, but how the bacteria survive in these conditions is unclear, making it difficult to prevent the disease spreading to humans. They hypothesize that S. Typhi survive in biofilms associated with sediments in riverbeds, and that the composition of this niche promotes its ability to infect humans. To test this, they will sample aquatic biofilms from areas of high, low, and zero typhoid incidence in Fiji, and identify the microbial communities supporting S. Typhi survival using antibody capture and metagenomics. They will also use fluorescence in situ hybridization to determine the spatial organization of S. Typhi in multispecies biofilms. In addition, they will analyze the composition of the sediments and soil of the riverbeds, and the nutrients being taken up by resident fish and crustaceans. By combining these results with their epidemiological data, they can identify the ecological niches that support high typhoid incidence, which will help develop and guide intervention strategies to block transmission to humans.

S. Typhi and Protozoa in Contaminated Water in Zimbabwe

Robert KingsleyQuadram Institute BioscienceNorwich, United Kingdom
Grand Challenges Explorations
Salmonella Typhi
1 Nov 2019

Robert Kingsley of the Quadram Institute Bioscience in the United Kingdom will locate the typhoid fever-causing bacteria S. Typhi in water reservoirs in Harare, Zimbabwe, and identify any associated protozoa species present in the water that may be supporting disease spread. Typhoid fever is endemic in Zimbabwe, with several major outbreaks reported in the last decade. The bacteria persist in unclean aquatic environments, possibly supported by protozoa, and are transmitted to humans through ingestion of contaminated drinking water. They will detect S. Typhi in sewage effluent and low-quality drinking water in hotspots of typhoid transmission by enrichment culture and PCR, and use whole genome sequencing to establish the phylogenetic relationship between these bacteria and clinical typhoid isolates in the same city. They will also amplify 18S rDNA from the sewage and drinking water samples to characterize the microbial community in water and define the protozoa population. These data will help identify potential synergistic interactions between S. Typhi and other microbes to inform prevention strategies.

Mobile Solutions for Mobile Populations: Closing the Gap

Ernest DarhokBroadReachCape Town, South Africa
Grand Challenges Explorations
Immunization Demand
1 Nov 2019

Ernest Darhok of Broadreach in South Africa will use mobile technology to improve access to child immunization services for populations living on the Kenya-Uganda border and help ensure all children are fully vaccinated. Refugee populations living in cross-border settings and migrant communities are particularly difficult to cover because of limited access, poor coordination across borders, and lack of efficient tracking. They have been using a human-centered approach to understand what these populations need to vaccinate their children, and have pilot tested the use of near-field communication cards with an immunization application that holds a child’s vaccination and health data for caregivers, which they can also use to plan more convenient appointments. This card can then be viewed and updated by health workers on both sides of the border using a mobile system. They will extend this pilot study to a wider population in Kenya and Uganda to evaluate the effect on vaccination rates against polio, and apply machine learning methods to better forecast vaccination needs at cross-border facilities to avoid stocks running out. They will obtain user feedback at all stages to help improve their approach.

Missed Opportunities for Vaccination Equity (MOVE)

Anita ShetJohns Hopkins University Bloomberg School of Public HealthBaltimore, Maryland, United States
Grand Challenges Explorations
Immunization Demand
1 Nov 2019

Anita Shet of Johns Hopkins School of Public Health in the U.S. will seek to increase childhood vaccination coverage in India and Nigeria by identifying opportunities for catch-up vaccinations when under-vaccinated children are hospitalized. Of the three million people who die each year from vaccine-preventable diseases, about half are children under the age of five, many of whom live in areas where vaccinations are available, but inequitably distributed. Inadequately vaccinated children frequently become sick and are hospitalized, yet most leave the hospital without receiving catch-up vaccines because of physical and policy barriers, or perceived contraindications. They will engage stakeholders, including hospital policy makers and community workers to launch MOVE (Missed Opportunities for Vaccine Equity) to identify and correct missed opportunities for vaccination by using child hospital visits to provide vaccine education and access. MOVE has three components: inpatient in-reach, where MOVE staff check immunization records and inform hospital personnel of missing vaccines; immunization service linkage to inpatient care, which ensures that vaccines are available and provides a vaccination schedule at discharge; and community outreach to provide follow-up reminders and education. They will modify an immunization application and reminder tool to record the data and maintain a cloud-based registry, and test their approach in two large community hospitals in India and Nigeria.

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