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

<h2>Background</h2><p>Much new knowledge has accumulated about links between the "innate", evolutionarily very old immune system, based largely on the recognition of pathogen-associated molecular patterns, and the "adaptive" immune system of vertebrate species. A recent revolution in understanding how to trigger the innate immune response specifically and how that may determine the course of an acquired immune response prompts the conclusion that research on adjuvants could now become more scientific and less empiric. Additionally, new insight into the biology of memory cells sets the stage for a more designed approach to stimulating long-lasting immunity.</p><h2>Roadblock</h2><p>We do not know how to deliver the antigen in order to elicit a long lasting protective response after a single dose. In particular, we do not know the rules whereby adjuvants, which strengthen the immune response, also guide it in particular directions, such as formation of high affinity antibodies, Th1 helper T lymphocytes and/or CD8+ T lymphocytes, and assure the production of long-term immunologic memory.</p><h2>Challenge</h2><p>To develop and clinically evaluate new adjuvants suitable for human use which could strengthen immune responses and guide them down chosen pathways relevant to the disease concerned in order to create vaccines that could produce specific and robust immunity after a single dose of vaccine and capable of effectively stimulating even the immune system of newborns.</p><h2>Potential Benefits</h2><ul><li>Increased effectiveness of immunization</li><li>Decreased cost of immunization systems</li><li>Decreased early childhood mortality and morbidity</li></ul>

Grand Challenges in Global Health

Create Effective Single Dose Vaccines That Can Be Used Soon After Birth

<h2>Background</h2>

<p>New approaches to the identification of antigens and to the control of immune system activity suggest the possibility of altering the immune response to chronic and persistent infections in order to cure the infection and/or prevent their ability to cause disease.</p>

<h2>Roadblock</h2>

<p>We do not know how to direct the immune system to specifically kill cells chronically infected with viruses, particularly where the virus has integrated into the host genome.&nbsp; Furthermore, in bacterial or protozoal diseases, cells can harbor pathogens which lie dormant until some form of reactivation.</p>

<h2>Challenge</h2>

<p>To develop a vaccine or other approach that enhances the natural ability of the immune system (to keep the percentage of infected cells below some critical level), in order to completely remove the infected cells, or to terminate infection without inducing autoimmunity.</p>

<h2>Potential Benefits</h2>

<p>Development of vaccines that eliminate chronic infection and reduce the incidence of virus-induced cancers</p>

<h2>Priority Areas</h2>

<ul>
	<li>HBV</li>
	<li>HCV</li>
	<li>HPV</li>
	<li>HIV</li>
	<li>Tuberculosis</li>
	<li>Schistosomiasis</li>
</ul>


Create Immunological Methods that can Cure Chronic Infections

<h2>Background</h2>

<p>The explosion of information about technologies that measure gene expression opens the opportunity to ascertain at the molecular level in any organism the pathways that are essential to the latent and/or persistently infected state, thus providing new targets for drugs.</p>

<h2>Roadblock</h2>

<p>We lack the ability to selectively eliminate a latently infected cell (e.g. HIV or herpes virus) and/or a persistent microbe within an impenetrable microenvironment within the host (e.g., granuloma for TB) as well as to remove or neutralize the latent component of the microbe within the cells.&nbsp;</p>

<h2>Challenge</h2>

<p>To develop novel, currently unproven methodologies that can identify a cell latently infected with a virus, identify both the pathogen and host molecules used in and essential for the latent state, and deliver treatment into the cell that would either eliminate the cell or remove the latent component of the virus.&nbsp; In the case of persistent bacterial or parasitic infections (e.g., TB or schistosomiasis), to deliver an effective intervention that will eliminate the pathogen.</p>

<h2>Potential Benefits</h2>

<p>Permanent cure of diseases in which active microbial replication has been controlled pharmacologically or immunologically and the latent or persistent microbe is the last vestige of infection in the patient</p>

<h2>Priority Areas</h2>

<ul>
	<li>HIV</li>
	<li>HBV</li>
	<li>Herpes</li>
	<li>TB</li>
	<li>Schistosomiasis</li>
	<li>Toxoplasmosis</li>
</ul>


Create Therapies that Can Cure Latent Infection

<h2>Background</h2>

<p>In the developing world, people often eat a diet with limited variety, consisting of a single staple crop that is poor in nutritional content.&nbsp; Recent developments in molecular biology and genetics have created an opportunity to develop modified plant varieties with specifically desired characteristics.&nbsp; However, most of the modifications confer only a single new, desirable trait; moreover, even when crops have been fortified for the diet of one region, the variety may not be ecologically adjusted to or traditionally consumed in other regions.</p>

<h2>Roadblock&nbsp;</h2>

<p>We currently lack a strategy for the effective, efficient, and socially and culturally acceptable alteration of a major dietary staple, to achieve the delivery of multiple micronutrients, such as minerals and vitamins, to poor populations in a single food.&nbsp; Moreover, genetic changes could ensure higher protein content and the presence of essential amino acids.</p>

<h2>Challenge&nbsp;</h2>

<p>To use transgenesis, biochemistry, selective breeding of plants, and other appropriate technologies such as apomixes, to provide combinations of micronutrients, vitamins, and essential amino acids in a bioavailable form in local crops, such as rice, wheat, sorghum, millets, cassava, potatoes, maize, bananas and others, or to enhance energy density and improve protein quality in such foods, in a socially and culturally acceptable way.</p>

<h2>Potential Benefits</h2>

<ul>
	<li>Reduction of morbidity and mortality from malnutrition</li>
	<li>Amelioration of related susceptibility to infections and other diseases</li>
</ul>

<h2>Priority Areas</h2>

<ul>
	<li>Fe, Zn, and Se deficiencies</li>
	<li>Vitamin A and E deficiencies</li>
	<li>Protein deficiency</li>
</ul>


Create a Full Range of Optimal, Bioavailable Nutrients in a Single Staple Plant Species

Create a Full Range of Optimal Bioavailable Nutrients in a Single Staple Plant Species

<h2>Background</h2>

<p>Multiple advances in formulation and drug delivery and new ideas for activating immune cells in skin and in various mucosal surfaces create the possibility of effective immunization routes that may optimize the development of protective immunity and avoid the multiple risks and drawbacks of the use of needles in vaccination.</p>

<h2>Roadblock</h2>

<p>Most current childhood vaccines require syringe and needle administration for effective immunization.&nbsp; This route is associated with increased risk of infections (HIV, HBV, HCV) through inappropriate re-use of needles or syringes and a major waste disposal problem.</p>

<h2>Challenge</h2>

<p>To develop effective needle-free delivery systems for vaccine administration via mucosal (oral, nasal, aerosol), transcutaneous and other approaches.</p>

<h2>Potential Benefits</h2>

<ul>
	<li>Simplicity and ease of administration</li>
	<li>Avoidance of infection from inappropriate re-use of needles</li>
	<li>Improved access and compliance</li>
	<li>Reduction of logistic cost</li>
</ul>


Develop Needle-Free Delivery Systems

<h2>Background</h2>

<p>High throughput approaches to genomics, proteomics and the measurement of other analytes, coupled with novel technologies of miniaturization and highly parallel detection create the possibility of radically new ways to detect and diagnose health and disease states in an individual, even in remote or impoverished settings.</p>

<h2>Roadblock</h2>

<p>Lack of convenient accurate point-of-care assessment tools in the developing world, means that many health risks and illnesses remain poorly defined and receive inappropriate treatment.&nbsp; In addition, little information about the burden of disease is available to guide population health decisions.</p>

<h2>Challenge</h2>

<p>To develop and optimize the needed performance characteristics of novel, accurate, feasible technologies for achieving definitive point-of-care assessment of individuals’ health status, including robust, simple-to-use technologies for achieving parallel, open-ended, multi-pathogen and reliable and valid clinical measures in developing world settings.</p>

<h2>Potential Benefits</h2>

<ul>
	<li>Unequivocal identification of pathogen type and subtype and drug sensitivity profile</li>
	<li>Rapid assessment of susceptibility and immunity to health threats</li>
	<li>Rapid diagnosis of exposure and disease</li>
	<li>Rapid detection of emerging pathogens</li>
	<li>Rapid parallel diagnosis of multiple infectious agents&nbsp;</li>
	<li>Accurate assessment of disease stage and prognosis</li>
	<li>Better detection and management of outbreaks and emerging acute and chronic health&nbsp;threats</li>
	<li>Quantification of disease incidence in endemic countries</li>
</ul>


Develop Technologies that Allow Assessment of Multiple Conditions and Pathogens at Point-of-Care

<h2>Background</h2>

<p>Among the most striking recent developments in human biology are entirely novel means to measure molecular, clinical and epidemiologic aspects of human biology and the mathematical tools to analyze complex biologic data.&nbsp; These assays and analytic methods have the potential to alter the practice of public health in fundamental ways.</p>

<h2>Roadblock</h2>

<p>Lack of robust population health assessment technologies and methods applicable to developing countries prevents accurate assessment of the burden of injury and disease and evidence-based decisions about prioritizing scarce health resources.</p>

<h2>Challenge</h2>

<p>To develop valid, accurate, comparable, and convenient technologies and analytic methods that incorporate clinical, biological, and behavioral markers for quantitative assessment of the burden of disease and population health status as a critical input into priority setting and intervention evaluation in resource-poor settings.</p>

<h2>Potential Benefits</h2>

<ul>
	<li>Standardized global system for assessing population health status</li>
	<li>Accurate assessment of injury and disease prevalence and incidence&nbsp;</li>
	<li>Accurate assessment of morbidity and mortality&nbsp;</li>
	<li>Accurate quantification of preventable fraction of injury and disease&nbsp;</li>
	<li>Accurate algorithms to prioritize and evaluate injury and disease prevention and control interventions</li>
</ul>


Develop Technologies that Permit Quantitative Assessment of Population Health Status

<h2>Background</h2>

<p>Proof-of-concept laboratory experiments have demonstrated that genetic strategies and heritable biological control strategies can reduce substantially the capacity of insect vectors to transmit disease agents.&nbsp; Furthermore, similar strategies have succeeded in reducing or eliminating certain agricultural pests.&nbsp;&nbsp;&nbsp;</p>

<h2>Roadblock</h2>

<p>While we can enumerate the technological requirements for the control of disease-transmitting insects, we have not solved the full range of problems that would allow us to either replace an insect vector population in the field with one incapable of transmitting a pathogen, or to control insect vector population numbers by genetic approaches or by heritable biological control approaches.&nbsp; We also cannot accurately predict all of the ecological consequences.&nbsp;&nbsp;&nbsp;</p>

<h2>Challenge</h2>

<p>To develop a coherent strategy either for making vector populations incompetent to transmit disease agents or for substantially reducing the prevalence of the vector, by the introduction of genetic constructs or microbial agents.&nbsp; The strategy must ensure effectiveness in the field, safety, and social and environmental acceptability.&nbsp;Requirements for success would include:</p>

<ul>
	<li>heritable biocontrol approaches that decrease the number or lifespan of vector organisms responsible for disease transmission or that interfere with pathogen replication within the vector;</li>
	<li>alternately, heritable constructs that confer to the vector conditional or temporally-delayed dominant lethality;</li>
	<li>alternately, genetic approaches that combine gene drive mechanisms—to overcome a likely loss of fitness and permit rapid, species-specific fixation of the desired traits in the vector population—with mechanisms that target vector competence, numbers, or lifespan;</li>
	<li>methods for cost-effective production and delivery of the appropriately modified vectors;</li>
	<li>detailed understanding of vector population dynamics, dispersal, and diversity, including barriers to gene flow in regions for potential intervention, and accordingly tailoring the intervention; and</li>
	<li>development of appropriate mechanisms to address the scientific, ethical, social, and regulatory aspects in partnership with the affected communities.</li>
</ul>

<h2>Potential Benefits</h2>

<p>Permanent disruption of the disease transmission cycle, achieving prevention without need to treat the human population</p>

<h2>Priority Areas</h2>

<ul>
	<li>Malaria</li>
	<li>Dengue and other tropical arboviral diseases</li>
</ul>


Develop a Biological Strategy to Deplete or Incapacitate a Disease-transmitting Insect Population

<h2>Background</h2>

<p>Chemical interventions (mainly insecticides) have been instrumental for abatement of disease transmission by vectors, but are severely compromised by the development of insecticide resistance and environmental concerns.&nbsp; The recent sequencing of the genomes of both insect-transmitted pathogens and their disease transmitting vectors has opened a new set of possibilities, when coupled with studies of the biology, immunology and behavior of the organisms, to identify the molecular components required for the disease transmission cycle, offering routes into the development of molecularly targeted drugs that may replace traditional insecticides.</p>

<h2>Roadblock</h2>

<p>Despite advances in knowledge that have opened up novel and unexplored possibilities, we have not yet succeeded in devising new effective chemicals to control insect vector populations to block their access to humans, or to interfere with their ability to transmit disease.&nbsp;</p>

<h2>Challenge</h2>

<p>To develop a coherent chemical strategy for making vector populations incompetent to transmit disease agents, or for substantially reducing the prevalence of the vector.&nbsp; The strategy must ensure effectiveness in the field, safety, and social and environmental acceptability.&nbsp; Potential approaches include identifying and validating novel targets for development of safe, efficacious and environmentally acceptable molecularly-directed chemical interventions that are specific for vectors.&nbsp; The targets could be the molecular components of biochemical and physiological pathways that are critical for vector survival, for vector behavior and attraction to humans, or for the inherent competence of the vector to transmit the pathogens.&nbsp; The intent may be to find small molecules, microbial preparations, or other factors that can serve as effective insecticides, modify vector behavior such as anthropophily, serve as effective repellents or lures, or can be used as “smart sprays” to make vectors incompetent to transmit the disease agent.</p>

<h2>Potential Benefits</h2>

<ul>
	<li>Effective disruption of the disease transmission cycle, achieving prevention without need to treat the human population</li>
	<li>Production of environmentally safe agents that remain effective for extended periods of time</li>
</ul>

<h2>Priority Areas</h2>

<ul>
	<li>Malaria</li>
	<li>Dengue</li>
	<li>Trypanosomiasis</li>
</ul>


Develop a Chemical Strategy to Deplete or Incapacitate a Disease-transmitting Insect Population

<h2>Background</h2>

<p>Historically, attenuated live microbes have proven to be highly effective.&nbsp; The advent of genomics, molecular genetics, and high through put screening methods has raised the possibility of generating safe candidate live agents---viruses for which no effective vaccine exists, bacteria, and even protozoa---that might be designed to lose virulence yet retain immunogenicity.&nbsp;</p>

<h2>Roadblock</h2>

<p>We currently lack suitable means for testing live attenuated candidate vaccine agents capable of providing reliable and predictive information about both immunogenicity and pathogenicity, short of subjecting them to clinical trials in human subjects.</p>

<h2>Challenge</h2>

<p>To develop suitable model systems for testing the behavior of candidate attenuated live vaccines for residual virulence, immunogenicity relevant to protection against infection, replication capacity, cellular host range, and reversion to full virulence.&nbsp; Such systems might be generated in cell or organ culture in vitro, but more likely would require adaptation of rodent or primate animal hosts by genetic means or transplantation to more closely resemble the human host for that agent with respect to replication, pathogenesis, and the immune response.</p>

<h2>Potential Benefits</h2>

<p>Acceleration of the development of highly effective, stable vaccines<br />
Elucidation of principles to guide the development of additional live vaccines</p>

<h2>Priority Areas</h2>

<ul>
	<li>Viruses refractory to vaccine development (such as HIV, HCV, herpes viruses, etc.)</li>
	<li>Pathogenic bacteria</li>
	<li>Selected complex pathogens (protozoa, yeasts, fungi, etc.)</li>
</ul>
