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.

Challenges

Grand Challenges

Metagenomic Next Generation Sequencing to Detect, Identify, and Characterize Pathogens

<h2>Background</h2>
Next generation sequencing (NGS) has proven to be indispensable in the current SARS-CoV2 pandemic, from pathogen discovery to variant characterization to novel vaccine development in record-time. This approach to using NGS underscores the potential value of this technology and its application to many other diseases from Ebola to cholera to Pathogen X. Building upon the success of previous Bill &amp; Melinda Gates Foundation, Chan Zuckerberg Initiative (CZI) and Chan Zuckerberg Biohub (CZ Biohub) <a href="https://gcgh.grandchallenges.org/challenge/application-metagenomic-next-generation-sequencing-detect-and-identify-pathogens-round-22" target="_blank" rel="noopener noreferrer">Grand Challenges collaborations</a>, this year's opportunity will continue to offer exceptional opportunities for capacity building, on-going mentorship and the foundations of scientific, collaborative networks to detect, identify, and characterize pathogens. The ultimate goal will be to impact infectious disease decision making and public health by empowering local scientists with gold standard knowledge, experience and access to equipment and software.
Through this Grand Challenge, the Bill and Melinda Gates Foundation and Chan Zuckerberg Initiative will jointly offer funding for 10 scientific groups to explore the identification, characterization, and context of infectious disease in LMIC settings.
<h2>The Opportunity</h2>
One of the overwhelming lessons learned from the ongoing SARS-CoV-2 pandemic, has been the importance of being able to identify existing and emerging infectious diseases efficiently, in order to more effectively address and contain outbreaks, both locally and regionally. It has never been so important for clinicians and the global health community to have access to both accurate and timely estimates of disease burden and distribution. Traditionally, summaries of these data have been manually reported by national health ministries from regional clinical data, aggregated from local health centers. Local institutions, however, face multiple challenges to accurately assess the emerging needs of their community with current toolsets. For example, most clinical tests are based on common or easily detectable pathogens previously identified, which can miss occult and/or emerging pathogens. In addition, curation of large-scale pathogen data across multiple locations/platforms is time consuming and expensive, preventing facile integration of individual patient-level diagnostic data into a larger pathogen landscape on the regional and national level.
Over the last 18 months, we have seen how, when local institutions have the capacity – both at the hardware and software level - to detect emerging infections using pathogen sequencing technology, they are able to perform near-real-time data analysis that is rapidly translated into actionable public health decision making. At the heart of the ability to pivot to pathogen-specific sequencing during the pandemic, was the successful establishment of metagenomic sequencing platforms in low- and middle-resource settings, where there have traditionally been limitations in access or availability of the following essential components: a) equipment/reagents, b) specialized biochemical training, c) accurate reference pathogen sequence databases, and d) advanced computational analytics.
<h2>The Challenge</h2>
Recognizing barriers for adoption of next-generation sequencing in global health, the Bill &amp; Melinda Gates Foundation has partnered with the Chan Zuckerberg Biohub and the Chan Zuckerberg Initiative to enable populations in low- and middle-resource settings to benefit from cutting-edge pathogen detection, discovery and characterization. This partnership will provide highly specialized training in biosample preparation and sequencing to technical staff from awardee global health centers. Trainees will learn to use the open-source, open-access <a href="http://www.idseq.net/" target="_blank" rel="noopener noreferrer">IDseq</a> software developed by the Chan Zuckerberg Initiative (CZI) for the global health community to upload and analyze sequencing data, among other software such as Nextstrain. The BMGF-CZ Biohub-CZI partnership will therefore aim to provide selected applicants the benefits of onsite next generation sequencing and rapid pathogen detection to better understand their local pathogen landscape. We are also specifically seeking projects that endeavor to build upon their initial locally-focused effort to contribute to future data-informed decision-making at the population level via data sharing and pathogen data comparison across sites (multi-site studies will be prioritized).
This Grand Challenges (GC) award will support travel and accommodation of grantees to San Francisco for training at the CZ Biohub, and the following items: 1) <a href="https://gcgh.grandchallenges.org/sites/default/files/files/metagenomic_next_generation_sequencing_compatible_sequencers.pdf" target="_blank" rel="noopener noreferrer">a sequencer suitable for the global health environment</a><a href="#_bookmark1">[1]</a><a id="_bookmark0" name="_bookmark0"></a>, 2) a dedicated sequencing technician, and 3) sequencing reagents for the duration of the award. CZ Biohub and CZI training will include pilot analysis of samples from their home region during hands-on, intensive mentoring. This 2-week instructional period will include both biochemical sample preparation for sequencing and bioinformatic analysis using the IDseq software platform. Specifically, the hands-on training for bench scientists will include best practices and standards for sample processing, DNA &amp; RNA extraction, library preparation and data analysis on the global IDseq software platform. The combination of intensive training with molecular, capital equipment, reagent, and personnel support is intended to maximize the potential for sustainable, prospective, onsite analysis of patient samples upon return to the home site.
Molecular data generated at individual global sites is intended to be linked and automatically aggregated into IDseq for referencing by all participating clinics and associated sites. This method of local sequence analysis coupled with cross-site comparison could serve as a model for a process that would eventually lead to a network of pathogen detection nodes that could provide increased global transparency into regional pathogen distribution in an accurate and timely manner, and in ultimate support of a global pathogen surveillance network.
Examples of insights could include:
<ol><li>Investigating infectious etiologies for unknown medical cases</li>
<li>Identification of new pathogens</li>
<li>Detection of local outbreaks</li>
<li>Characterization of the local pathogen landscape, including vector-borne diseases</li>
<li>Assessment of emerging zoonotic disease, including wildlife and domestic animal reservoir sampling</li>
<li>Detection and classification of Antimicrobial Resistance (AMR) Markers, with potential for insight into antibiotic treatment discordance</li>
<li>Data-informed healthcare and resource allocation</li>
<li>Subsequent follow-up leveraging genomic epidemiology for public health, incorporating local epidemiological data and genomic analysis</li>
</ol>We are specifically looking for sites that believe in collaborative approaches and data sharing. Grantees will be expected to partner closely with scientists and engineers and provide feedback to help guide the cloud computing software’s development. Sites will also be expected to share data and collaborate with other labs in the network.
Funding level: up to USD $200,000 for each project, with a grant term of up to 24 months depending on the scope of the project.
We will consider sites that:
<ul><li>Provide a clearly scoped initial project that demonstrates why this technology will provide insights that are not currently possible.</li>
<li>Have space and capacity to run samples on a basic sequencer once provided with training, reagents, sequencer, and a dedicated computer. Have consistent access to electricity and the ability to upload data via the internet to a designated cloud server at least once a day.</li>
<li>Are willing to give product feedback and collaborate with an engineering team through scheduled video calls, email, or other messaging service. Are committed to open science, preprints, and data sharing.</li>
<li>Already have, or can rapidly acquire, necessary IRB approval for pathogen DNA and RNA sequence sharing from patients.</li>
<li>Are representative of larger geographic regions</li>
</ul>We will not consider sites that:
<ul><li>Do not articulate how they will leverage the value of next generation sequencing to impact health outcomes.</li>
<li>Are interested exclusively in Whole Genome Sequencing of human samples</li>
<li>Do not plan to share their pathogen data and discoveries.</li>
<li>Have extremely limited internet access.</li>
<li>Are limited to previously stored samples, without substantial potential for prospective sample collection.</li>
</ul>_____________________________________________
<a id="_bookmark1" name="_bookmark1"></a><a href="#_bookmark0">[1]</a> To ensure the sequencer continues to be used for purposes consistent with the foundation’s charitable objectives, we may request that funded applicants other than charities, universities, and similar organizations donate any sequencer purchased with grant funds to a charity or university, after the term of the project.

Recognizing barriers for adoption of next-generation sequencing in global health, the Bill &amp; Melinda Gates Foundation has partnered with the Chan Zuckerberg Biohub and the Chan Zuckerberg Initiative to enable populations in low- and middle-resource settings to benefit from cutting-edge pathogen detection, discovery and characterization. This partnership will provide highly specialized training in biosample preparation and sequencing to technical staff from awardee global health centers.

<h2>Overview</h2>

The emerging SARS-COV-2 variants of concern (VOC) demonstrate the urgent need for local scientific communities to have the capacity to rapidly detect and evaluate the immunological implications of new variants. The current VOC situation also provides the proving ground for such scientific collaborative infrastructure to inform and impact local and global equitable decision making around vaccines, herd immunity and therapeutics.

Global Immunology and Immune Sequencing for Epidemic Response (GIISER) is envisioned as a collection of geographically distinct sites that can pair their local pathogen sequencing surveillance and clinical epidemiology with local immunological understanding and tools. GIISER sites can connect via standard protocols, bioinformatics pipelines, data sharing guidelines and training opportunities to participate in coordinated international efforts to respond to emerging epidemic threats.

Importantly, the local immunological evaluation provided by GIISER extends to the rapid discovery of novel monoclonal antibodies that are critical tools for probing protein structure, detecting variant proteins, and identifying neutralizing epitopes for vaccine immunogen design. In addition, they may be developed as therapeutics for prevention or treatment of disease. Underlying all aspects of the work is the need for a global collaboration framework which includes rapid sharing of data and information with key international bodies (such as WHO, GISRS, and Africa CDC) and networks to inform an effective, equitable global pandemic response.

<h2>GIISER Project Goals</h2>

This specific effort aims to increase the in-country capacity for the rapid immunological evaluation of SARS-CoV-2 variants of concern on the African continent. It builds off of the African Pathogen Genomics Institute (PGI) sequencing capabilities (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434434/pdf/main.pdf" target="_blank">Tessema et al, Lancet Microbe Oct 2020),</a> local human subjects research (clinical epidemiology), and adds in local virology and immunology expertise to allow in-country scientists to rapidly evaluate new variants for immune escape and cross protection. This data is essential for understanding the impact of new variants on vaccines, diagnostic assays, therapeutics and natural immunity.

The near-term goals of the GIISER program are 1. Systematic production of data quantifying immune escape and cross protection for variants of local concern/interest and 2. Identification of monoclonal antibodies that specifically recognize and potentially neutralize variants of local concern/interest isolated from convalescent individuals with sequence-confirmed SARS-CoV-2 infections.

A successful GIISER site will leverage existing pathogen sequencing surveillance infrastructure to rapidly identify emerging SARS-CoV-2 variants, obtain sera and blood cells from the appropriate infected individuals with appropriate informed consent, and perform detailed immunological characterization of sera/plasma (binding and neutralization assays), as well as single cell analytics for monoclonal antibody discovery. This information will be produced and communicated rapidly enough to inform public health decisions and policy makers within the local and international community. Many of these pieces already exist but are currently siloed. Some pieces need technological innovation to be rapid and effective.

Other pieces are nascent but training of local scientists by collaborators willing and able to share knowledge and tools will create the necessary capabilities.

A long-term goal is to establish a sustainable, local infrastructure that can be activated to respond to any new emerging pathogen locally and strengthen connections and collaborations between sites and with international decision-making bodies.

GIISER Scope of Work Outline (see <a href="#_bookmark2">Figure 1 </a><a name="_bookmark0"></a>below)

<ol>
	<li>Identify SARS-CoV-2 pathogen variants and appropriate subjects.
	<ol>
		<li>Ethics approvals and clinical protocols in place with appropriate consent forms that allow for use of the donor sample for all downstream R&amp;D which will support the connection of pathogen sequencing, longitudinal/contextual clinical data (including demographics and other relevant metadata) and subsequent immunological analysis. Build on capacity generated from prior initiatives (e.g., H3Africa human subjects research expertise and ethics frameworks)</li>
		<li>Pathogen sequencing and analytical infrastructure in place that meets international quality standards and shares sequence data publicly in a timely manner (via GISAID for example).</li>
	</ol>
	</li>
	<li>Sample Collection, Virus Isolation and B cell sorting
	<ol>
		<li>Laboratory capacity for virus sampling for sequencing and virus outgrowth (nasal swabs or other), including BSL3 capacity.</li>
		<li>Laboratory capacity for blood draws, including serum, plasma, PBMCs, B cell and/or plasmablast enrichment.</li>
		<li>Antigen specific B cell sorting via flow cytometry with tagged protein baits (generated locally or provided by collaborators).</li>
	</ol>
	</li>
	<li>Assessment of natural- and vaccine-induced polyclonal antibody immunity to novel variants
	<ol>
		<li>Quantitative assays measuring polyclonal antisera binding against both prior and novel VOC spike proteins (ELISA, MSD or other), calibrated against international standards or reference panels.</li>
		<li>Surrogate neutralization assays measuring inhibition of binding to ACE2 by polyclonal sera/plasma.</li>
		<li>Generation and use of VSV or lentivirus pseudoviruses containing novel spike protein sequences to quantitatively measure pseudovirus neutralization activity in sera/plasma, calibrated against international standards or reference panels.</li>
		<li>Implementation of live virus neutralization assays in BSL3 facilities to measure neutralization activity in polyclonal sera/plasma, calibrated against international standards or reference panels.</li>
	</ol>
	</li>
</ol>

<ol start="3">
	<li>
	<ol start="5">
		<li>Assessment of virus neutralizing activity in sera/plasma from prior infections with sequence- confirmed viral infections and vaccinated individuals to determine magnitude and breadth of natural and vaccine-induced cross neutralization.</li>
		<li>Coordinate with other GIISER sites, international networks (WHO, AfCDC, CEPI, etc.) to share high quality binding and neutralization results. Establish appropriate MTAs between sites to share materials.</li>
	</ol>
	</li>
	<li>Monoclonal Antibody Discovery: sequencing and repertoire analysis
	<ol>
		<li>Single cell immunoglobulin heavy and light chain sequencing from B cells enriched for binding to VoC spike proteins. This can be accomplished by any of a number of different technologies, including 10X, Seqwell, or others. Multiple specific baits and labels could be used for enrichment, targeting VOC specific mAbs (unique epitopes) or broadly neutralizing mAbs (conserved epitopes), or both.</li>
		<li>Proficiency in immunoglobulin sequence bioinformatics and clustering algorithms to assess somatic hypermutation, assign clonal lineages and evaluate Ab repertoire. Leverage opportunities such as those available via H3Bionet, Human Cell Atlas and GH-VAP to assist.</li>
		<li>Choose representative heavy + light chain pairs for subsequent expression and in vitro screening assays (See E).</li>
		<li>Engage with international antibody sequencing databases and consortia to share mAb repertoire information and sequences as appropriate, with future-use data sharing terms clearly outlined.</li>
	</ol>
	</li>
	<li>Monoclonal Antibody Discovery: Screening and functional evaluation
	<ol>
		<li>Small scale production of selected high quality mAbs from cDNA sequence.</li>
		<li>Systematic screening of mAbs for binding to a variety of spike proteins, including epitope mapping.</li>
		<li>Evaluation of neutralizing activity of selected mAbs against VOCs using the live virus and pseudovirus assays from step C above. Evaluate neutralization breadth and cross protection.</li>
		<li>Disseminate findings and engage with additional partners to share mAbs that have utility as either research tools or potential developability as therapeutics. Participate in international consortia such as COVIC when sufficient data supports such a move.</li>
	</ol>
	</li>
</ol>

Evaluation Metrics and Criteria

GIISER sites will be evaluated based on their ability to link together pathogen sequencing, clinical epidemiology, immunology and monoclonal antibody discovery to rapidly produce high-quality, interpretable and informative data on neutralization breadth and cross protection for locally identified SARS-CoV-2 variants of concern. This includes, but is not limited to, outgrowth of variant SARS-CoV-2 virus in appropriate BLS3 containment labs for live virus neutralization assays. Examples of anticipated results: <a href="https://www.nature.com/articles/s41586-021-03471-w" target="_blank">Cele et al Nature 2021, </a><a href="https://www.nejm.org/doi/full/10.1056/NEJMc2104192?query=main_nav_lg" target="_blank">Moyo-Gwete et al NEJM 2021, </a><a href="https://www.nejm.org/doi/full/10.1056/NEJMc2103740?query=main_nav_lg" target="_blank">Shen et al NEJM 2021 </a>and <a href="https://www.nature.com/articles/s41591-021-01285-x">Wibmer et al</a> <a href="https://www.nature.com/articles/s41591-021-01285-x" target="_blank">Nature Medicine 2021.</a>

A key rationale for this effort is rapid data generation to inform decision making, thus the speed at which high quality data can be disseminated is an important consideration in the design and execution of each program. Within the first year of a two year investment, a well-functioning GIISER site will be communicating results from the first round of steps A-C within 1-2 months of identifying a variant of local concern, and steps D and E within an additional 2-3 months.

At the end of a two-year investment, we expect that each GIISER site will have a monoclonal antibody discovery pipeline that can feed lead candidates into product development. Of particular interest is to provide a pipeline for regionally distributed small footprint manufacturing which could further reduce the cycle time between discovery and delivery to LMICs

Sites will also be evaluated on their ability to leverage existing local expertise, collaborate and share data effectively with other GIISER sites and international networks (<a href="#_bookmark3">Figure 2 </a><a name="_bookmark4"></a>)

Requirements

A successful GIISER sites will have access to existing pathogen sequencing capacity and bioinformatics, access to existing cohorts or clinical infrastructure, access to existing BLS3 labs and trained virologists and immunologists with some expertise in protein reagent generation, mAb discovery and/or single cell analytics/bioinformatics. Not every site will have everything in place, but enthusiastic, creative and collaborative groups who want to get things done are encouraged to include specific requests for the support they need to get there (training, connections, technology, etc.).

What we are not looking to fund

We are not looking to fund pathogen genomics surveillance, expansion of surveillance sequencing capacity, or establishment of new clinical cohorts. We expect these to already be in place via other funding and for GIISER to build productive collaborations with these existing programs. Studies focused on T cell immunity and characterizing the overall immune response to SARS-CoV-2 are out of scope.

<a name="_bookmark2"></a><a href="#_bookmark0">Figure 1: </a>

<img alt="Figure 1" height="483" src="https://gcgh.grandchallenges.org/sites/default/files/images/figure-1.jpg" width="976" />

<a name="_bookmark3"></a><a href="#_bookmark4">Figure 2: </a>

<img alt="Figure 2" height="659" src="https://gcgh.grandchallenges.org/sites/default/files/images/figure-2.jpg" width="1290" />

NOTE: This opportunity was open to an invited set of African investigators.

Global Immunology and Immune Sequencing for Epidemic Response (GIISER) Sites in Africa

<h2>Background</h2>

The COVID-19 pandemic has brought unprecedented challenges for Africa, with every country potentially at risk for unmitigated spread of SARS-CoV-2. Like most health systems in the world, there is a significant risk for current levels of care to be overwhelmed by sheer volume of patients requiring intensive care and ventilatory support. In addition, health care workers are at risk of acquiring SARS-CoV-2 and given limited infection control practices in many settings, there is also risk of nosocomial transmission of SARS-CoV-2 among patients.

The emergence of new SARS-CoV-2 variants is further raising concerns of the possibility of re-infection among those previously infected with the 'wild type' virus. A recent survey conducted by the African Academy of Sciences Scientific Priority setting initiative found that the most important questions that African scientists, health care workers and public health officials should study included the detailed epidemiology and transmission dynamics in African settings, as well as infection prevention and control for health care workers. These are questions that are widely applicable across the continent yet require local context and expertise to address in a timely and effective manner.

Pathogen genomic sequencing (PGS) has been increasingly used in wealthy countries to help respond to outbreaks of infectious diseases, from MDR bacteria to Ebola to Yellow Fever, Measles, and Polio. Already, PGS has been shown to be important in understanding the transmission dynamics and epidemiology of SARS-CoV-2 in the US, Europe, and China. PGS has been used for outbreak size estimation based on phylodynamic analyses and to identify and characterize new variants.

The emergence of new SARS-CoV-2 variants in multiple locations across the world, including in Africa, has highlighted the need for genomic sequencing in surveillance and epidemiology. PGS has enabled the identification of emergent strains and provided the ability to monitor their spread. Genomic data has allowed for characterization of mutations, providing insights into possible mechanistic changes and biological implications. These insights provide the first clue of potential impact on the effectiveness of therapeutics, such as monoclonal antibodies, and vaccines that may warrant further investigation. Furthermore, the ability for genomic sequencing to differentiate which SARS-CoV-2 variant someone has been infected with, makes PGS an important tool for aiding in the investigation of changes to transmissibility and impact on clinical outcomes of new variants.

Genomic sequencing of SARS-CoV-2 can also help in effectively managing and controlling the epidemic in the continent by providing information to allow a precise identification of transmission clusters and of mutations of the virus. The information obtained can also help in tailoring new vaccine and/or treatment efforts within Africa by for example combining genetic, clinical, and epidemiological data.

Contrary to initial models and forecasts, the reported number of cases and mortality rates reflect a markedly less severe epidemiologic picture of COVID-19 in Africa. Consequently, SARS-CoV-2 sequencing (COVID-19 genomics) may also shed some light on the underlying factors possibly explaining these differences between Africa and those other parts of the world. It is important to note that human genomics will not be covered by this call. Furthermore, sequencing can help to monitor and characterize the changes to the genetic epidemiology of the COVID-19 pandemic after vaccine introduction. Unfortunately, PGS is not in widespread use in Africa. A rapid introduction of PGS in Africa will help in the fight to control SARS-CoV-2 and help prepare the continent for the next epidemic not yet identified.

Over the past three years, the Africa CDC has established expertise in PGS. In 2020 along with partners, Africa CDC launched the Africa Pathogen Genomics Initiative, which will include many activities to strengthen the capacity for and public health use of PGS in Africa. One such activity is the development of a continental laboratory network that will eventually have advanced sequencing capacity at national public health institutes across at least 20 African countries. Africa CDC has the mandate and vision to bring together African thought leaders in PGS in a coherent and sustainable peer network through the pan-continent Africa Pathogen Genomics Initiative. The challenge will support the parallel development of a cadre of African scientists and public laboratories who can contribute substantively to this initiative.

<h2>The Challenge</h2>

Grand Challenges Africa, in partnership with the Bill &amp; Melinda Gates Foundation and the Swedish International Development Cooperation Agency (SIDA) invites proposals that will primarily support public-health-use cases of PGS in African settings to respond to the Covid-19 pandemic. Grand Challenges Africa (GC Africa) is a program that seeks to promote Africa-led scientific innovations to help countries better achieve the Sustainable Development Goals by awarding seed and full grants to the continent's most impressive solutions and has covered topics such as Data Science Approaches to Improve Maternal and Child Health in Africa, Innovation for WASH (Water, Sanitation, and Hygiene) in Urban Settings, &amp; Drug Discovery. Through this partnership, we seek to make awards that will support increased understanding of SARS-CoV-2 in Africa for use in public health decision making.

Specifically, the objectives of the challenge will be:

<ol>
	<li>Use of PGS to establish routine genomic surveillance and understand the epidemiology and transmission of SARS-CoV-2</li>
	<li>Use of PGS in public health field epidemiology response for SARS-CoV-2 to investigate new virus variants and their impact on the epidemiology of Covid-19</li>
	<li>Use of PGS to monitor the impact of vaccine introduction on the epidemiology of SARS-CoV-2 in terms of transmission dynamics and/or incidence of virus variants.</li>
	<li>Use PGS to inform the development of diagnostics and/or therapeutics and/or monitor the impact of new product introduction.</li>
</ol>

Projects addressing more than one challenge (e.g. clinical and field epidemiology) are encouraged. In some geographies many of these challenges exist simultaneously, at different times for different populations; in other geographies only one or two of these challenges predominate. Applications should clearly state which of these challenges is being targeted and provide clear rationale for why the project is likely to address the challenge.

Applications should also state how the knowledge generated from their proposal would be produced in a timely manner in order to inform public health decision making. We expect that PGS data on SARS-CoV-2 will be shared immediately with local government health officials as well as uploaded to a standard repository for genetic data such as GISAID, NCBI or ENA, all in compliance with applicable data protection laws. Such sharing is important for the public health response locally but also globally.

Responding to the above challenges requires a multidisciplinary approach. Thus, collaborative work is highly encouraged.

What we are looking for:

We will highly preference funding for projects in national public health institutes or other public laboratories with links to the public health systems that focus on pathogen genomic sequencing.

All applications should:

<ul>
	<li>Describe how laboratory and staff can immediately put to use PGS technology at your site to respond to at least one of the challenges listed above.</li>
	<li>Describe how the data generated from your project will be used to inform public health decision making in your country and/or region in a timely manner. How will you communicate your findings and engage with stakeholders to ensure uptake and use of your findings for these public health purposes?</li>
	<li>Given the fast-moving nature of the research field into SARS-CoV-2, how will you ensure that the results that your work produces are timely, and the question being addressed is still relevant at the time when the results are available.</li>
	<li>Describe the sampling approach for obtaining specimens for genomic sequencing and how the sampling approach will be optimized to answer at least one of the challenges outlined above. In addition, describe how metadata and clinical, epidemiological or other data will be collected and combined with the PGS data to answer at least one of the challenges listed above.</li>
	<li>Articulate how the capacity built through the proposed project will strengthen your institute’s approach to using PGS for surveillance beyond the covid-19 pandemic.</li>
</ul>

A few of the many options we will consider include (but are not limited to) support for:

<ul>
	<li>Laboratory equipment, supplies and reagents needed for next generation pathogen genomic sequencing (PGS). Centers with Sanger sequencing capabilities can also apply.</li>
	<li>Field supplies for sample collection, transportation, storage and preparation.</li>
	<li>Collection of linked epidemiological data and meta-data.</li>
	<li>Laptop or computer with appropriate software for the analysis; high speed internet access and cloud compute time, if not provided through the Africa CDC lab network.</li>
	<li>Salary for personnel (including for example laboratory personnel, epidemiologist, field staff to collect samples).</li>
	<li>Training specific for PGS technology or bioinformatics, either online or in person.</li>
	<li>Travel to Africa CDC to support network development or to present findings at an international conference.</li>
	<li>Costs for high performance computing, where applicable.</li>
</ul>

We will not consider funding for projects that do not primarily respond to SARS-CoV-2 public health response. Human genomics will not be covered by this call.

NOTE: This opportunity was open to an invited set of African investigators.

Covid-19 Pathogen Genomic Sequencing (PGS) in Africa

The International COVID-19 Data Alliance (ICODA) and the Bill &amp; Melinda Gates Foundation’s Grand Challenges initiative, supported by the COVID-19 Therapeutics Accelerator, are announcing an open funding call for research studies to accelerate knowledge of COVID-19 through data science: Grand Challenges ICODA COVID-19 Data Science.

July 29, 2021 update: The International COVID-19 Data Alliance (ICODA) and the Bill &amp; Melinda Gates Foundation's Grand Challenges initiative, with support from the COVID-19 Therapeutics Accelerator and the Minderoo Foundation, <a href="https://icoda-research.org/grand-challenges-grants-awarded/" target="_blank">announced</a> an international set of grants awarded by Health Data Research UK (HDRUK) to 10 research organizations in 7 countries. The grants are for research studies to accelerate knowledge of COVID-19 through data science. Read summaries of the awarded grants <a href="https://gcgh.grandchallenges.org/grants/JTdCJTIyc29ydCUyMiUzQSUyMmRlc2NlbmRpbmclMjIlMkMlMjJzb3J0RmllbGQlMjIlM0ElMjJkYXRlJTIyJTJDJTIybnVtYmVyUGVyUGFnZSUyMiUzQTEwJTJDJTIycGFnZU51bWJlciUyMiUzQTAlN0Q=/JTdCJTIyeWVhcnMlMjIlM0ElNUIlMjIyMDIxJTIyJTVEJTJDJTIyY2hhbGxlbmdlcyUyMiUzQSU1QiUyMjExNyUyMiU1RCUyQyUyMnRlcm1zJTIyJTNBJTVCJTVEJTJDJTIyaW5pdGlhdGl2ZXMlMjIlM0ElNUIlMjI3ZWExOGIzNy1jMjk5LTQzZWUtYTg2Ni05NDM3ZTAxNWVmYzklMjIlNUQlMkMlMjJsb2NhdGlvbnMlMjIlM0ElNUIlNUQlN0Q=" target="_blank">here.</a>

Grand Challenges ICODA COVID-19 Data Science

The International COVID-19 Data Alliance (ICODA) and the Bill &amp; Melinda Gates Foundation’s Grand Challenges initiative, supported by the COVID-19 Therapeutics Accelerator, are announcing an open funding call for research studies to accelerate knowledge of COVID-19 through data science: Grand Challenges ICODA COVID-19 Data Science.

**NOTE: This opportunity is only open to participants who registered for and attended the 2020 Grand Challenges Annual Meeting (virtual format).

<h2>THE OPPORTUNITY</h2>

The Grand Challenges Annual Meeting - held in <a href="https://grandchallenges.org/annual-meeting" target="_blank">11 countries</a> over the past 15 years and in a virtual format this year - fosters innovation and international collaboration to address the biggest challenges in global health and development. Our goal is to support a global community of problem solvers who work together to set an innovation agenda and do the breakthrough science to deliver on it. Recognizing the pressing global threat of COVID-19, this year's Annual Meeting will focus on how to accelerate transformational innovation for global health crises. The meeting will seek to facilitate collaboration among scientists, decision makers, and policymakers to discover, develop, and deploy the solutions needed to curb the COVID-19 pandemic, mitigate its impact, and prepare for future global health emergencies. Additionally, the meeting will explore how to harness the energy and lessons from COVID-19 to drive continued progress against a broad range of global health and development goals. Besides this Call-to-Action request for proposals from meeting participants, there are three public <a href="https://gcgh.grandchallenges.org/grant-opportunities" target="_blank">grant opportunities</a> addressing global health and development that are opening at the meeting.

<h2>THE CHALLENGE</h2>

The Call-to-Action provides an opportunity for Grand Challenges Annual Meeting participants to take action based on ideas they developed and people they met at the meeting. The <a href="https://gcgh.grandchallenges.org/grants/eyJzb3J0IjoiZGVzY2VuZGluZyIsInNvcnRGaWVsZCI6ImRhdGUiLCJudW1iZXJQZXJQYWdlIjoxMDAsInBhZ2VOdW1iZXIiOjB9/eyJ5ZWFycyI6W10sImNoYWxsZW5nZXMiOlsiMTI5Il0sInRlcm1zIjpbXSwiaW5pdGlhdGl2ZXMiOltdLCJsb2NhdGlvbnMiOltdfQ==" target="_blank">grants awarded</a> for the 2018 and 2019 Call-to-Action were for projects arising &nbsp;from diverse types of opportunities – as noted by applicants in their submitted proposals – to interact at the meeting and to bring together combinations of expertise and perspective to speed the impact of what would otherwise be separate work by individual investigators. We hope that interactive elements at this year's virtual meeting will still provide ways to catalyze collaborative grant applications and that the extra urgency of the meeting's focus this year will inspire projects with a goal and design that will yield a tangible solution to a key problem by the end of the grant.

Funding

Each meeting participant will have one opportunity to apply as the primary applicant for a USD $100,000 grant or a collaborative USD $200,000 grant, both with an 18-month grant duration. Collaborative awards require the participation of at least two meeting participants from different institutions. While restricted to one application as the primary applicant, meeting participants may participate as collaborators in multiple collaborative applications. Priority will be given to new or newly expanded collaborations, rather than to existing partners seeking new funding.

We will give highest priority to proposed projects that:

<ul>
	<li>Contribute to a network of creative people, anchored around the investigators and implementors who are closest to the problems in the countries most burdened by global health and development inequity and have the knowledge and perspective to direct the right approaches to the right parts of the problems to help ensure success – their collective action and directed energy is helping solve today's key problems in global health and development, while building a mechanism ready to solve tomorrow's</li>
	<li>Specifically address the meeting's goals and content around the response to the COVID-19 pandemic and beyond, noting that this funding opportunity is not designed to more broadly address COVID-19</li>
	<li>Are likely to yield a tangible answer to a question or solution to a problem within the grant term under the current and likely near-term constraints associated with the COVID-19 pandemic</li>
	<li>Are explicitly aligned with the content within the meeting's scientific tracks, noting that proposals will be reviewed based on their alignment with one primary track. Eligible scientific tracks for this Call-to-Action are listed below, and they include one separate scientific session (Novel Technologies for Global Health) as well as the entire Keystone Symposia Global Health Series conference overlapping with the Grand Challenges Annual Meeting. The Smart Farming Innovations track is not eligible, because it has its own separate <a href="https://gcgh.grandchallenges.org/grant-opportunities" target="_blank">request for proposals</a>.</li>
</ul>

Scientific tracks eligible for the Call-to-Action

<ul>
	<li>Addressing Challenges to Manage COVID-19: The Indian Experience - Addressing the need, the status, and the gaps that are unique to each solution and discussing the way forward for making all of these solutions accessible and affordable from an Indian perspective</li>
	<li>Applying a Translational Lens to Global Health - Exploring the use of translational tools in nutrition and COVID-19, including the challenges and opportunities from planning and executing clinical trials in a pandemic</li>
	<li>Global Partnerships &amp; Grand Challenges – Supporting local innovators solving local problems, helping build a critical mass of innovation champions linked through a global network to collectively address the most pressing global health and development challenges</li>
	<li>Leveraging Pathogen Genetic Sequencing - Sequencing SARS-CoV-2 during the COVID-19 pandemic, sequencing applied to epidemic and endemic pathogens, and building a suite of interoperable and open-source data analytics and visualization software packages for use in real-time epidemic and endemic disease control</li>
	<li>Optimizing Birth, Growth, and Development – Addressing the COVID-19 pandemic's direct and indirect effect on global health work around maternal, newborn, and child health, including pivoting resources during COVID-19, respiratory support in low- and middle-income countries, and studies of maternal (intrauterine) nutrition and fetal growth</li>
	<li>Repurposing Drugs for COVID-19: Approaches and Challenges – Exploring ongoing efforts to identify candidate drugs to repurpose for COVID-19 treatment and prophylaxis, including screening platforms and model systems</li>
	<li>Novel Technologies for Global Health – Showcasing development of the COVID-19 Cell Atlas and exploring the COVID-19 Human Tissue Atlas and a systems biology approach together with additional technologies</li>
	<li>Enabling Crop Analytics at Scale - Removing bottlenecks to large-scale collection, use, and sharing of ground truth data or processes for smallholder farmer applications</li>
	<li>Optimizing Nutrition for Maternal, Newborn, and Child Health (Keystone Symposia) – Emphasizing interdisciplinary research and connecting global nutrition and molecular nutrition experts</li>
</ul>

We will not consider funding approaches that:

<ul>
	<li>Are not explicitly aligned with the content within the meeting's scientific tracks eligible for this request for proposals that are listed above</li>
	<li>Are not accomplishable within the grant term under the current and likely near-term constraints associated with the COVID-19 pandemic</li>
</ul>

Note (added November 12, 2020): The Bill &amp; Melinda Gates Foundation will consider proposals targeting topics under the meeting scientific tracks and sessions listed in the request for proposals – the Radical Mental Health track and Leveraging Digital Technologies to Address Health Crises and Beyond track are not part of this particular request for proposals. Proposals submitted under the Global Partnerships &amp; Grand Challenges track should address one of the listed eligible meeting tracks or sessions and bring a specific focus on partnership.

2020 Grand Challenges Annual Meeting Call-to-Action

**NOTE: This opportunity is only open to participants who registered for and attended the 2020 Grand Challenges Annual Meeting (virtual format).
<h2>THE OPPORTUNITY</h2>
The Grand Challenges Annual Meeting - held in <a href="https://grandchallenges.org/annual-meeting" target="_blank" rel="noopener noreferrer">11 countries</a> over the past 15 years and in a virtual format this year - fosters innovation and international collaboration to address the biggest challenges in global health and development. Our goal is to support a global community of problem solvers who work together to set an innovation agenda and do the breakthrough science to deliver on it. Recognizing the pressing global threat of COVID-19, this year's Annual Meeting will focus on how to accelerate transformational innovation for global health crises. The meeting will seek to facilitate collaboration among scientists, decision makers, and policymakers to discover, develop, and deploy the solutions needed to curb the COVID-19 pandemic, mitigate its impact, and prepare for future global health emergencies. Additionally, the meeting will explore how to harness the energy and lessons from COVID-19 to drive continued progress against a broad range of global health and development goals. Besides this Call-to-Action request for proposals from meeting participants, there are three public <a href="https://gcgh.grandchallenges.org/grant-opportunities" target="_blank" rel="noopener noreferrer">grant opportunities</a> addressing global health and development that are opening at the meeting.
<h2>THE CHALLENGE</h2>
The Call-to-Action provides an opportunity for Grand Challenges Annual Meeting participants to take action based on ideas they developed and people they met at the meeting. The <a href="https://gcgh.grandchallenges.org/grants/eyJzb3J0IjoiZGVzY2VuZGluZyIsInNvcnRGaWVsZCI6ImRhdGUiLCJudW1iZXJQZXJQYWdlIjoxMDAsInBhZ2VOdW1iZXIiOjB9/eyJ5ZWFycyI6W10sImNoYWxsZW5nZXMiOlsiMTI5Il0sInRlcm1zIjpbXSwiaW5pdGlhdGl2ZXMiOltdLCJsb2NhdGlvbnMiOltdfQ==" target="_blank" rel="noopener noreferrer">grants awarded</a> for the 2018 and 2019 Call-to-Action were for projects arising  from diverse types of opportunities – as noted by applicants in their submitted proposals – to interact at the meeting and to bring together combinations of expertise and perspective to speed the impact of what would otherwise be separate work by individual investigators. We hope that interactive elements at this year's virtual meeting will still provide ways to catalyze collaborative grant applications and that the extra urgency of the meeting's focus this year will inspire projects with a goal and design that will yield a tangible solution to a key problem by the end of the grant.
Funding
Each meeting participant will have one opportunity to apply as the primary applicant for a USD $100,000 grant or a collaborative USD $200,000 grant, both with an 18-month grant duration. Collaborative awards require the participation of at least two meeting participants from different institutions. While restricted to one application as the primary applicant, meeting participants may participate as collaborators in multiple collaborative applications. Priority will be given to new or newly expanded collaborations, rather than to existing partners seeking new funding.
We will give highest priority to proposed projects that:
<ul><li>Contribute to a network of creative people, anchored around the investigators and implementors who are closest to the problems in the countries most burdened by global health and development inequity and have the knowledge and perspective to direct the right approaches to the right parts of the problems to help ensure success – their collective action and directed energy is helping solve today's key problems in global health and development, while building a mechanism ready to solve tomorrow's</li>
<li>Specifically address the meeting's goals and content around the response to the COVID-19 pandemic and beyond, noting that this funding opportunity is not designed to more broadly address COVID-19</li>
<li>Are likely to yield a tangible answer to a question or solution to a problem within the grant term under the current and likely near-term constraints associated with the COVID-19 pandemic</li>
<li>Are explicitly aligned with the content within the meeting's scientific tracks, noting that proposals will be reviewed based on their alignment with one primary track. Eligible scientific tracks for this Call-to-Action are listed below, and they include one separate scientific session (Novel Technologies for Global Health) as well as the entire Keystone Symposia Global Health Series conference overlapping with the Grand Challenges Annual Meeting. The Smart Farming Innovations track is not eligible, because it has its own separate <a href="https://gcgh.grandchallenges.org/grant-opportunities" target="_blank" rel="noopener noreferrer">request for proposals</a>.</li>
</ul>Scientific tracks eligible for the Call-to-Action
<ul><li>Addressing Challenges to Manage COVID-19: The Indian Experience - Addressing the need, the status, and the gaps that are unique to each solution and discussing the way forward for making all of these solutions accessible and affordable from an Indian perspective</li>
<li>Applying a Translational Lens to Global Health - Exploring the use of translational tools in nutrition and COVID-19, including the challenges and opportunities from planning and executing clinical trials in a pandemic</li>
<li>Global Partnerships &amp; Grand Challenges – Supporting local innovators solving local problems, helping build a critical mass of innovation champions linked through a global network to collectively address the most pressing global health and development challenges</li>
<li>Leveraging Pathogen Genetic Sequencing - Sequencing SARS-CoV-2 during the COVID-19 pandemic, sequencing applied to epidemic and endemic pathogens, and building a suite of interoperable and open-source data analytics and visualization software packages for use in real-time epidemic and endemic disease control</li>
<li>Optimizing Birth, Growth, and Development – Addressing the COVID-19 pandemic's direct and indirect effect on global health work around maternal, newborn, and child health, including pivoting resources during COVID-19, respiratory support in low- and middle-income countries, and studies of maternal (intrauterine) nutrition and fetal growth</li>
<li>Repurposing Drugs for COVID-19: Approaches and Challenges – Exploring ongoing efforts to identify candidate drugs to repurpose for COVID-19 treatment and prophylaxis, including screening platforms and model systems</li>
<li>Novel Technologies for Global Health – Showcasing development of the COVID-19 Cell Atlas and exploring the COVID-19 Human Tissue Atlas and a systems biology approach together with additional technologies</li>
<li>Enabling Crop Analytics at Scale - Removing bottlenecks to large-scale collection, use, and sharing of ground truth data or processes for smallholder farmer applications</li>
<li>Optimizing Nutrition for Maternal, Newborn, and Child Health (Keystone Symposia) – Emphasizing interdisciplinary research and connecting global nutrition and molecular nutrition experts</li>
</ul>We will not consider funding approaches that:
<ul><li>Are not explicitly aligned with the content within the meeting's scientific tracks eligible for this request for proposals that are listed above</li>
<li>Are not accomplishable within the grant term under the current and likely near-term constraints associated with the COVID-19 pandemic</li>
</ul>Note (added November 12, 2020): The Bill &amp; Melinda Gates Foundation will consider proposals targeting topics under the meeting scientific tracks and sessions listed in the request for proposals – the Radical Mental Health track and Leveraging Digital Technologies to Address Health Crises and Beyond track are not part of this particular request for proposals. Proposals submitted under the Global Partnerships &amp; Grand Challenges track should address one of the listed eligible meeting tracks or sessions and bring a specific focus on partnership.

**NOTE: This opportunity is only open to participants who registered for and attended the 2020 Grand Challenges Annual Meeting (virtual format).

<h2>THE OPPORTUNITY</h2>

Embracing the tradition of microbial fermentation to transform locally available foods into naturally vitamin-fortified, toxin-free, flavorful, and shelf-stable products could empower local communities to mitigate the impact of COVID-19 on supply chain/food security and improve the health and nutrition of mothers and children in the most vulnerable settings. Historical advances in food processing have largely employed strategies that involve supplementation with micronutrients and additives to improve nutritional content and stability, but these approaches require highly centralized supply chains.<a href="#_edn1" name="_ednref1" title="">1</a> In addition, chemical additives for preservation, flavor and texture purposes may have unintended consequences of contributing to compromised gut health and increased prevalence of metabolic disease (hypertension, diabetes, obesity).<a href="#_edn2" name="_ednref2" title="">2</a>

Fermentation is an ancient practice through which locally-sourced food substrates can be transformed naturally by environmentally occurring microbes. These processes are thought to be intricately intertwined with human biology, and it is hypothesized that our primate ancestors adapted to natural fermentation processes millions of years ago.<a href="#_edn3" name="_ednref3" title="">3</a> While many fermented foods (e.g., yogurt, cheese, coffee and alcohol) remain popular, certain types of fermentation are a dwindling art in many settings, representing a loss of cultural heritage and a natural way to improve the qualities of foods across several distinct axes<a href="#_edn4" name="_ednref4" title="">4</a>:

<ul>
	<li>Improve macro- and micro-nutrient quality and bioavailability (e.g., B vitamins)<a href="#_edn5" name="_ednref5" title="">5</a></li>
	<li>Remove anti-nutrients (mycotoxins; phytates, which decrease iron availability)<a href="#_edn6" name="_ednref6" title="">6</a></li>
	<li>Transform taste, flavor and texture<a href="#_edn7" name="_ednref7" title="">7</a></li>
	<li>Improve the preservation and stability of foods by excluding pathogens (through lowering pH, bacteriocin production, removing simple sugars)<a href="#_edn8" name="_ednref8" title="">8</a></li>
</ul>

Historical approaches of macronutrient supplementation and micronutrient fortification have been the basis for transformative global health nutrition interventions, ultimately saving millions of lives each year.<a href="#_edn9" name="_ednref9" title="">9</a> These approaches have also focused on pediatric populations, although recent work suggests that solutions targeting maternal nutrition may be even more impactful on pediatric health and have the important benefit of also improving maternal health.<a href="#_edn10" name="_ednref10" title="">10</a> Given limited access of nutritional interventions by the populations in greatest need<a href="#_edn11" name="_ednref11" title="">11</a> and formulations that are not optimized for gut and metabolic health,<a href="#_edn12" name="_ednref12" title="">12</a> malnutrition remains one of the most significant global health problems facing society today.

COVID-19, with disruption of supply chains and a predilection for individuals with metabolic diseases, has served to increase the urgency for identifying locally-sourceable health-promoting maternal nutrition solutions that treat undernutrition without increasing the risk of obesity, diabetes, and hypertension. Ironically, it may be that these new solutions already exist in the form of ancient traditions reevaluated and revalued through a next-generation and evidence-based lens.

<h2>THE CHALLENGE</h2>

Beyond many of the well-known examples of microbial fermentation, the vast majority of fermentation processes around the world remain uncharacterized and their potential human health benefits are unknown. These ancient practices may hold the key to impactful and locally targeted nutritional interventions that combine tradition and science to tackle malnutrition. Rigorous scientific evaluation has been limited and characterization to understand potential benefits could be pursued to validate and underscore the importance of preserving this cultural heritage.

What we are looking for

This call seeks to fund pilot studies that investigate the biological effect of traditional locally fermented foods on key microbiome, gut, and health biomarkers in local populations. The goal is to provide investigators in Sub-Saharan Africa and South Asia with the resources to build local capacity to investigate fermented foods as novel maternal nutrition interventions. In particular, sequencing technology – a transformative tool that has enabled in-depth investigation of microbial communities – will be provided to all investigators to democratize the ability to investigate foods and health effects, and build local capacity. Ultimately, the goal is to empower local communities to develop geography and culture specific interventions powered by fermentation, in country.

Proposals should specifically address the following core elements, but investigators are welcome to propose creative strategies and designs to accomplish the core goals of this call and account for local cultural traditions. In addition, it is expected that study design will be refined after award through a collaborative forum invovling other awardees and the foundation:

<ul>
	<li>Identification of a local (geographic/cultural) fermented food for study
	<ul>
		<li>Many foods may not be colloquially considered to be fermented, but any process that incorporates biotransformation by microbes is acceptable</li>
		<li>Living microbes were actively employed as a part of the fermentation process and final product consumed retains live organisms</li>
		<li>Fermentation may be driven by known organisms, e.g. bacterial Lactobacillus sp., fungal Aspergillus sp., or less studied food-borne organisms</li>
		<li>Must be plant-based (e.g., grain or staple crop). Plant-based fermented foods are a requirement due to lower cost of goods for scalability compared to animal-based foods</li>
		<li>Food with a cultural precedent in maternal nutrition are of high interest</li>
		<li>The food being investigated must be produced in compliance under all relevant local food manufacturing regulations and modern food safety practices</li>
	</ul>
	</li>
	<li>Pilot study design for longitudinal intervention study for understanding the effect of the fermented food in a naïve (no, or limited, fermented food consumption) population
	<ul>
		<li>The target population should be women of reproductive age, and a naive population not currently consuming or with limited consumption of the target fermented food to better understanding the biological effects of the food itself. Different subpopulations (urban vs. rural, various cultural groups, different sub-geographies within a country, etc.) with lower consumption of the target fermented food could be specifically targeted. If populations traditionally consuming fermented foods are considered, it would be important to undertake a baseline to understand the additive effect after consumption of "target foods".</li>
		<li>Longitudinal intervention studies are recommended, with small cohort sizes (20-30 participants) and sustained exposure to the fermented food (e.g., at least daily &gt;5 days) but ultimately the study design should be motivated by the end goal of characterizing the effects of the food on maternal nutrition through host (blood and fecal) and gut microbiome biomarkers.</li>
		<li>A template dietary questionnaire will be provided and can be customized to local foods and traditions</li>
		<li>Existing infrastructure that may improve ability to execute on the proposed study can and should be highlighted</li>
	</ul>
	</li>
	<li>Biological sample biobanking and characterization before and after food intervention
	<ul>
		<li>Fermented foods themselves (metagenomic analysis of fungal [ITS] and bacterial [16S] constituents), potentially across distinct batches and preparation methods</li>
		<li>Serial fecal samples from participants (metagenomic analysis; lipocalin-2, myeloperoxidase, and calprotectin of particular interest)</li>
		<li>Serial serum/blood samples from participants (Iron studies, B-vitamin analysis; lipocalin-2, IL-6 and CRP are of particular interest given the association of inflammation biomarkers with maternal nutrition and birth outcomes) <a href="#_edn13" name="_ednref13" title="">13</a></li>
		<li>Other characterization approaches of food (including effects of fermentation on the nutritional profile) or biological samples using conventional or existing techniques</li>
		<li>Proposals should specifically address existing laboratory infrastructure and capacity for integrating next generation sequencing into existing laboratory workflows (e.g. nucleic acid extraction, PCR, etc.)</li>
	</ul>
	</li>
</ul>

As a part of this 18 month Grand Challenges award, sequencing platforms (funded with up to USD $40K for sequencing technology out of this USD $200K award) and training will be provided to investigators to enable local sequence-based characterization of the fermented foods and microbiome effects. The output of this study will be pilot data evaluating the biological effect of traditional fermented foods on gut, microbiome and health axes in local populations. Any additional points on the sustainability of the intervention and the empowerment of local champions to continue the work, integrating with state and national level Maternal, Infant and Young Child Nutrition (MIYCN) programs would also be welcome.

What we will not consider funding 

<ul>
	<li>Investigators and institutions not located in Sub-Saharan Africa or South Asia</li>
	<li>Investigators not studying local foods (specific to the culture or geography)</li>
	<li>Investigators not investigating local populations</li>
	<li>Proposals that do not contain a human interventional study targeted towards women of reproductive age. No studies on child populations will be funded.</li>
	<li>Proposals not addressing all the stated study design criteria above</li>
	<li>Proposals that do not demonstrate a capacity to perform the research proposed; investigators should describe capacity for human studies, sample collection, processing and storage, including but not limited to:
	<ul>
		<li>Relevant approvals from local authorities/institutions/Government on the research methodology and sharing of data among collaborators, eventually for global access</li>
		<li>Data analysis and adherence to relevant local laws/ policies pertaining to data sharing, hosting and data protection.</li>
		<li>Secure handling of personally identifiable information data and research results</li>
		<li>Institutional Review Boards or equivalent human study regulation strategy</li>
		<li>Sample collection capacity/protocols and capacity for sample storage</li>
		<li>Ability to perform human biological sample characterization as proposed</li>
	</ul>
	</li>
</ul>

___________________________________

References

<a href="#_ednref1" name="_edn1" title="">[1]</a> <a href="https://www.fao.org/3/a-i3953e.pdf" target="_blank">https://www.fao.org/3/a-i3953e.pdf</a>

<a href="#_ednref2" name="_edn2" title="">[2]</a> <a href="https://www.nature.com/articles/nature14232/" target="_blank">https://www.nature.com/articles/nature14232/</a>

<a href="#_ednref3" name="_edn3" title="">[3]</a> <a href="https://www.pnas.org/content/112/2/458" target="_blank">https://www.pnas.org/content/112/2/458</a>

<a href="#_ednref4" name="_edn4" title="">[4]</a> <a href="https://www.sciencedirect.com/science/article/pii/S0958166919300990" target="_blank">https://www.sciencedirect.com/science/article/pii/S0958166919300990</a>

<a href="#_ednref5" name="_edn5" title="">[5]</a> <a href="https://academic.oup.com/advances/article/4/4/463/4259633" target="_blank">https://academic.oup.com/advances/article/4/4/463/4259633</a>

<a href="#_ednref6" name="_edn6" title="">[6]</a> <a href="https://www.sciencedirect.com/science/article/abs/pii/0963996994900965" target="_blank">https://www.sciencedirect.com/science/article/abs/pii/0963996994900965</a>

<a href="#_ednref7" name="_edn7" title="">[7]</a> <a href="https://ifst.onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2621.1999.00245.x" target="_blank">https://ifst.onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2621.1999.00245.x</a>

<a href="#_ednref8" name="_edn8" title="">[8]</a> <a href="https://www.karger.com/Article/Abstract/104752" target="_blank">https://www.karger.com/Article/Abstract/104752</a>

<a href="#_ednref9" name="_edn9" title="">[9]</a> <a href="https://link.springer.com/article/10.1186/2046-4053-2-67" target="_blank">https://link.springer.com/article/10.1186/2046-4053-2-67</a>

<a href="#_ednref10" name="_edn10" title="">[10]</a> <a href="https://academic.oup.com/ajcn/article/109/2/457/5307124" target="_blank">https://academic.oup.com/ajcn/article/109/2/457/5307124</a>

<a href="#_ednref11" name="_edn11" title="">[11]</a> <a href="https://www.who.int/maternal_child_adolescent/topics/child/malnutrition/en/" target="_blank">https://www.who.int/maternal_child_adolescent/topics/child/malnutrition/en/</a>

<a href="#_ednref12" name="_edn12" title="">[12]</a> <a href="https://science.sciencemag.org/content/365/6449/eaau4732" target="_blank">https://science.sciencemag.org/content/365/6449/eaau4732</a>

<a href="#_ednref13" name="_edn13" title="">[13]</a> <a href="https://pubmed.ncbi.nlm.nih.gov/28274163/" target="_blank">https://pubmed.ncbi.nlm.nih.gov/28274163/</a>

Integrating Tradition and Technology for Fermented Foods for Maternal Nutrition

<h2>THE OPPORTUNITY</h2>
Embracing the tradition of microbial fermentation to transform locally available foods into naturally vitamin-fortified, toxin-free, flavorful, and shelf-stable products could empower local communities to mitigate the impact of COVID-19 on supply chain/food security and improve the health and nutrition of mothers and children in the most vulnerable settings. Historical advances in food processing have largely employed strategies that involve supplementation with micronutrients and additives to improve nutritional content and stability, but these approaches require highly centralized supply chains.<a href="#_edn1" name="_ednref1" title="" id="_ednref1">1</a> In addition, chemical additives for preservation, flavor and texture purposes may have unintended consequences of contributing to compromised gut health and increased prevalence of metabolic disease (hypertension, diabetes, obesity).<a href="#_edn2" name="_ednref2" title="" id="_ednref2">2</a>
Fermentation is an ancient practice through which locally-sourced food substrates can be transformed naturally by environmentally occurring microbes. These processes are thought to be intricately intertwined with human biology, and it is hypothesized that our primate ancestors adapted to natural fermentation processes millions of years ago.<a href="#_edn3" name="_ednref3" title="" id="_ednref3">3</a> While many fermented foods (e.g., yogurt, cheese, coffee and alcohol) remain popular, certain types of fermentation are a dwindling art in many settings, representing a loss of cultural heritage and a natural way to improve the qualities of foods across several distinct axes<a href="#_edn4" name="_ednref4" title="" id="_ednref4">4</a>:
<ul><li>Improve macro- and micro-nutrient quality and bioavailability (e.g., B vitamins)<a href="#_edn5" name="_ednref5" title="" id="_ednref5">5</a></li>
<li>Remove anti-nutrients (mycotoxins; phytates, which decrease iron availability)<a href="#_edn6" name="_ednref6" title="" id="_ednref6">6</a></li>
<li>Transform taste, flavor and texture<a href="#_edn7" name="_ednref7" title="" id="_ednref7">7</a></li>
<li>Improve the preservation and stability of foods by excluding pathogens (through lowering pH, bacteriocin production, removing simple sugars)<a href="#_edn8" name="_ednref8" title="" id="_ednref8">8</a></li>
</ul>Historical approaches of macronutrient supplementation and micronutrient fortification have been the basis for transformative global health nutrition interventions, ultimately saving millions of lives each year.<a href="#_edn9" name="_ednref9" title="" id="_ednref9">9</a> These approaches have also focused on pediatric populations, although recent work suggests that solutions targeting maternal nutrition may be even more impactful on pediatric health and have the important benefit of also improving maternal health.<a href="#_edn10" name="_ednref10" title="" id="_ednref10">10</a> Given limited access of nutritional interventions by the populations in greatest need<a href="#_edn11" name="_ednref11" title="" id="_ednref11">11</a> and formulations that are not optimized for gut and metabolic health,<a href="#_edn12" name="_ednref12" title="" id="_ednref12">12</a> malnutrition remains one of the most significant global health problems facing society today.
COVID-19, with disruption of supply chains and a predilection for individuals with metabolic diseases, has served to increase the urgency for identifying locally-sourceable health-promoting maternal nutrition solutions that treat undernutrition without increasing the risk of obesity, diabetes, and hypertension. Ironically, it may be that these new solutions already exist in the form of ancient traditions reevaluated and revalued through a next-generation and evidence-based lens.
<h2>THE CHALLENGE</h2>
Beyond many of the well-known examples of microbial fermentation, the vast majority of fermentation processes around the world remain uncharacterized and their potential human health benefits are unknown. These ancient practices may hold the key to impactful and locally targeted nutritional interventions that combine tradition and science to tackle malnutrition. Rigorous scientific evaluation has been limited and characterization to understand potential benefits could be pursued to validate and underscore the importance of preserving this cultural heritage.
What we are looking for
This call seeks to fund pilot studies that investigate the biological effect of traditional locally fermented foods on key microbiome, gut, and health biomarkers in local populations. The goal is to provide investigators in Sub-Saharan Africa and South Asia with the resources to build local capacity to investigate fermented foods as novel maternal nutrition interventions. In particular, sequencing technology – a transformative tool that has enabled in-depth investigation of microbial communities – will be provided to all investigators to democratize the ability to investigate foods and health effects, and build local capacity. Ultimately, the goal is to empower local communities to develop geography and culture specific interventions powered by fermentation, in country.
Proposals should specifically address the following core elements, but investigators are welcome to propose creative strategies and designs to accomplish the core goals of this call and account for local cultural traditions. In addition, it is expected that study design will be refined after award through a collaborative forum invovling other awardees and the foundation:
<ul><li>Identification of a local (geographic/cultural) fermented food for study
<ul><li>Many foods may not be colloquially considered to be fermented, but any process that incorporates biotransformation by microbes is acceptable</li>
<li>Living microbes were actively employed as a part of the fermentation process and final product consumed retains live organisms</li>
<li>Fermentation may be driven by known organisms, e.g. bacterial Lactobacillus sp., fungal Aspergillus sp., or less studied food-borne organisms</li>
<li>Must be plant-based (e.g., grain or staple crop). Plant-based fermented foods are a requirement due to lower cost of goods for scalability compared to animal-based foods</li>
<li>Food with a cultural precedent in maternal nutrition are of high interest</li>
<li>The food being investigated must be produced in compliance under all relevant local food manufacturing regulations and modern food safety practices</li>
</ul></li>
<li>Pilot study design for longitudinal intervention study for understanding the effect of the fermented food in a naïve (no, or limited, fermented food consumption) population
<ul><li>The target population should be women of reproductive age, and a naive population not currently consuming or with limited consumption of the target fermented food to better understanding the biological effects of the food itself. Different subpopulations (urban vs. rural, various cultural groups, different sub-geographies within a country, etc.) with lower consumption of the target fermented food could be specifically targeted. If populations traditionally consuming fermented foods are considered, it would be important to undertake a baseline to understand the additive effect after consumption of "target foods".</li>
<li>Longitudinal intervention studies are recommended, with small cohort sizes (20-30 participants) and sustained exposure to the fermented food (e.g., at least daily &gt;5 days) but ultimately the study design should be motivated by the end goal of characterizing the effects of the food on maternal nutrition through host (blood and fecal) and gut microbiome biomarkers.</li>
<li>A template dietary questionnaire will be provided and can be customized to local foods and traditions</li>
<li>Existing infrastructure that may improve ability to execute on the proposed study can and should be highlighted</li>
</ul></li>
<li>Biological sample biobanking and characterization before and after food intervention
<ul><li>Fermented foods themselves (metagenomic analysis of fungal [ITS] and bacterial [16S] constituents), potentially across distinct batches and preparation methods</li>
<li>Serial fecal samples from participants (metagenomic analysis; lipocalin-2, myeloperoxidase, and calprotectin of particular interest)</li>
<li>Serial serum/blood samples from participants (Iron studies, B-vitamin analysis; lipocalin-2, IL-6 and CRP are of particular interest given the association of inflammation biomarkers with maternal nutrition and birth outcomes) <a href="#_edn13" name="_ednref13" title="" id="_ednref13">13</a></li>
<li>Other characterization approaches of food (including effects of fermentation on the nutritional profile) or biological samples using conventional or existing techniques</li>
<li>Proposals should specifically address existing laboratory infrastructure and capacity for integrating next generation sequencing into existing laboratory workflows (e.g. nucleic acid extraction, PCR, etc.)</li>
</ul></li>
</ul>As a part of this 18 month Grand Challenges award, sequencing platforms (funded with up to USD $40K for sequencing technology out of this USD $200K award) and training will be provided to investigators to enable local sequence-based characterization of the fermented foods and microbiome effects. The output of this study will be pilot data evaluating the biological effect of traditional fermented foods on gut, microbiome and health axes in local populations. Any additional points on the sustainability of the intervention and the empowerment of local champions to continue the work, integrating with state and national level Maternal, Infant and Young Child Nutrition (MIYCN) programs would also be welcome.
What we will not consider funding 
<ul><li>Investigators and institutions not located in Sub-Saharan Africa or South Asia</li>
<li>Investigators not studying local foods (specific to the culture or geography)</li>
<li>Investigators not investigating local populations</li>
<li>Proposals that do not contain a human interventional study targeted towards women of reproductive age. No studies on child populations will be funded.</li>
<li>Proposals not addressing all the stated study design criteria above</li>
<li>Proposals that do not demonstrate a capacity to perform the research proposed; investigators should describe capacity for human studies, sample collection, processing and storage, including but not limited to:
<ul><li>Relevant approvals from local authorities/institutions/Government on the research methodology and sharing of data among collaborators, eventually for global access</li>
<li>Data analysis and adherence to relevant local laws/ policies pertaining to data sharing, hosting and data protection.</li>
<li>Secure handling of personally identifiable information data and research results</li>
<li>Institutional Review Boards or equivalent human study regulation strategy</li>
<li>Sample collection capacity/protocols and capacity for sample storage</li>
<li>Ability to perform human biological sample characterization as proposed</li>
</ul></li>
</ul>___________________________________
References
<a href="#_ednref1" name="_edn1" title="" id="_edn1">[1]</a> <a href="https://www.fao.org/3/a-i3953e.pdf" target="_blank" rel="noopener noreferrer">https://www.fao.org/3/a-i3953e.pdf</a>
<a href="#_ednref2" name="_edn2" title="" id="_edn2">[2]</a> <a href="https://www.nature.com/articles/nature14232/" target="_blank" rel="noopener noreferrer">https://www.nature.com/articles/nature14232/</a>
<a href="#_ednref3" name="_edn3" title="" id="_edn3">[3]</a> <a href="https://www.pnas.org/content/112/2/458" target="_blank" rel="noopener noreferrer">https://www.pnas.org/content/112/2/458</a>
<a href="#_ednref4" name="_edn4" title="" id="_edn4">[4]</a> <a href="https://www.sciencedirect.com/science/article/pii/S0958166919300990" target="_blank" rel="noopener noreferrer">https://www.sciencedirect.com/science/article/pii/S0958166919300990</a>
<a href="#_ednref5" name="_edn5" title="" id="_edn5">[5]</a> <a href="https://academic.oup.com/advances/article/4/4/463/4259633" target="_blank" rel="noopener noreferrer">https://academic.oup.com/advances/article/4/4/463/4259633</a>
<a href="#_ednref6" name="_edn6" title="" id="_edn6">[6]</a> <a href="https://www.sciencedirect.com/science/article/abs/pii/0963996994900965" target="_blank" rel="noopener noreferrer">https://www.sciencedirect.com/science/article/abs/pii/0963996994900965</a>
<a href="#_ednref7" name="_edn7" title="" id="_edn7">[7]</a> <a href="https://ifst.onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2621.1999.00245.x" target="_blank" rel="noopener noreferrer">https://ifst.onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2621.1999.00245.x</a>
<a href="#_ednref8" name="_edn8" title="" id="_edn8">[8]</a> <a href="https://www.karger.com/Article/Abstract/104752" target="_blank" rel="noopener noreferrer">https://www.karger.com/Article/Abstract/104752</a>
<a href="#_ednref9" name="_edn9" title="" id="_edn9">[9]</a> <a href="https://link.springer.com/article/10.1186/2046-4053-2-67" target="_blank" rel="noopener noreferrer">https://link.springer.com/article/10.1186/2046-4053-2-67</a>
<a href="#_ednref10" name="_edn10" title="" id="_edn10">[10]</a> <a href="https://academic.oup.com/ajcn/article/109/2/457/5307124" target="_blank" rel="noopener noreferrer">https://academic.oup.com/ajcn/article/109/2/457/5307124</a>
<a href="#_ednref11" name="_edn11" title="" id="_edn11">[11]</a> <a href="https://www.who.int/maternal_child_adolescent/topics/child/malnutrition/en/" target="_blank" rel="noopener noreferrer">https://www.who.int/maternal_child_adolescent/topics/child/malnutrition/en/</a>
<a href="#_ednref12" name="_edn12" title="" id="_edn12">[12]</a> <a href="https://science.sciencemag.org/content/365/6449/eaau4732" target="_blank" rel="noopener noreferrer">https://science.sciencemag.org/content/365/6449/eaau4732</a>
<a href="#_ednref13" name="_edn13" title="" id="_edn13">[13]</a> <a href="https://pubmed.ncbi.nlm.nih.gov/28274163/" target="_blank" rel="noopener noreferrer">https://pubmed.ncbi.nlm.nih.gov/28274163/</a>

Grand Challenges seeks pilot studies that investigate the biological effect of traditional locally fermented foods on key microbiome, gut, and health biomarkers in local populations. The goal is to provide investigators in Sub-Saharan Africa and South Asia with the resources to build local capacity to investigate fermented foods as novel maternal nutrition interventions.

Note: Please see the request for proposals document with additional background as a PDF file on the right.

<h2>Summary</h2>

Smart Farming Innovations for Small-Scale Producers Request for Proposals (RFP) seeks Smart Farming solutions that leverage digital technology innovations that have the potential to drive positive impact for smallscale producer (SSP) entrepreneurs delivered through bundled farmer services and enabled by scalable digital and data platforms (<a href="#Fig1" id="_Fig1">Figure 1</a>). Solutions should address one or more challenges faced by smallscale crop and livestock producers in one or more areas of agricultural advisory, farm management decision support, input supply, finance, insurance, market access and linkages. Solutions should use human-centered design to elucidate the barriers that prevent SSPs from improving productivity, profitability and income – then propose Smart Farming solutions that can help elevate smallscale production entrepreneurs. Some of the fundamental challenges to address include: 1) low productivity driven by lack of access to information and services; climate change, weather variability and pest and disease outbreaks; 2) lack of access to tailored financial and insurance products, and 3) lack of access to and choice of market and offtake options. Additionally, solutions will need to consider barriers to adoption of digital farmer services, such as low language and digital literacy, the high relative cost of services and devices and, in particular, gender gaps and other potential downsides of digital solutions (e.g. the growing digital divide).

<img alt="" height="406" src="https://stage-drupal.grandchallenges.org/sites/default/files/images/farming-digital-technologies-diagram.jpg" width="414" />

<a href="#_Fig1" id="Fig1">Figure 1</a>. Smart Farming Innovations for SSPs

Awards: There are two grant types – Seed Grants and Scale-Up Grants – each with its own requirements. Applicants can only apply for one of these grant types must select which level for which they are applying (proposal should not be submitted for both grant types).

Seed Grants – Up to USD 250,000 to be implemented up to 12 months. Seed Grants are proposals for Smart Farming solutions that can demonstrate potential in meeting the following criteria:

<ul>
	<li>Leveraging digital technology innovations with the potential to scale, for example, utilizing a proven technology that has been applied in agriculture in another geography; transferring a technology from another sector such as health, infrastructure or finance; sourcing an entirely new technology;</li>
	<li>Show potential to improve SSP incomes, productivity and ability to adapt to climate change;</li>
	<li>Address barriers to scaled adoption of digital services, such as access, affordability and language and digital literacy. This includes addressing women's access to digital services and closing the digital divide between those who have access and marginalized populations who do not;</li>
	<li>Have the potential to be bundled with multiple farmer-facing services into an integrated solution;</li>
	<li>Are enabled by robust digital and data technology platforms and services;</li>
	<li>Provide fit-for-purpose solutions (e.g. developed using human-centered design) for SSP enterprises who seek to sell a portion of production to markets;</li>
	<li>Show potential to be scaled using a sustainable business model and are affordable and able to provide positive return on investment at a smallholder farm level through successful pilots, scaling partners, or higher volume production driving down prices.</li>
</ul>

Scale-Up Grants – Up to USD 1,500,000 to be implemented up to 24 months. Scale-Up Grants are proposals with demonstrated ability and sufficient evidence to have positive impact. In addition to the criteria listed above for Seed Grants, Scale-Up Grants must also:

<ul>
	<li>Leverage digital technology innovations with demonstrated readiness to scale and proven ability to bundle with other services;</li>
	<li>Meet all criteria regarding technology innovations, scalable platforms, and sustainable bundled service delivery models;</li>
	<li>Demonstrate that additional funding will enable value capture by SSPs or other value chain actors and sustainable and viable service delivery models over the long term.</li>
	<li>Please upload a separate document – 1 additional page maximum – that describes your partner consortium in more detail, including the various partners' capabilities, and additional evidence of value add, income, productivity, women's empowerment and long-term sustainability of the solution.</li>
</ul>

Consortiums: To increase the probability that projects funded through this RFP will continue after the initial project completion and evolve into a continuing global public good or sustained solution, applicants are encouraged to consider of a range of partners to form a consortium. This investment will prioritize those who partner with organizations interested in Smart Farming in low- and middle-income countries (LMICs) as long-term opportunities. There are several types of organizations we envisage being part of consortia submitting proposals: Enterprise Technology Platforms (Big-Tech), Enterprise Agriculture (Big-Ag), Ag-Tech Startups (Ag-Tech + Farm-Tech), Research Organizations (R&amp;D), national and international NGOs and farmer-based organizations (Implementors), Government and International Organizations.

Geographies: While we primarily seek solutions applicable to the LMICs listed below and favor those forming local partnerships. Other geographies will be considered if a strong case is made for doing so.

<ul>
	<li>Africa: Kenya, Uganda, Ethiopia, Tanzania, Rwanda, Ghana, Senegal, Mali, Burkina Faso, Malawi, Zambia, Mozambique, Nigeria</li>
	<li>Asia: India (Bihar, Odisha, Uttar Pradesh, Andhra Pradesh), Bangladesh</li>
</ul>

Smart Farming Innovations for Small-Scale Producers

Note: Please see the request for proposals document with additional background as a PDF file on the right.
<h2>Summary</h2>
Smart Farming Innovations for Small-Scale Producers Request for Proposals (RFP) seeks Smart Farming solutions that leverage digital technology innovations that have the potential to drive positive impact for smallscale producer (SSP) entrepreneurs delivered through bundled farmer services and enabled by scalable digital and data platforms (<a href="#Fig1" id="_Fig1">Figure 1</a>). Solutions should address one or more challenges faced by smallscale crop and livestock producers in one or more areas of agricultural advisory, farm management decision support, input supply, finance, insurance, market access and linkages. Solutions should use human-centered design to elucidate the barriers that prevent SSPs from improving productivity, profitability and income – then propose Smart Farming solutions that can help elevate smallscale production entrepreneurs. Some of the fundamental challenges to address include: 1) low productivity driven by lack of access to information and services; climate change, weather variability and pest and disease outbreaks; 2) lack of access to tailored financial and insurance products, and 3) lack of access to and choice of market and offtake options. Additionally, solutions will need to consider barriers to adoption of digital farmer services, such as low language and digital literacy, the high relative cost of services and devices and, in particular, gender gaps and other potential downsides of digital solutions (e.g. the growing digital divide).
<img alt="" height="406" src="https://stage-drupal.grandchallenges.org/sites/default/files/images/farming-digital-technologies-diagram.jpg" width="414" />
<a href="#_Fig1" id="Fig1">Figure 1</a>. Smart Farming Innovations for SSPs
Awards: There are two grant types – Seed Grants and Scale-Up Grants – each with its own requirements. Applicants can only apply for one of these grant types must select which level for which they are applying (proposal should not be submitted for both grant types).
Seed Grants – Up to USD 250,000 to be implemented up to 12 months. Seed Grants are proposals for Smart Farming solutions that can demonstrate potential in meeting the following criteria:
<ul><li>Leveraging digital technology innovations with the potential to scale, for example, utilizing a proven technology that has been applied in agriculture in another geography; transferring a technology from another sector such as health, infrastructure or finance; sourcing an entirely new technology;</li>
<li>Show potential to improve SSP incomes, productivity and ability to adapt to climate change;</li>
<li>Address barriers to scaled adoption of digital services, such as access, affordability and language and digital literacy. This includes addressing women's access to digital services and closing the digital divide between those who have access and marginalized populations who do not;</li>
<li>Have the potential to be bundled with multiple farmer-facing services into an integrated solution;</li>
<li>Are enabled by robust digital and data technology platforms and services;</li>
<li>Provide fit-for-purpose solutions (e.g. developed using human-centered design) for SSP enterprises who seek to sell a portion of production to markets;</li>
<li>Show potential to be scaled using a sustainable business model and are affordable and able to provide positive return on investment at a smallholder farm level through successful pilots, scaling partners, or higher volume production driving down prices.</li>
</ul>Scale-Up Grants – Up to USD 1,500,000 to be implemented up to 24 months. Scale-Up Grants are proposals with demonstrated ability and sufficient evidence to have positive impact. In addition to the criteria listed above for Seed Grants, Scale-Up Grants must also:
<ul><li>Leverage digital technology innovations with demonstrated readiness to scale and proven ability to bundle with other services;</li>
<li>Meet all criteria regarding technology innovations, scalable platforms, and sustainable bundled service delivery models;</li>
<li>Demonstrate that additional funding will enable value capture by SSPs or other value chain actors and sustainable and viable service delivery models over the long term.</li>
<li>Please upload a separate document – 1 additional page maximum – that describes your partner consortium in more detail, including the various partners' capabilities, and additional evidence of value add, income, productivity, women's empowerment and long-term sustainability of the solution.</li>
</ul>Consortiums: To increase the probability that projects funded through this RFP will continue after the initial project completion and evolve into a continuing global public good or sustained solution, applicants are encouraged to consider of a range of partners to form a consortium. This investment will prioritize those who partner with organizations interested in Smart Farming in low- and middle-income countries (LMICs) as long-term opportunities. There are several types of organizations we envisage being part of consortia submitting proposals: Enterprise Technology Platforms (Big-Tech), Enterprise Agriculture (Big-Ag), Ag-Tech Startups (Ag-Tech + Farm-Tech), Research Organizations (R&amp;D), national and international NGOs and farmer-based organizations (Implementors), Government and International Organizations.
Geographies: While we primarily seek solutions applicable to the LMICs listed below and favor those forming local partnerships. Other geographies will be considered if a strong case is made for doing so.
<ul><li>Africa: Kenya, Uganda, Ethiopia, Tanzania, Rwanda, Ghana, Senegal, Mali, Burkina Faso, Malawi, Zambia, Mozambique, Nigeria</li>
<li>Asia: India (Bihar, Odisha, Uttar Pradesh, Andhra Pradesh), Bangladesh</li>
</ul>

Grand Challenges seeks innovative digital solutions with potential to scale and integrate with bundled farmer services. Solutions should address one or more challenges facing small scale crop and livestock producer entrepreneurs in the areas of agricultural advisory, input supply, finance, insurance, market access, and decision support tools.

Balance the Equation - A Grand Challenge for Algebra 1

Balance the Equation is the first-ever Grand Challenge focused on U.S. education. The Bill &amp; Melinda Gates Foundation is seeking to disrupt the deeply imbalanced system against this generation – and previous generations – of Black, Latino, English Learners (ELs), and students experiencing poverty in the United States, who we will refer to as priority students, as it relates to their Algebra 1 experience in 7th, 8th, or 9th grade, in-class or online.

<h2>BACKGROUND</h2>

Cesarean section (CS) is a life-saving procedure for mother and newborn. However, too often c-section is not available, is provided without adequate quality, or is provided when not medically indicated - all dimensions that lead to maternal and newborn mortality and morbidity. We see an opportunity to nurture the field to identify and demonstrate feasibility of interventions to address challenges related to safe, timely, and appropriate cesarean section in low and middle income countries.

<h2>THE CHALLENGE</h2>

We invite proposals for interventions to address the following challenges related to the cesarean section:

<ol>
	<li>Increasing access to cesarean section where it is currently inadequate</li>
	<li>Increasing quality and safety of cesarean section to reduce iatrogenic harm to both mothers and newborns</li>
	<li>Reducing rates of non-medically indicated cesarean section.</li>
</ol>

Interventions addressing more than one challenge (e.g. quality and access) are encouraged. In some geographies all three of these challenges exist simultaneously, at different times for different populations; in other geographies only one or two of these challenges predominate. Applications should clearly state which of these three challenges is being targeted and provide clear rationale for why the intervention is likely to address the challenge. We are particularly interested in geographies with high fertility and weak health systems that will face challenges to ensure the provision of safe c-sections can keep pace with medical need, and we will thus consider applications proposing activities to be implemented in Sub-Saharan Africa or South Asia (India, Pakistan, Bangladesh).

Grant Funding Levels

We seek to make Seed Grants to generate proof of concept of novel interventions together with Validation Grants to generate further evidence of feasibility at a larger scale for existing interventions.

<ul>
	<li>Seed Grants of $100K for up to 24 months: These grants are intended to provide proof of concept of an intervention that is entirely novel at small scale (e.g., single facility or district). Applicants should conduct a literature review to verify that the proposed intervention has no documented evidence; documentation of the methods and outcomes of this review must be provided in the application. These grants should demonstrate the feasibility of a novel intervention and its impact on one or more of the c-section challenges identified in this call for applications.</li>
	<li>Validation Grants of $300K for up to 24 months: These grants are intended to demonstrate the feasibility of a single intervention or a combination of interventions at the scalable unit <a href="#_ftn1" id="_ftnref1">[1]</a> of a health system. Validation grants must replicate, confirm or more rigorously test one intervention - or multiple interventions - that have previously demonstrated proof of concept at a smaller scale. Given the complexity of the problem, we acknowledge that multi-component interventions are required, and we eoncourage applications exploring these.</li>
</ul>

What We Are Looking For:

All applications should:

<ul>
	<li>Focus on health service or delivery innovation. This call for applications excludes development of new medical devices and non-interventional analysis of data</li>
	<li>Describe how the intervention will be tailored to the epidemiology and health system where it will be implemented</li>
	<li>Ensure that women and newborns receive care that respects and preserves their dignity, including informed consent<a href="#_ftn2" id="_ftnref2" name="_ftnref2">[2]</a></li>
	<li>Include participation from institutions based in South Asia and sub-Saharan Africa; applications led by institutions from these geographies are encouraged</li>
	<li>Propose interventions that align with the attributes of scalable health innovations<a href="#_ftn3" id="_ftnref3" name="_ftnref3">[3]</a></li>
	<li>Report impact on c-section rates disaggregated by Robson classification<a href="#_ftn4" id="_ftnref4" name="_ftnref4">[4]</a>, and safety with indicators such as case fatality rates and rates of post-operative complication</li>
	<li>Propose activities to be implemented in a country in Sub-Saharan Africa or South Asia (India, Pakistan, Bangladesh).</li>
</ul>

A few of the many options we will consider include (but are not limited to): clinical team huddles for improving quality of CS; interventions to improve immediate breastfeeding and bonding among mother-infant pairs after CS; interventions to improve communication between patient and care team; restructuring labor wards to facilitate latent phase labor management; adjustments to financial incentives related to CS; policy and liability reform.

We will not consider funding for approaches that have been widely used and evaluated in LMIC settings to scale up access to cesarean section (e.g., task shifting); activities to improve quality of care that already have extensive evidence of effectiveness; emergency transport interventions; mass media campaigns; or development of new tools for surgery, anesthesia, or patient monitoring.

Collaboration

This request for proposals seeks to create a consortium of individually funded projects that will benefit from sharing information between projects. We expect that such sharing will help to ensure that the goals of the innovative approaches in individual projects are ultimately integrated with each other, thereby increasing the chances that the programs will be greater than the sum of their parts. Furthermore, we expect that sharing experimental methods, data, and resources will ultimately improve the ability to compare and validate local research findings and to develop interventions and products. We expect to bring together all grantees after 18-24 months to share what they have learned in their work and to discuss how to accelerate progress with these lessons.

<drupal-media data-align="center" data-entity-type="media" data-entity-uuid="6e3e1e63-035c-4e42-93c0-8ddc90679019"></drupal-media>

Figure 1. Framework for considering cesarean section

________________________________

<a href="#_ftnref1" id="_ftn1">[1]</a><a href="https://implementationscience.biomedcentral.com/articles/10.1186/s13012-016-0374-x" target="_blank">Barker P, Reid A, Schall M. A Framework for scaling up health interventions: lessons learned from large scale improvement initiatives in Africa. Implementation Science. 2016</a>.

<a href="#_ftnref2" name="_ftn2" title="">[2]</a><a href="https://www.who.int/maternal_child_adolescent/documents/improving-maternal-newborn-care-quality/en/" target="_blank">WHO. Standards for Improving Quality of Maternal and Newborn Care in Health Facilities. 2016.</a>

<a href="#_ftnref3" name="_ftn3" title="">[3]</a><a href="https://www.sciencedirect.com/science/article/pii/S0277953614006133" target="_blank">Spicer et al. "Scaling-up is a craft not a science: Catalysing scale-up of health innovations…" Social Science and Medicine. 2014"</a>

<a href="#_ftnref4" name="_ftn4" title="">[4]</a><a href="https://www.who.int/reproductivehealth/publications/maternal_perinatal_health/robson-classification/en/" target="_blank">WHO. Robson Classification: Implementation Manual. 2017</a>

Improving Access to and Use of Safe and Appropriate Cesarean Section

<h2>BACKGROUND</h2>
Cesarean section (CS) is a life-saving procedure for mother and newborn. However, too often c-section is not available, is provided without adequate quality, or is provided when not medically indicated - all dimensions that lead to maternal and newborn mortality and morbidity. We see an opportunity to nurture the field to identify and demonstrate feasibility of interventions to address challenges related to safe, timely, and appropriate cesarean section in low and middle income countries.
<h2>THE CHALLENGE</h2>
We invite proposals for interventions to address the following challenges related to the cesarean section:
<ol><li>Increasing access to cesarean section where it is currently inadequate</li>
<li>Increasing quality and safety of cesarean section to reduce iatrogenic harm to both mothers and newborns</li>
<li>Reducing rates of non-medically indicated cesarean section.</li>
</ol>Interventions addressing more than one challenge (e.g. quality and access) are encouraged. In some geographies all three of these challenges exist simultaneously, at different times for different populations; in other geographies only one or two of these challenges predominate. Applications should clearly state which of these three challenges is being targeted and provide clear rationale for why the intervention is likely to address the challenge. We are particularly interested in geographies with high fertility and weak health systems that will face challenges to ensure the provision of safe c-sections can keep pace with medical need, and we will thus consider applications proposing activities to be implemented in Sub-Saharan Africa or South Asia (India, Pakistan, Bangladesh).
Grant Funding Levels
We seek to make Seed Grants to generate proof of concept of novel interventions together with Validation Grants to generate further evidence of feasibility at a larger scale for existing interventions.
<ul><li>Seed Grants of $100K for up to 24 months: These grants are intended to provide proof of concept of an intervention that is entirely novel at small scale (e.g., single facility or district). Applicants should conduct a literature review to verify that the proposed intervention has no documented evidence; documentation of the methods and outcomes of this review must be provided in the application. These grants should demonstrate the feasibility of a novel intervention and its impact on one or more of the c-section challenges identified in this call for applications.</li>
<li>Validation Grants of $300K for up to 24 months: These grants are intended to demonstrate the feasibility of a single intervention or a combination of interventions at the scalable unit<a href="#Note1">1</a> of a health system. Validation grants must replicate, confirm or more rigorously test one intervention - or multiple interventions - that have previously demonstrated proof of concept at a smaller scale. Given the complexity of the problem, we acknowledge that multi-component interventions are required, and we eoncourage applications exploring these.</li>
</ul>What We Are Looking For:
All applications should:
<ul><li>Focus on health service or delivery innovation. This call for applications excludes development of new medical devices and non-interventional analysis of data</li>
<li>Describe how the intervention will be tailored to the epidemiology and health system where it will be implemented</li>
<li>Ensure that women and newborns receive care that respects and preserves their dignity, including informed consent<a href="#Note2">2</a></li>
<li>Include participation from institutions based in South Asia and sub-Saharan Africa; applications led by institutions from these geographies are encouraged</li>
<li>Propose interventions that align with the attributes of scalable health innovations<a href="#Note3">3</a></li>
<li>Report impact on c-section rates disaggregated by Robson classification<a href="#Note4">4</a>, and safety with indicators such as case fatality rates and rates of post-operative complication</li>
<li>Propose activities to be implemented in a country in Sub-Saharan Africa or South Asia (India, Pakistan, Bangladesh).</li>
</ul>A few of the many options we will consider include (but are not limited to): clinical team huddles for improving quality of CS; interventions to improve immediate breastfeeding and bonding among mother-infant pairs after CS; interventions to improve communication between patient and care team; restructuring labor wards to facilitate latent phase labor management; adjustments to financial incentives related to CS; policy and liability reform.
We will not consider funding for approaches that have been widely used and evaluated in LMIC settings to scale up access to cesarean section (e.g., task shifting); activities to improve quality of care that already have extensive evidence of effectiveness; emergency transport interventions; mass media campaigns; or development of new tools for surgery, anesthesia, or patient monitoring.
Collaboration
This request for proposals seeks to create a consortium of individually funded projects that will benefit from sharing information between projects. We expect that such sharing will help to ensure that the goals of the innovative approaches in individual projects are ultimately integrated with each other, thereby increasing the chances that the programs will be greater than the sum of their parts. Furthermore, we expect that sharing experimental methods, data, and resources will ultimately improve the ability to compare and validate local research findings and to develop interventions and products. We expect to bring together all grantees after 18-24 months to share what they have learned in their work and to discuss how to accelerate progress with these lessons.
<a href="https://gcgh.grandchallenges.org/sites/default/files/C-Section_Chart_Square.jpg" target="_parent"><img alt="" src="https://gcgh.grandchallenges.org/sites/default/files/C-Section_Chart_Square.jpg" /></a> 
Figure 1. Framework for considering cesarean section
________________________________
<a name="#Note1" id="#Note1">1</a><a href="https://implementationscience.biomedcentral.com/articles/10.1186/s13012-016-0374-x" target="_blank" rel="noopener noreferrer">Barker P, Reid A, Schall M. A Framework for scaling up health interventions: lessons learned from large scale improvement initiatives in Africa. Implementation Science. 2016</a>.
<a name="#Note2" id="#Note2">2</a><a href="https://www.who.int/maternal_child_adolescent/documents/improving-maternal-newborn-care-quality/en/" target="_blank" rel="noopener noreferrer">WHO. Standards for Improving Quality of Maternal and Newborn Care in Health Facilities. 2016.</a>
<a name="#Note3" id="#Note3">3</a><a href="https://www.sciencedirect.com/science/article/pii/S0277953614006133" target="_blank" rel="noopener noreferrer">Spicer et al. "Scaling-up is a craft not a science: Catalysing scale-up of health innovations…" Social Science and Medicine. 2014"</a>
<a name="#Note4" id="#Note4">4</a><a href="https://www.who.int/reproductivehealth/publications/maternal_perinatal_health/robson-classification/en/" target="_blank" rel="noopener noreferrer">WHO. Robson Classification: Implementation Manual. 2017</a>

Grand Challenges seeks ideas for interventions to address the following challenges related to cesarean section: 1) increasing access to cesarean section where it is currently inadequate, 2) increasing quality and safety of cesarean section to reduce iatrogenic harm to both mothers and newborns, 3) reducing rates of non-medically indicated cesarean section. Proposed activities should be implemented in Sub-Saharan Africa or South Asia (India, Pakistan, Bangladesh).

"That's the idea behind Grand Challenges - to focus bright scientists on the problems of the poorest, take some risks, and deliver results." Bill Gates

"Family planning and access to contraception - including information, supplies, and services - is an issue that I am passionate about, and it has become one of my personal priorities at the foundation. 
I believe it's one of the most urgent issues of our time." Melinda Gates

<h2>Background</h2>

Family planning is one of the most cost-effective ways to reduce maternal, infant and child mortality and contributes to the empowerment of women and families, as well as the expansion of opportunities for economic development. In recent decades, there have been tremendous improvements in the reproductive health of women in low resource settings. Global efforts have substantially accelerated progress toward the goal of reaching 120 million additional users of contraception by 2020 in the world’s poorest countries, an achievement well worth celebrating. Nonetheless, it is estimated that over 214 million women in developing countries have an unmet need for modern contraception.

While current contraceptive methods for women include exceptionally safe and effective options, not all methods are suitable for or acceptable to all women at all stages of their reproductive lives, and concerns about undesirable side effects remain a significant barrier to greater uptake and continued use of existing methods. As a result, women who desire to avoid pregnancy often find themselves without viable options that meet their needs. In particular, changes in uterine bleeding patterns are associated with use of hormonal contraceptive methods and copper intrauterine devices and, combined with access challenges and social or religious norms related to contraceptive use or menstrual bleeding, contribute to high discontinuation rates for these methods (up to 40% in the first year of use). While the concept of developing a non-hormonal pharmaceutical contraceptive with an improved tolerability profile as a suitable alternative has been promoted through research efforts and publications, a focused discovery effort has not been systematically pursued.

<h2>THE CHALLENGE</h2>

The Bill &amp; Melinda Gates Foundation is committed to a long-term vision of expanding contraceptive options for the most vulnerable women in low-resource settings through development of new methods that better align with women’s preferences. Contraceptive product innovation will be required to achieve this goal. Specifically, the emphasis for this work is on developing safe and effective non-hormonal contraceptive agents with both improved overall tolerability and a side effect profile differentiated from hormonal methods. This emphasis is based on an understanding that overall tolerability of and side effects from hormonal methods present real and meaningful barriers to women realizing their reproductive intentions.

This vision demands establishment of a strong research foundation upon which to build a robust pipeline of product candidates, recognizing that the attrition rate of products in preclinical and clinical development will likely be substantial due to the high bar for safety and efficacy. In order to establish a set of critical reproductive biology and early stage discovery capabilities, insource novel ideas from other areas of science, and improve the knowledge base needed to support such an effort, the foundation is launching the "Accelerating Discovery for Non-Hormonal Contraceptives" Grand Challenge in 2020. The goal of this Grand Challenge is to identify new approaches and concepts directed at the characterization of novel contraceptive drug targets, the identification of active contraceptive compounds useful for target validation and proof-of-principle studies, and the development of novel and impactful research tools with the potential to revolutionize the field of contraceptive R&amp;D.

The ultimate outcome driving the foundation’s investment in this area is the discovery new drug candidates that i) provide safe and effective contraception, ii) do not rely on systemic administration of reproductive steroid hormones or act through perturbation of sex steroid pathways, and iii) are suitable and appropriate for deployment in a low resource setting. The focus of this Grand Challenge is on broadly enhancing the research ecosystem for contraceptive discovery and advancing novel and bold ideas that can accelerate drug discovery in this field. We do not expect that novel contraceptive product candidates ready for entry into preclinical development will be identified in this early stage of funding. We anticipate, however, that projects funded through this Grand Challenge will identify new drug discovery approaches and technologies that have yet to be effectively applied to contraceptive R&amp;D. We expect to engage a broad range of expertise across disciplines in a collaborative and coordinated research program. It is anticipated, but not guaranteed, that success in these efforts would justify additional investment in a broader drug discovery effort by the Bill &amp; Melinda Gates Foundation, with the goal of developing innovative non-hormonal contraceptive methods to better serve the needs of women.

Approach

As approaches to discovery of new drugs for other indications have become increasingly sophisticated, these advances have not been applied to field of contraceptives. As a result, critical technical barriers continue to hamper progress and limit our ability to effectively identify novel contraceptive agents. These barriers include, but are not limited to:

<ul>
	<li>The inability to appropriately replicate in the laboratory a number of complex multi-cellular reproductive processes for the purposes of compound screening (e.g. ovulation);</li>
	<li>Poor understanding of contraceptive drug targets associated with key fertility pathways, and a lack of validated and scalable approaches to validate and assay potential targets;</li>
	<li>Lack of appropriate medium- to high-throughput phenotypic screening methodologies for identifying compounds capable of exerting a specific and potent contraceptive effect;</li>
	<li>Lack of appropriate in vitro and in vivo preclinical assays and biomarkers to assess i) the efficacy of agents targeting novel contraceptive mechanisms and ii) the potential side effects of novel agents.</li>
</ul>

It is our belief that these challenges can be addressed, and that doing so will create substantial new opportunities for contraceptive drug discovery. We seek to leverage advances in other areas of reproductive biology, both basic and applied, and emerging technologies in drug discovery to establish a suite of capabilities that can support a robust drug discovery program. It is not our intention to establish fully integrated end-to-end drug discovery capabilities with individual institutions through this program, but rather to fund a network of researchers, with each bringing a unique approach, and facilitate interactions between partners to maximize impact. Applicants should keep this in mind when articulating a project plan and focus on the key strengths that their expertise, approach, and technology can provide. Proposals should be aligned with one or more of the funding focus areas outlined below.

We are looking for proposals that:

<ul>
	<li>Engage scientists across a variety of disciplines, including those new to the field of contraceptive R&amp;D;</li>
	<li>Demonstrate innovative thinking by applying or incorporating concepts, methods or technologies not currently being used for contraceptive discovery;</li>
	<li>Present concepts and strategies that are "off the beaten track", significantly radical in conception, and daring in premise;</li>
</ul>

We will NOT consider funding for:

<ul>
	<li>Proposals focused on development of male contraceptives, including work on sperm-based approaches that could only feasibly be applied as vaginal methods;</li>
	<li>Proposals targeting the endometrium for the prevention on embryo implantation;</li>
	<li>Proposals on novel drug delivery systems for contraception;</li>
	<li>Discovery of adjunct or complementary molecules intended for co-delivery with hormonal contraceptive regimens;</li>
	<li>Basic studies of human reproductive biology without a clear connection to enabling non-hormonal contraceptive discovery;</li>
	<li>Pre-clinical or clinical development of advanced leads and candidates;</li>
	<li>Social science, marketing, or acceptability studies related to contraceptive use and uptake.</li>
</ul>

Awardees through this Grand Challenge may have the opportunity to access other Gates Foundation-funded resources, technology platforms, and grantee networks to help support their projects, facilitated by their Gates Foundation Program Officer. Applicants should, as completely as possible, describe what the proposed project will deliver within the scope of the application and the potential path forward, even if that encompasses activities that are beyond the scope of the current funding opportunity. Applicants invited to submit full proposals following LOI review (see the Review Process as detailed in the Rules and Guidelines) should expect to include critical milestones and relevant go/no-go decisions for the proposed project.

Funding Focus Areas:

<ol>
	<li>Biological Assay Development

	Many aspects of female reproduction remain challenging to replicate or model in a tractable, physiologically relevant, and highly reproducible fashion, but such tools and models will be fundamentally important to identifying and profiling contraceptive drug targets and contraceptive compounds. A better toolset of in vitro assays is needed that can recapitulate oocyte and follicle development, follicle selection, follicular rupture/ovulation, corpus luteum formation, cumulus-oocyte complex dynamics, and fertilization, including peri-fertilization events. New models should focus on assay tractability as well as establishing physiological relevance and modeling closely relevant features of the in vivo environment. Applicants seeking to develop such systems should clearly describe the planned approach and how this would improve upon existing methods. Including approaches to validate with human samples or human genetics/genomic information would be viewed favorably. Proposals should include a discussion on how assays will be standardized, validated, and scaled, including where possible the use of genetic or chemical probes as positive controls to demonstrate biologically relevant outcomes following assay perturbation.
	</li>
	<li>Drug Target Identification and Validation
	In the past two decades, target-based drug discovery approaches have become increasingly sophisticated and powerful, but further and complementary approaches are needed to sustain a pipeline of potential drug targets and enhance our understanding of target biology. Emphasis will be placed on unbiased approaches to identify potential contraceptive drug targets. These may include (but are not limited to):

	<ul>
		<li>RNAi- or CRISPR-based methods utilizing a robust and relevant biological assay,</li>
		<li>chemical genomics or proteomics linking probe compound activity to specific drug targets or pathways,</li>
		<li>analyses of human infertility as a pathway to identify relevant drug targets, or</li>
		<li>artificial intelligence-enabled approaches to target identification.</li>
	</ul>

	 
	Target characterization and validation efforts should focus on the determination of whether any particular gene that is critical for a reproductive process is vulnerable to inhibition by a small molecule inhibitor (using, for example, tunable knockdown or inducible degradation techniques), can likely be safely modulated by such an inhibitor (including assessment of roles in somatic tissue and activity of closely related homologs), and is likely to provide the desired contraceptive effect at realistic levels of inhibition (as opposed to complete loss-of-function). Applicants should clearly describe the critical assays, methods, or approaches they are proposing to underpin this work, and describe how such approaches will yield compelling and relevant data that could be used to support entry of identified targets into target-based drug discovery activities.
	</li>
	<li>Chemical genomics, probe generation, pilot screening
	The availability of active compounds that interfere with key steps in fertility would open up many avenues for further biological exploration and target validation, but methods for screening small compound libraries for chemical probe discovery are currently limited. Applications will be considered that propose small pilot-scale screening in complex systems for the purposes of identifying active compounds interfering with key reproductive functions. Applicants must detail how screening systems will be developed, tested, and validated in a format suitable for testing compounds, and should detail the type and source of chemical libraries that would be utilized. Biologically-informed hypotheses may be proposed to select mechanism- or target class-focused libraries as a starting point. We will not consider applications for screening of a single proposed target, but mechanism-focused approaches that interrogate multiple targets involved in a key reproductive process would be considered. Applicants must then describe an approach to deduce the specific targets of compounds identified in cell-based screens and demonstrate concordance between target-based activity and functional activity in validated in vitro systems.
	</li>
	<li>Contraceptive Antibodies
	While the cost and practicality of antibody-based therapeutics has historically been a challenge, particularly for application in a low resource setting, new advances in antibody half-life extension and cost-effective production open up the possibility that antibodies may be a more tractable option in the future, particularly if used in an "on demand" contraceptive modality. Moreover, this may allow consideration of targets that would otherwise not be amenable to small molecule inhibitors and may provide an enhanced safety window. Applications focused on contraceptive antibodies should clearly articulate the data supporting the validation of the proposed antigen target, the methods to be used for antibody identification, and the assays to be used relevant to determination of antibody function.

	(Note: the foundation is not accepting applications based on contraceptive immunization as an intervention modality, though such approaches could be applied experimentally for target validation.)
	</li>
	<li>Translational Science/Preclinical Evaluation Tools
	In addition to target and hit discovery activities, downstream aspects of drug and product development require early consideration to ensure the appropriate tools and data are in place once advanced leads and candidates are identified. We would consider funding for projects aimed at the following issues:

	<ul>
		<li>Identifying candidate biomarkers of efficacy for non-hormonal contraceptive mechanisms-of-action, including biochemical or imaging markers, that can be applied to preclinical in vivo models and, ideally, that could be applicable for validation in human clinical studies.</li>
		<li>Improving our understanding and prediction of reproductive tract and reproductive tissue pharmacokinetics to assist in building PK/PD models and enable early dose selection and safety risk evaluation.</li>
		<li>Improved and tractable in vivo models for contraceptive efficacy that overcome limitations of existing rodent and primate models.</li>
		<li>Innovative methods for early assessment of safety, toxicity, and side effect risk, with particular emphasis on the potential for endocrine disruption and bleeding side effects.</li>
	</ul>
	</li>
</ol>

There are clear thematic overlaps in the focus areas described above, and we would be happy to receive proposals that are directed at multiple focus areas, so long as the application demonstrates strength in all related areas of proposed work.

Award

This Grand Challenges request for proposals intends to fund individual awards of up to USD $2 million and for up to 3 years, based on the scope of the proposed project. The proposed budget must realistically reflect the technical work and project deliverables within a 3-year timeframe; in some cases, a smaller budget may be justified to establish initial proof-of-concept. Budgets and scope may be negotiated with applicants as part of the review process to ensure the foundation’s ability to fund a robust and balanced portfolio with existing available budget (see the Review Process as detailed in the Rules and Guidelines).

Successful award recipients may have the opportunity to apply for additional funding at the end of the grant period, based on technical success, portfolio fit, and continued strategic alignment with the foundation’s priorities. We reserve the right to determine eligibility for subsequent funding for this call based on these criteria.

Accelerating Discovery for Non-Hormonal Contraceptives

"That's the idea behind Grand Challenges - to focus bright scientists on the problems of the poorest, take some risks, and deliver results." Bill Gates
"Family planning and access to contraception - including information, supplies, and services - is an issue that I am passionate about, and it has become one of my personal priorities at the foundation. 
I believe it's one of the most urgent issues of our time." Melinda Gates
<h2>Background</h2>
Family planning is one of the most cost-effective ways to reduce maternal, infant and child mortality and contributes to the empowerment of women and families, as well as the expansion of opportunities for economic development. In recent decades, there have been tremendous improvements in the reproductive health of women in low resource settings. Global efforts have substantially accelerated progress toward the goal of reaching 120 million additional users of contraception by 2020 in the world’s poorest countries, an achievement well worth celebrating. Nonetheless, it is estimated that over 214 million women in developing countries have an unmet need for modern contraception.
While current contraceptive methods for women include exceptionally safe and effective options, not all methods are suitable for or acceptable to all women at all stages of their reproductive lives, and concerns about undesirable side effects remain a significant barrier to greater uptake and continued use of existing methods. As a result, women who desire to avoid pregnancy often find themselves without viable options that meet their needs. In particular, changes in uterine bleeding patterns are associated with use of hormonal contraceptive methods and copper intrauterine devices and, combined with access challenges and social or religious norms related to contraceptive use or menstrual bleeding, contribute to high discontinuation rates for these methods (up to 40% in the first year of use). While the concept of developing a non-hormonal pharmaceutical contraceptive with an improved tolerability profile as a suitable alternative has been promoted through research efforts and publications, a focused discovery effort has not been systematically pursued.
<h2>THE CHALLENGE</h2>
The Bill &amp; Melinda Gates Foundation is committed to a long-term vision of expanding contraceptive options for the most vulnerable women in low-resource settings through development of new methods that better align with women’s preferences. Contraceptive product innovation will be required to achieve this goal. Specifically, the emphasis for this work is on developing safe and effective non-hormonal contraceptive agents with both improved overall tolerability and a side effect profile differentiated from hormonal methods. This emphasis is based on an understanding that overall tolerability of and side effects from hormonal methods present real and meaningful barriers to women realizing their reproductive intentions.
This vision demands establishment of a strong research foundation upon which to build a robust pipeline of product candidates, recognizing that the attrition rate of products in preclinical and clinical development will likely be substantial due to the high bar for safety and efficacy. In order to establish a set of critical reproductive biology and early stage discovery capabilities, in-source novel ideas from other areas of science, and improve the knowledge base needed to support such an effort, the foundation is launching the "Accelerating Discovery for Non-Hormonal Contraceptives" Grand Challenge in 2020. The goal of this Grand Challenge is to identify new approaches and concepts directed at the characterization of novel contraceptive drug targets, the identification of active contraceptive compounds useful for target validation and proof-of-principle studies, and the development of novel and impactful research tools with the potential to revolutionize the field of contraceptive R&amp;D.
The ultimate outcome driving the foundation’s investment in this area is the discovery new drug candidates that i) provide safe and effective contraception, ii) do not rely on systemic administration of reproductive steroid hormones or act through perturbation of sex steroid pathways, and iii) are suitable and appropriate for deployment in a low resource setting. The focus of this Grand Challenge is on broadly enhancing the research ecosystem for contraceptive discovery and advancing novel and bold ideas that can accelerate drug discovery in this field. We do not expect that novel contraceptive product candidates ready for entry into preclinical development will be identified in this early stage of funding. We anticipate, however, that projects funded through this Grand Challenge will identify new drug discovery approaches and technologies that have yet to be effectively applied to contraceptive R&amp;D. We expect to engage a broad range of expertise across disciplines in a collaborative and coordinated research program. It is anticipated, but not guaranteed, that success in these efforts would justify additional investment in a broader drug discovery effort by the Bill &amp; Melinda Gates Foundation, with the goal of developing innovative non-hormonal contraceptive methods to better serve the needs of women.
Approach
As approaches to discovery of new drugs for other indications have become increasingly sophisticated, these advances have not been applied to field of contraceptives. As a result, critical technical barriers continue to hamper progress and limit our ability to effectively identify novel contraceptive agents. These barriers include, but are not limited to:
<ul><li>The inability to appropriately replicate in the laboratory a number of complex multi-cellular reproductive processes for the purposes of compound screening (e.g. ovulation);</li>
<li>Poor understanding of contraceptive drug targets associated with key fertility pathways, and a lack of validated and scalable approaches to validate and assay potential targets;</li>
<li>Lack of appropriate medium- to high-throughput phenotypic screening methodologies for identifying compounds capable of exerting a specific and potent contraceptive effect;</li>
<li>Lack of appropriate in vitro and in vivo preclinical assays and biomarkers to assess i) the efficacy of agents targeting novel contraceptive mechanisms and ii) the potential side effects of novel agents.</li>
</ul>It is our belief that these challenges can be addressed, and that doing so will create substantial new opportunities for contraceptive drug discovery. We seek to leverage advances in other areas of reproductive biology, both basic and applied, and emerging technologies in drug discovery to establish a suite of capabilities that can support a robust drug discovery program. It is not our intention to establish fully integrated end-to-end drug discovery capabilities with individual institutions through this program, but rather to fund a network of researchers, with each bringing a unique approach, and facilitate interactions between partners to maximize impact. Applicants should keep this in mind when articulating a project plan and focus on the key strengths that their expertise, approach, and technology can provide. Proposals should be aligned with one or more of the funding focus areas outlined below.
We are looking for proposals that:
<ul><li>Engage scientists across a variety of disciplines, including those new to the field of contraceptive R&amp;D;</li>
<li>Demonstrate innovative thinking by applying or incorporating concepts, methods or technologies not currently being used for contraceptive discovery;</li>
<li>Present concepts and strategies that are "off the beaten track", significantly radical in conception, and daring in premise;</li>
</ul>We will NOT consider funding for:
<ul><li>Proposals focused on development of male contraceptives, including work on sperm-based approaches that could only feasibly be applied as vaginal methods;</li>
<li>Proposals targeting the endometrium for the prevention on embryo implantation;</li>
<li>Proposals on novel drug delivery systems for contraception;</li>
<li>Discovery of adjunct or complementary molecules intended for co-delivery with hormonal contraceptive regimens;</li>
<li>Basic studies of human reproductive biology without a clear connection to enabling non-hormonal contraceptive discovery;</li>
<li>Pre-clinical or clinical development of advanced leads and candidates;</li>
<li>Social science, marketing, or acceptability studies related to contraceptive use and uptake.</li>
</ul>Awardees through this Grand Challenge may have the opportunity to access other Gates Foundation-funded resources, technology platforms, and grantee networks to help support their projects, facilitated by their Gates Foundation Program Officer. Applicants should, as completely as possible, describe what the proposed project will deliver within the scope of the application and the potential path forward, even if that encompasses activities that are beyond the scope of the current funding opportunity. Applicants invited to submit full proposals following LOI review (see the Review Process as detailed in the Rules and Guidelines) should expect to include critical milestones and relevant go/no-go decisions for the proposed project.
Funding Focus Areas:
<ol><li>Biological Assay Development
Many aspects of female reproduction remain challenging to replicate or model in a tractable, physiologically relevant, and highly reproducible fashion, but such tools and models will be fundamentally important to identifying and profiling contraceptive drug targets and contraceptive compounds. A better toolset of in vitro assays is needed that can recapitulate oocyte and follicle development, follicle selection, follicular rupture/ovulation, corpus luteum formation, cumulus-oocyte complex dynamics, and fertilization, including peri-fertilization events. New models should focus on assay tractability as well as establishing physiological relevance and modeling closely relevant features of the in vivo environment. Applicants seeking to develop such systems should clearly describe the planned approach and how this would improve upon existing methods. Including approaches to validate with human samples or human genetics/genomic information would be viewed favorably. Proposals should include a discussion on how assays will be standardized, validated, and scaled, including where possible the use of genetic or chemical probes as positive controls to demonstrate biologically relevant outcomes following assay perturbation.
</li>
<li>Drug Target Identification and Validation
In the past two decades, target-based drug discovery approaches have become increasingly sophisticated and powerful, but further and complementary approaches are needed to sustain a pipeline of potential drug targets and enhance our understanding of target biology. Emphasis will be placed on unbiased approaches to identify potential contraceptive drug targets. These may include (but are not limited to):
<ul><li>RNAi- or CRISPR-based methods utilizing a robust and relevant biological assay,</li>
<li>chemical genomics or proteomics linking probe compound activity to specific drug targets or pathways,</li>
<li>analyses of human infertility as a pathway to identify relevant drug targets, or</li>
<li>artificial intelligence-enabled approaches to target identification.</li>
</ul>
	Target characterization and validation efforts should focus on the determination of whether any particular gene that is critical for a reproductive process is vulnerable to inhibition by a small molecule inhibitor (using, for example, tunable knockdown or inducible degradation techniques), can likely be safely modulated by such an inhibitor (including assessment of roles in somatic tissue and activity of closely related homologs), and is likely to provide the desired contraceptive effect at realistic levels of inhibition (as opposed to complete loss-of-function). Applicants should clearly describe the critical assays, methods, or approaches they are proposing to underpin this work, and describe how such approaches will yield compelling and relevant data that could be used to support entry of identified targets into target-based drug discovery activities.
</li>
<li>Chemical genomics, probe generation, pilot screening
The availability of active compounds that interfere with key steps in fertility would open up many avenues for further biological exploration and target validation, but methods for screening small compound libraries for chemical probe discovery are currently limited. Applications will be considered that propose small pilot-scale screening in complex systems for the purposes of identifying active compounds interfering with key reproductive functions. Applicants must detail how screening systems will be developed, tested, and validated in a format suitable for testing compounds, and should detail the type and source of chemical libraries that would be utilized. Biologically-informed hypotheses may be proposed to select mechanism- or target class-focused libraries as a starting point. We will not consider applications for screening of a single proposed target, but mechanism-focused approaches that interrogate multiple targets involved in a key reproductive process would be considered. Applicants must then describe an approach to deduce the specific targets of compounds identified in cell-based screens and demonstrate concordance between target-based activity and functional activity in validated in vitro systems.
</li>
<li>Contraceptive Antibodies
While the cost and practicality of antibody-based therapeutics has historically been a challenge, particularly for application in a low resource setting, new advances in antibody half-life extension and cost-effective production open up the possibility that antibodies may be a more tractable option in the future, particularly if used in an "on demand" contraceptive modality. Moreover, this may allow consideration of targets that would otherwise not be amenable to small molecule inhibitors and may provide an enhanced safety window. Applications focused on contraceptive antibodies should clearly articulate the data supporting the validation of the proposed antigen target, the methods to be used for antibody identification, and the assays to be used relevant to determination of antibody function.
(Note: the foundation is not accepting applications based on contraceptive immunization as an intervention modality, though such approaches could be applied experimentally for target validation.)
</li>
<li>Translational Science/Preclinical Evaluation Tools
In addition to target and hit discovery activities, downstream aspects of drug and product development require early consideration to ensure the appropriate tools and data are in place once advanced leads and candidates are identified. We would consider funding for projects aimed at the following issues:
<ul><li>Identifying candidate biomarkers of efficacy for non-hormonal contraceptive mechanisms-of-action, including biochemical or imaging markers, that can be applied to preclinical in vivo models and, ideally, that could be applicable for validation in human clinical studies.</li>
<li>Improving our understanding and prediction of reproductive tract and reproductive tissue pharmacokinetics to assist in building PK/PD models and enable early dose selection and safety risk evaluation.</li>
<li>Improved and tractable in vivo models for contraceptive efficacy that overcome limitations of existing rodent and primate models.</li>
<li>Innovative methods for early assessment of safety, toxicity, and side effect risk, with particular emphasis on the potential for endocrine disruption and bleeding side effects.</li>
</ul></li>
</ol>There are clear thematic overlaps in the focus areas described above, and we would be happy to receive proposals that are directed at multiple focus areas, so long as the application demonstrates strength in all related areas of proposed work.
Award
This Grand Challenges request for proposals intends to fund individual awards of up to USD $2 million and for up to 3 years, based on the scope of the proposed project. The proposed budget must realistically reflect the technical work and project deliverables within a 3-year timeframe; in some cases, a smaller budget may be justified to establish initial proof-of-concept. Budgets and scope may be negotiated with applicants as part of the review process to ensure the foundation’s ability to fund a robust and balanced portfolio with existing available budget (see the Review Process as detailed in the Rules and Guidelines).
Successful award recipients may have the opportunity to apply for additional funding at the end of the grant period, based on technical success, portfolio fit, and continued strategic alignment with the foundation’s priorities. We reserve the right to determine eligibility for subsequent funding for this call based on these criteria.

Grand Challenges seeks new approaches and concepts for the characterization of contraceptive drug targets, the identification of active contraceptive compounds, and the development of novel and impactful research tools with the potential to revolutionize the field of contraceptive R&amp;D. We seek to leverage advances in reproductive biology, both basic and applied, and emerging technologies in drug discovery to establish a suite of capabilities that can support drug discovery in this challenging area.