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Biennial Report of the Director

Research in Diseases, Disorders, and Health Conditions
Infectious Diseases and Biodefense

NIH builds and maintains a base of fundamental knowledge about infectious and immune-related diseases and uses that knowledge to develop new and improved diagnostics, therapeutics, and preventive measures, including vaccines. At the same time, NIH continues to develop a flexible domestic and international infrastructure that allows it to respond to newly emerging and re-emerging threats wherever they occur, thereby protecting public health in the U.S. and abroad.

Infectious diseases are caused by microbial pathogens—bacteria, viruses, fungi, protozoa, and helminths (worms)—that invade the body and multiply, causing physiological damage and illness. Pathogens cause a range of diseases from minor to life-threatening and can be transmitted in many ways. Influenza and tuberculosis (TB), for example, can be transmitted from person to person through the air; HIV, which causes AIDS, and some forms of viral hepatitis are transmitted through exposure to blood or other body fluids; and malaria is caused by a microscopic parasite that is transmitted by an insect “vector,” in this case a mosquito.

ransmissible infectious diseases can devastate large human populations rapidly and easily cross international borders.
Threats to public health change continually as new pathogens emerge in nature, and as familiar microbes reemerge with new properties or in unusual settings. Public health threats that could cause large-scale disruption and devastation also include the deliberate release of pathogenic agents such as anthrax or smallpox, biological toxins, chemical weapons such as nerve gas, or radioactive substances.

The NIH biodefense strategy integrates basic, applied, and clinical research knowledge and capabilities into a flexible and adaptable approach designed to create interventions that target single as well as multiple pathogens. The overall goal of research on biodefense and emerging and re-emerging infectious diseases is to develop the knowledge and tools to respond quickly and effectively as public health threats emerge, whether they occur naturally or deliberately.

Although NIAID has primary responsibility for infectious diseases and biodefense research, many other NIH ICs play critical roles, including FIC, NEI, NICHD, NIDDK, NIEHS, NIGMS, NINDS, and OAR. All of the NIH ICs support AIDS-related research activities, consistent with their individual missions. The ICs that conduct most of the research on AIDS and its associated co-infections, malignancies, cardiovascular and metabolic complications, and behavioral and social science issues are NIAID, NIDA, NCI, NIMH, NCRR, NICHD, NIDDK, and NHLBI. All NIH AIDS research is coordinated by OAR.

NIH-wide research on infectious diseases and biodefense includes basic research to understand fundamental mechanisms by which microorganisms cause disease, the host response to pathogens, and mechanisms by which insects and other vectors transmit infectious diseases. Translational research builds on basic research findings with the aim of developing new and improved diagnostics, therapeutics, and vaccines. NIH conducts and supports clinical research to assess the efficacy and safety of candidate drugs, vaccines, and other products. As NIH pursues these goals, an overarching priority is to reduce health disparities and improve health for all people.

Infectious diseases and biodefense inherently are global concerns. Among U.S. academic institutions and scientists there is rapidly growing interest in the expansion of international collaborative research and training. In response to this interest and important scientific opportunities, NIH engages in international research and training partnerships focused on disease detection, prevention, treatment, and control. It also supports international programs to foster research and research capacity enhancement in developing countries. Increasingly, these programs involve cooperative funding, which engage NIH foreign counterpart organizations in cost-sharing strategies. Within the U.S., NIH seeks strategic partnerships with other governmental and nongovernmental organizations, many of which share an interest in the scientific opportunities provided by global research.

NIH supports and conducts research on hundreds of pathogens and the diseases they cause, including HIV/AIDS, TB, malaria, and emerging and re-emerging infectious diseases, such as hemorrhagic fevers caused by Ebola and other viruses, West Nile virus, Lyme disease, prion diseases, plague and other diseases caused by biodefense pathogens, and influenza .

NIH research on biodefense and emerging and re-emerging infectious diseases is fully integrated and includes the development of infrastructure and capacity-building, that is, scientific and human resources needed to conduct research on pathogens safely and effectively; basic research on microbes and host immune defenses; the targeted development of medical countermeasures, including vaccines, therapeutics, and diagnostics; and training for emergency and skilled workers that would be needed in the event of a biological, chemical, or radiological weapons attack or other public health emergency.

Infectious diseases cause approximately 26 percent of all deaths worldwide. Each year, more than 11 million people die from infectious diseases; the vast majority of deaths occur in low- and middle-income countries. The infectious diseases that today cause the greatest number of human deaths worldwide are lower respiratory infections, HIV/AIDS, diarrheal diseases, malaria, and TB.285 The top infectious disease killers in those countries for people ages 15 to 59 are HIV/AIDS, TB, and lower respiratory infections.286 Worldwide, HIV causes nearly 2.0 million deaths each year,287 TB kills 1.4 million each year,288 and lower respiratory infections in 2008 caused an estimated 3.46 million deaths.289 Malaria is a serious problem, especially in Africa, where one in every five childhood deaths is due to the effects of the disease.290

Each year infectious diseases kill approximately 6.5 million children, most of whom live in developing countries. For children younger than age 14, infectious diseases account for seven of the top 10 causes of death. In this age group, the leading infectious diseases are lower respiratory infections, diarrheal diseases, and malaria.291

285 For more information, see http://www.dcp2.org/main/Home.html. Exit Disclaimer
286 For more information, see WHO Disease Control Priorities Project Infectious Diseases chapter (April 2006) http://www.dcp2.org/file/6/DCPP-InfectiousDiseases.pdf. Exit Disclaimer
287 For more information on the global HIV/AIDS pandemic, see
http://www.unaids.org/en/KnowledgeCentre/HIVData/EpiUpdate/EpiUpdArchive/2009/2009epidemic_update.asp Exit Disclaimer.
288 For more information on tuberculosis, see http://www3.niaid.nih.gov/topics/tuberculosis.
289 For more information, see http://www.who.int/mediacentre/factsheets/fs310/en/index.html. Exit Disclaimer
290 For more information, see http://www.who.int/features/factfiles/malaria/en/index.html.
Exit Disclaimer
291 For more information, see WHO Disease Control Priorities Project, Infectious Diseases chapter (April 2006) http://www.dcp2.org/file/6/DCPP-InfectiousDiseases.pdf Exit Disclaimer.

The burden of infectious diseases is not evenly shared, even among developing nations. People who live in sub-Saharan Africa are most affected, particularly by HIV/AIDS, which accounts for one in five deaths in that region. Africa and the most populous countries of Asia harbor the largest number of TB cases. Together, Bangladesh, China, India, Indonesia, and Pakistan account for half of new TB cases each year.

In the United States, infectious diseases add significantly to the overall burden of illness. Together, influenza and pneumonia account for more than 50,000 deaths annually.292 More than 1.2 million people are living with HIV in the United States, and each year brings another 50,000 new infections. Unfortunately, approximately one-fifth of those people living with HIV are unaware of their infection.293 An estimated 2.7 to 3.9 million people in the U.S. have chronic hepatitis C, and 800,000 to 1.4 million are affected by chronic hepatitis B.294

Many infectious diseases increasingly are difficult to treat because pathogens are developing resistance to antimicrobial drugs.295For example, in recent years there have been dramatic increases in antiretroviral drug resistance in HIV, chloroquine resistance in malaria, the emergence of multidrug-resistant TB (MDR TB) and extensively drug-resistant TB (XDR TB), and methicillin-resistant Staphylococcus aureus (MRSA) infection.

NIH Funding for Infectious Diseases and Biodefense Research

NIH funding for infectious diseases research was $3,890 million in FY 2010 and $3,883 million in FY 2011 for non-ARRA (regular appropriations) and $568 million in FY 2010 for ARRA appropriations.296 NIH funding for biodefense research was $1,794 million in FY 2010 and $1,803 million in FY 2011 for non-ARRA (regular appropriations) and $221 million in FY 2010 for ARRA appropriations.297

Summary of NIH Activities

NIAID conducts and supports basic research to better understand infectious agents and the response of host organisms by studying the cellular and molecular biology of pathogen and host, physiologic processes, and genome sequences and structures. Their findings elucidate pathogen entry mechanisms, survival strategies, and immune evasion techniques; evolutionary adaptations; activation of the host immune system; and cellular and whole organism responses to infection and vaccination. The following describe selected NIAID basic research activities; NIAID also supports a broad portfolio of investigator-initiated basic research.

292 For more information, see FASTSTATS - Deaths and Mortality http://www.cdc.gov/nchs/fastats/deaths.htm.
293 For more information on the latest U.S. HIV/AIDS statistics from CDC, see http://www.cdc.gov/hiv/topics/surveillance/index.htm.
294 For more information, see http://www.cdc.gov/hepatitis/PDFs/disease_burden.pdf.
295 For more information about antimicrobial resistance, see http://www.niaid.nih.gov/topics/antimicrobialresistance/Pages/default.aspx.
296 For funding of various Research, Condition, and Disease Categories (RCDC), see http://report.nih.gov/categorical_spending.aspx.
297 Reporting for this category does not follow the standard RCDC process. The total amount reported is consistent with reporting requirements for this category to the U.S. Office of Management & Budget (OMB). The project listing does not include non-project or other support costs associated with the annual total for this category. For more information, see http://www.niaid.nih.gov/topics/biodefenserelated/pages/default.aspx.

NIAID supports 11 Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases (RCEs). The overall goal of the RCEs is to establish and maintain strong infrastructure and multifaceted research and development activities. These activities are providing scientific information and translational research capacity to facilitate the development of the next generation of countermeasures against biodefense and emerging infectious disease agents. To date, over 2000 papers have been published by RCE-supported scientists.

NIAID is tackling some of the most vexing questions in the study of human immunology through its Human Immunology Project Consortium. Launched in 2010, the Consortium supports research to define functionally relevant changes in the human immune system, through human (rather than animal) studies, in response to vaccination or infection. The Consortium was funded in its first year by the American Recovery and Reinvestment Act, and contributes to developing technologies to accelerate discovery. Findings will assist in development of vaccines and other interventions for a variety of infectious diseases including influenza, malaria, tuberculosis, and HIV/AIDS.

Vaccines to prevent infectious diseases are among the most effective and economical measures available to improve human health. Many vaccines include compounds called adjuvants to increase their effectiveness and reduce the number of shots and the amount of immunizing materials needed to produce a protective immune response.

Two NIAID initiatives are energizing the adjuvant research field. NIAID established the Innate Immune Receptors and Adjuvant Discovery Program in FY 2003/2004 and renewed it in FY 2009. Currently, investigators supported by this program are working to identify and characterize novel compounds to be used as vaccine adjuvants to prevent infection or as stand-alone immunotherapeutics for the treatment of acute infection. To move beyond discovery, NIAID initiated the Adjuvant Development Program in FY 2008. This program supports preclinical studies of lead vaccine adjuvants to bring them toward licensing for human use.

The NIAID Strategic Plan for Research on Vaccine Adjuvants, released in 2011, describes NIAID’s future plans for adjuvant research. The plan originated from a blue ribbon panel of experts convened by NIAID in November 2010. With existing productive programs and clear steps to achieve the plan’s ambitious goals, continued NIAID investment will contribute to the success of future adjuvants and development of improved protective vaccines, and may reduce illness-associated healthcare costs.

How immunity develops at the earliest stages of life, such as within the first year after birth, remains a mystery. Unlike adults, infants lack the ability to mount strong, protective, targeted antibody and cellular immune responses to infectious diseases. Infants can receive antibodies from their mothers while breastfeeding, but cellular immunity cannot be passively transferred. Understanding how the infant immune system develops could provide insights into improving the effectiveness of vaccinations against common childhood infections.

In FY 2011, NIAID announced a new initiative, the Infant Immune System: Implications for Vaccines and Response to Infections program. This program supports research to understand how the innate and adaptive immune responses mature and to determine how the immune system learns how to tolerate non-pathogenic bacteria that reside in the intestinal tract.
Infectious organisms are a major cause of pregnancy complications, including premature labor and maternal and fetal death and disease. Problems with the placenta are a major cause of fetal death, and studies have suggested that undiagnosed infection of the placenta and/or the fetus may be a significant cause of unexplained stillbirths. However, the mechanisms of placental and fetal infection and disease development are poorly understood. In FY 2011, NIAID partnered with NICHD to solicit proposals for new and innovative studies of infectious organisms (pathogens) that affect placental function and fetal well-being. The knowledge gained through this initiative will provide a basis for developing interventions against these pathogens, and for meeting the long-term goal of reducing their adverse impact on pregnancy and fetal health.

Major Infectious Diseases

NIH conducts research on hundreds of infectious diseases, with special emphasis on those that claim large numbers of lives each year. Research includes studies of major infectious diseases such as TB, malaria, and HIV/AIDS, as well as studies to ensure the health of special populations—individuals whose immune systems are compromised, the elderly, adolescents, young children, and infants. NIH also explores how human behaviors as well as social, cultural, economic, and geographic factors affect disease transmission. The ultimate goal is to translate knowledge gained through basic research into interventions that improve public health in the U.S. and other countries.

HIV/AIDS

HIV/AIDS remains a leading cause of death worldwide, especially in sub-Saharan Africa. Although not as prevalent in the United States, new infections continue to impede efforts to curtail the epidemic domestically as well as internationally. Furthermore, even though the advent of antiretroviral therapy (ART) has significantly improved the longevity of HIV-infected individuals, AIDS-related illnesses remain a significant cause of morbidity and premature mortality. Without an effective preventive vaccine or improved treatments that allow HIV-infected individuals to discontinue ART, the burden of HIV/AIDS will increase as new infections and use of ART continue to rise. The NIH is committed to developing new prevention methods and treatment strategies in the hopes of achieving an “AIDS-Free Generation” through the combined use of prevention and treatment tools.

The best long-term hope for controlling the AIDS pandemic is the development of a safe and effective HIV vaccine that can prevent HIV infection either by itself or in combination with other prevention strategies. This is one of the highest research priorities of the NIH. In October 2010, the New England Journal of Medicine published the results of the AIDS vaccine trial RV144. Better known as the “Thai Trial,” RV144 was the first HIV vaccine trial to demonstrate a modest reduction in the risk of HIV transmission (31.2 percent efficacy) and thereby provide the long sought after proof-of-concept that it is possible to induce an immune response against HIV in humans with a vaccine. The vaccination approach utilized a novel prime-boost vaccine strategy that involves two components: the “prime” with a replication-defective pox virus that included genetic components of HIV, and the “boost” with a recombinant HIV envelope protein. NIH will build on the results of the RV144 vaccine trial through the Pox-Protein-Public-Private-Partnership (P5) initiative. The P5 will advance a similar HIV vaccination strategy through clinical development and, if successful, to licensure, based on testing in populations with high HIV incidence in Southern Africa and Thailand.

New vaccine concepts spawned through basic research and developed through translational studies are critical for providing novel vaccine strategies. In 2010, NIH-led scientists discovered and characterized human antibodies that can block a wide range of HIV strains from infecting human cells in the laboratory. Understanding how these antibodies neutralize HIV could serve as the foundation for the rational design for future vaccine candidates. In addition, a new AIDS vaccine research consortium is supporting basic and translational research to better understand the earliest events of mucosal HIV infection and how vaccines can be optimized to block these early events by inducing protective mucosal immune responses.

NIH continues to investigate treatment as a strategy to prevent new HIV infections--a promising new area of HIV/AIDS prevention research. An NIH clinical trial utilizing supported pre-exposure prophylaxis (PrEP) as a prevention method demonstrated that male-to-male transmission of HIV was reduced in high risk individuals who were treated with daily antiretroviral drugs. Furthermore, the NIH conducted a phase III clinical trial which showed that in HIV-discordant, heterosexual couples, HIV transmission to uninfected partners was reduced by 96 percent if antiretroviral treatment was started earlier in the HIV-infected partners. This unprecedented result from the study known as HPTN052 was selected as the 2011 “Breakthrough of the Year” by the journal Science. Indeed, research shows that HIV treatment can prevent HIV transmission, in that patients treated with HAART not only have better health outcomes, but their decreased viral load and infectivity translates into decreased HIV transmission and incidence on a population level. Therefore, a priority research area for NIH is to create the infrastructure and linkages needed to implement the “Seek, Test, Treat, and Retain” strategy, which seeks out high-risk, hard-to-reach vulnerable populations (e.g. substance abusers), tests them for HIV, begins treatment in those who test positive, and retains patients in treatment and monitors their care. NIH is launching additional clinical trials to evaluate further how testing, treatment, education/counseling, and awareness can prevent HIV at both the community and population levels.

Another key strategy in HIV prevention is the use of ART to prevent mother-to-child transmission (MTCT). In 2010, based on the results of two NIH-funded studies, the World Health Organization revised its guidelines for the use of ART in both mothers and infants to minimize the development of drug-resistant HIV during treatment for MTCT. The NIH also initiated the PROMISE (Promoting Maternal-Infant Survival Everywhere) study, a phase III clinical trial designed to determine how best to reduce the risk of HIV transmission from infected pregnant women to their babies during pregnancy and breastfeeding while preserving the health of these children and mothers.

NIH is also committed to improving the outcomes of HIV treatment by developing strategies to minimize morbidity and mortality associated with ART. For example, the Strategic Timing of Antiretroviral Therapy (START) study will determine the optimal time to initiate treatment of asymptomatic HIV-infected individuals to maximize their long-term health.

The ultimate improvement in HIV treatment would be the development of novel therapeutics or treatment regimens that would result in complete eradication of residual HIV or long-term HIV remission so that ART is no longer necessary for HIV-infected individuals. NIH supported two new funding opportunities for research that aims to achieve these outcomes. The program Basic Research in HIV Persistence, which began in 2010, seeks toincrease understanding of the mechanisms that lead to HIV persistence and to identify the location of persistent reservoirs in individuals on ART. Similarly, the Martin Delaney Collaboratory supports basic and translational research in HIV persistence and latency with the end goal of identifying novel therapeutics and strategies to target and eliminate HIV reservoirs in HIV-infected individuals.

Another important area of prevention research that will particularly benefit women is the development and testing of microbicides. These products can be used alone or in combination with other strategies to prevent transmission of HIV and other sexually transmitted infections. Microbicides represent a promising approach to primary HIV prevention. NIH supports a comprehensive and innovative microbicide research program that includes the screening, discovery, development, preclinical testing, and clinical evaluation of microbicide candidates.

NIH is supporting research to develop better, less toxic treatments and to investigate how genetic determinants, sex, gender, race, age, nutritional status, treatment during pregnancy, and other factors interact to affect treatment success or failure and/or disease progression. Studies will continue to address the increased incidence of malignancies, neurologic, cardiovascular and metabolic complications, and premature aging associated with long-term HIV disease and ART. Translational research is focusing on the feasibility, effectiveness, and sustainability required to scale-up interventions from a structured behavioral or clinical study to a broader "real world" setting.

Malaria

 Malaria, caused by several parasites of the genus Plasmodium and transmitted by mosquitoes, continues to be the most important tropical parasitic disease in terms of annual mortality. About 3.3 billion people—half of the world's population—are at risk of contracting malaria. Worldwide, an estimated 216 million clinical cases of malaria occurred in 2010. 

People living in the poorest countries are the most vulnerable to malaria. Malaria is an especially serious problem in Africa, where one in every five childhood deaths is attributed to the disease. An African child has on average between 1.6 and 5.4 episodes of malaria fever each year. Every 50 seconds, a child dies from malaria. The magnitude of worldwide disease burden and the existing barriers to controlling infection, disease, and transmission require multiple approaches for prevention and treatment of malaria.
NIAID supports research that provides the knowledge and tools needed to make real improvements in disease prevention, control, and treatment. Several Global Health Initiative target areas, including malaria, are key foci of the NIAID research program, which has invested heavily in translational research to support the development of vaccines, therapeutics and diagnostics.

In FY 2010, NIAID announced approximately $14 million in first-year funding to establish 10 new malaria research centers in regions where malaria is endemic, including parts of Africa, Asia, the Pacific Islands, and Latin America. The International Centers of Excellence for Malaria Research (ICEMR) program will generate knowledge, tools, and evidence-based strategies to control malaria. Specifically, the ICEMRs are studying the complex interactions between the human host, the malaria parasite, the vector, and the ecology at the molecular, cellular, organism, population, and field levels. The ICEMRs also work with local governments, agencies, and academic institutions to enhance and sustain local laboratory and clinical research capacity.

NIAID-supported investigators also are working to develop a vaccine against malaria. NIAID currently provides product development support for eight malaria vaccine candidates in clinical trials. An effective malaria vaccine would produce large economic benefits by reducing healthcare costs and helping to stabilize the economies of countries where malaria is endemic. Initial positive results reported last year by the PATH Malaria Vaccine Initiative, GlaxoSmithKline Biologicals and their collaborators came as welcome news. In a late-stage clinical trial in approximately 6,000 African children, the candidate vaccine, known as RTS,S, reduced malaria infections by roughly half.298 Studies testing another malaria vaccine candidate in humans have started at the NIH Clinical Center, with results expected in 2012.

As part of its commitment to the Global Health Initiative, NIAID partners with organizations such as USAID, WHO, the Commission of the European Community, the European-Developing Countries Clinical Trials Partnership (EDCTP), the European Vaccine Initiative (EVI), the Wellcome Trust, the Bill & Melinda Gates Foundation, the PATH Malaria Vaccine Initiative (MVI), the Medicines for Malaria Venture (MMV), and the Multilateral Initiative on Malaria (MIM). Additionally, NIAID supports the Global Malaria Action Plan (GMAP),299an international framework for coordinated action designed to control, eliminate and eradicate malaria and provides access for U.S. and international scientists to multiple research resources as well as training for new investigators.

Because the risk of childhood malaria is related to exposure before birth to the malaria parasite through infected mothers, NIAID scientists recently initiated a program on malaria disease development in pregnant women and young children that could yield new preventive measures and treatments for these most vulnerable groups.

In 2011, researchers identified bacteria that render mosquitoes resistant to malaria parasites. Further study is needed,300 but it may one day be possible to break the cycle of infection by reducing the mosquito’s ability to transmit malaria parasites to people.
In 2010, researchers described a chemical that rids mice of malaria-causing parasites after a single oral dose, raising hopes that the chemical may eventually become a new malaria drug. The compound, NITD609, was identified by an international team of NIAID-funded extramural and intramural investigators following an analysis of over 12,000 chemicals using a robotic screening technique customized to detect compounds active against the most deadly malaria parasite. A clinical trial to assess NITD609’s activity in people has begun in Thailand. Research on NITD609 is a continuing collaboration among NIH-funded scientists, the pharmaceutical company Novartis, and the nonprofit Medicines for Malaria Venture.

298 For more information, see http://www.ncbi.nlm.nih.gov/pubmed/22007715.
299 For more information, see http://www.rbm.who.int/gmap/gmap.pdf Exit Disclaimer.
300 For more information, see http://www.niaid.nih.gov/news/newsreleases/2011/Pages/MalariaBacteria0513.aspx.

Tuberculosis

Tuberculosis (TB) remains a major cause of disability and death worldwide. Each year, more than 9 million people around the world become sick with TB and nearly 1.4 million people die of TB-related causes. The recent emergence of drug-resistant TB poses a major global health threat. NIAID has a long-standing effort to understand how TB causes disease, and is expanding its TB research agenda and capabilities to meet the challenge of drug resistance.

The World Health Organization estimates that almost half of all people with drug-resistant TB in 2008 were in China and India, with each reporting approximately 100,000 new cases. In response to this growing international public health challenge, NIAID has expanded its TB research in these areas. For example, NIAID and Chinese officials with the Henan Provincial Health Bureau launched the first study of the Sino-U.S. (Henan) Tuberculosis Prevention and Treatment Research Institute in Zhengzhou, China. The Institute will develop diagnostic tools, treatment options, and prevention methods for multidrug-resistant and extensively drug-resistant TB. NIAID is also contributing to the establishment of research cohorts in India in order to identify biological markers of infection and disease for TB, in the presence and absence of co-infections and co-morbidities that contribute to the TB epidemic in this country.

Among people with HIV/AIDS, TB is a major co-infection and the leading cause of death, responsible for killing approximately 350,000 HIV-infected individuals in 2010. The HIV/AIDS Networks plan to expand their capabilities so that they can address key scientific questions regarding the high rate of TB co-infection in HIV-infected individuals. NIAID continues to collaborate with the global TB research community, other funders, and the U.S. Federal Tuberculosis Task Force to coordinate resources, leverage support for fundamental and translational studies, and to assure that opportunities for contributing to the development of new health care interventions are realized. Through its Genomics Centers and Bioinformatics Resource Centers/Databases, NIAID is initiating collaborations with research partners in TB endemic countries. These studies are designed to provide insight into the genetic diversity of Mycobacterium tuberculosis and catalog genetic markers that underlie resistance to first and second line drugs.

enomics data and analysis from these studies will be made publicly available through NCBI and NIAID- funded databases and are expected to inform the development of molecular diagnostics for drug resistance testing, provide new targets for drug development and contribute to the understanding of the differences and commonalities of TB epidemiology in high burden countries. NIAID’s product development infrastructure, through its preclinical and clinical services programs, has contributed to the advancement of many drugs, vaccines and diagnostics that are part of the global TB product pipeline. Preclinical and clinical studies on new TB drugs and vaccines are benefitting from an improved understanding of host immune responses during infection and disease; innovative new immune assays to measure the effects of vaccines; and new drug targets identified through systems biology approaches that target key metabolic aspects of M. tuberculosis.

NIAID’s strategic efforts in coordination benefit all aspects of NIAID’s TB Program, from developing biomarkers and rapid, sensitive diagnostics to stimulating the development of preventive measures such as vaccines and treatments for latent (dormant) TB infections; to accelerating the development of new treatments by running adaptive Phase II combination trials, in which trial arms are added or dropped based on the interim trial results.

Some recent activities in TB research include the following:

Viral Hepatitis

At least five different hepatitis viruses (A through E) cause liver disease in humans. All five can cause acute hepatitis, while hepatitis B, C, and D viruses can also lead to a persistent infection and chronic hepatitis. (Additional information on viral hepatitis is included in the Chronic Diseases and Organ Systems section under “Digestive Diseases.”) Collectively, viral hepatitis is the most common cause of acute and chronic liver disease in the U.S. and worldwide. Chronic hepatitis B affects an estimated 800,000 to 1.4 million people in the U.S., and chronic hepatitis C affects an estimated 2.7 to 3.9 million people in the U.S.301 Furthermore, these diseases are often asymptomatic for many years after the initial infection until signs of cirrhosis or liver cancer develop, which may require liver transplantation.

NIDDK supports several research programs related to viral hepatitis, including The Hepatitis B Research Network, established in 2008 to advance understanding of disease processes and natural history of chronic hepatitis B, as well as to develop effective approaches to treatment with currently available therapies. The Network brings together clinical centers from throughout the U.S. and Canada. This multi-center Network is enrolling patients in multiple clinical trials in both adults and children with hepatitis B. In addition to the Network, NIDDK funds follow-up and ancillary studies of completed clinical trials on hepatitis C, including the Peginterferon and Ribavirin for Pediatric Patients with Chronic Hepatitis C (Peds-C) trial; Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial; Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C); and Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL), which is investigating approaches to mitigate recurrent hepatitis C infection after liver transplantation.

NIAID research is advancing or has helped to advance the development of new therapeutic agents for HCV (e.g., HCV Entry Inhibitor ITX 5061 [A5277], HCV Protease Inhibitor Boceprevir [A5294]) and adjunct treatments (e.g., pioglitazone, nitazoxanide) to increase response rate to pegylated interferon plus ribavirin treatment for HIV/HCV co-infected patients (A5239, A5269). HBV animal model contracts are supporting work in multiple therapeutic areas including novel antivirals, therapeutic vaccines, Toll-like receptor agonists, immunomodulators, interferon inducers, and new adjuvants. Researchers at Utah State University test drugs against HBV in the HBV transgenic mouse model, and researchers at Georgetown University screen therapeutics in a disease-producing woodchuck infection model.

In FY 2010, NIAID renewed support of the Hepatitis C Cooperative Research Centers, a network of five centers dedicated to defining successful immune response to HCV infection and to identifying new targets for antiviral drugs, vaccines, and other therapeutic strategies for the prevention or treatment of acute and chronic HCV infection. Research conducted at the Centers will continue to advance understanding of the immune response to infection and the factors that determine the outcome of infection, either spontaneous or therapy-induced clearance or chronic persistence of HCV.

NIAID intramural researchers, whose work has resulted in a marketed vaccine for hepatitis A and an effective hepatitis E vaccine, collaborate with partners worldwide to study the basic immunology of HCV infection in chimpanzees and humans and prospects for vaccine development. While current intramural research studies use chimpanzees, NIAID will phase out this research over time. Note: The recent IOM committee on the use of chimpanzees in biomedical and behavioral research did not reach a consensus decision on whether chimpanzees are essential to the development of a prophylactic HCV vaccine and if or how much the use of chimpanzees would accelerate or improve this work.

In FY 2011, NIAID funded three collaborative partnerships for research on HBV through the Partnerships for Development of New Therapeutic Classes for Select Viral and Bacterial Pathogens initiative. These partnership awards will help advance the development of new classes of therapeutic drugs for HBV.

Researchers in the NIDDK’s Peds-C Study Group conducted a clinical trial that showed combination therapy with the antiviral drugs peginterferon and ribavirin is more effective than therapy with peginterferon and placebo in treating chronic hepatitis C in children.302
In an NIDDK-supported study, scientists found that a dietary supplement, S-adenosylmethionine (SAMe), safely and effectively boosts response to combination antiviral therapy for hepatitis C in adults infected with a form of the virus that typically does not respond as well to such therapy.303

NIAID-funded researchers found that liver cell death is increased in the presence of HCV and HIV compared to HCV or HIV alone.

These results provide an additional mechanism for the accelerated liver disease progression observed in HCV–HIV co-infection.304
Two cell membrane proteins, CD81 and occludin, are the minimal human factors required to render mouse cells permissive to HCV entry in vitro. Researchers funded by NIAID demonstrated the expression of these proteins allows HCV infection in fully immunocompetent inbred mice. This is an important breakthrough towards a small animal model that can be used in HCV vaccine research.305

 NIAID-sponsored scientists showed the membrane-bound transcription factor CREB3L1 is activated in response to virus infection and inhibits proliferation of virus-infected cells. Because HCV infection often progresses to persistence, these results imply that CREB3L1 has to be silenced to enable HCV replication, providing a new line of investigation into the mechanism of chronic HCV persistence.306

301 For more information, see http://www.cdc.gov/hepatitis/PDFs/disease_burden.pdf.
302 Schwarz KB, et al. Gastroenterology. 2011;140(2):450–8. PMID: 21036173.
303 Feld JJ, et al. Gastroenterology. 2011;140(3):830–9. PMID: 20854821.
304 Jang JY, et al. J Hepatol. 2011;54(4):612–20. PMID: 21146890.
305 Dorner M, et al. Nature. 2011;474:208–11. PMID: 21654804.
306 Denard B, et al. Cell Host Microbe. 2011;10(1):65–74. PMID: 21767813.

Emerging Infectious Diseases and Biodefense (including seasonal and pandemic influenza)

NIH is the lead agency within HHS for conducting and supporting research on potential agents of bioterrorism and emerging infectious diseases that directly affect human health. Recognizing the potential for deliberate use of microorganisms as biological weapons, and the fact that previously controlled microorganisms can re-emerge with new properties (such as drug resistance) or in new settings, NIAID has integrated its biodefense research into the Institute’s larger emerging and re-emerging infectious diseases portfolio. This research provides the foundation for developing medical products and strategies to diagnose, treat, and prevent a wide range of infectious diseases, whether those diseases emerge naturally or are deliberately introduced into a population through an act of bioterrorism. No matter what the source of the infectious threat, the research approach is the same: understand the infectious agent and how it causes disease, and develop tools to diagnose, treat, and prevent illness caused by that microbe.

NIAID’s research efforts have evolved over the past decade from developing vaccines for specific pathogens to focusing on the fundamental basic research needed to better understand infectious agents. The goal of this basic research is to lay the groundwork for developing broad-spectrum antibiotics and antivirals—drugs that can prevent or treat diseases caused by multiple types of bacteria or viruses—and multi-platform technologies that potentially could be used to more efficiently develop vaccines against a variety of infectious agents.

This move from the “one bug-one drug” approach toward a more flexible, broad approach using sophisticated genomic and proteomic technologies has yielded numerous scientific advances and has equipped the United States with a much more integrated, coordinated approach to addressing public health crises. This was demonstrated during the SARS epidemic, pandemic flu preparedness efforts resulting from the H5N1 avian influenza outbreak, and the 2009 H1N1 influenza pandemic.

In addition to supporting and conducting basic, translational, and clinical research to develop safe and effective medical countermeasures, NIH supports programs to expand research infrastructure. NIH also provides a broad array of preclinical and clinical research resources and services to researchers to bridge gaps in the product development pipeline and lower the financial risks incurred by industry in the development of novel antimicrobials.

The NIH biodefense research program has achieved major successes in the development of countermeasures against significant bioterror threats. Some countermeasures are stockpiled or available for emergency use; others in the development pipeline have been transferred to the HHS Biomedical Advanced Research and Development Authority (BARDA) for advanced development. Candidates that have been transitioned from NIAID to BARDA include a broad-spectrum antiviral drug that potentially can be used to treat DNA viruses such as smallpox; a vaccine against smallpox and another against anthrax; and several therapeutics for anthrax, smallpox, and pandemic influenza.

NIAID continues to support the development of medical countermeasures against pathogens and diseases such as smallpox, anthrax, Ebola, Marburg, botulism, and pandemic influenza, many of which pose potential threats to the United States and international communities. As noted previously, central to this research is NIAID’s effort to change the paradigm for antimicrobial drug development from a “one-bug, one-drug” approach to a focus on broad-spectrum therapies that could be used against entire classes of pathogens. NIAID recently awarded four contracts to support the development of such broad-spectrum therapies, which can improve preparedness for all infectious threats, whether they occur naturally or are deliberately introduced.

Researchers have made advances in developing countermeasures to numerous disease-causing organisms. For example:

Another priority in emerging infectious diseases includes seasonal and pandemic influenza. Each annual influenza outbreak in the United States typically occurs between December and March. Every year in the United States, on average 5 percent to 20 percent of the population contracts influenza and more than 200,000 people are hospitalized with complications from influenza infection. And each year, seasonal influenza is estimated to kill an average of 36,000 Americans.

Influenza is a significant public health challenge, due in part to the limitations of current influenza vaccines and treatments. For example, resistance to influenza antiviral medications frequently emerges. In recent years, seasonal influenza viruses have become resistant to therapeutic agents, first to adamantanes and then to oseltamivir. Hence, it is critical to maintain a pipeline of new and improved anti-influenza medications. In addition, although egg-based manufacturing methods have served well for more than 40 years, they are logistically complex and can lead to delays or shortages if the vaccine strain of influenza virus will not grow efficiently.

IH and industry partners have made progress in accelerating the development of additional manufacturing methods including cell-based manufacturing. These advances will help build a more reliable domestic manufacturing capacity that could be rapidly mobilized in response to the emergence of a pandemic virus.

NIAID conducts and supports a broad range of basic and translational research on influenza, including research and development of new therapies, diagnostics, and vaccines for both seasonal and pandemic influenza strains. Included in these efforts is research to develop a “universal” influenza vaccine that induces a potent immune response to the common elements of the influenza virus that undergo very few changes from season to season, and from strain to strain. A universal influenza vaccine has the potential to protect against multiple strains of the virus over several years. In addition, improved antiviral treatments and vaccine manufacturing capacity for influenza could have broad applicability against other infectious diseases.

The NIAID intramural research program conducts collaborative influenza research with many public and private sector partners, and in FY 2010, NIAID intramural investigators engaged in a government-wide effort to understand the pathogenesis of mild to severe pandemic influenza and facilitate the development of novel therapies and strategies for treating severe influenza. Other major research programs include: needle-free pandemic influenza vaccine development through a collaboration with MedImmune, Inc.; nasal spray vaccine development and testing against H9N2, H5N1, H7N3, H2N2 and H6N1 viruses with pandemic potential; basic influenza biology, transmission, and pathogenesis studies in animal models; natural history studies of influenza viruses, including studies of human immune response and pathogenesis; and clinical studies at the NIH Clinical Center and elsewhere to characterize and treat severe influenza in various populations using existing and experimental therapeutic strategies.

NIAID ranks the development of a “universal” influenza vaccine as one of its top scientific priorities because it would eliminate the need to modify the influenza vaccine every season. NIAID intramural researchers recently demonstrated that a “prime-boost” vaccine strategy protected animals from infection with multiple strains of influenza. The vaccine produced an “unnatural immunity”, inducing a response to parts of the influenza virus that are conserved between even distantly related virus strains. More recently, this approach was evaluated in two small clinical trials, with participants producing evidence of cross-protective antibodies. A universal flu vaccine would be an extraordinary improvement over today’s seasonal flu vaccines, resulting in considerable savings and saved lives. In addition, a number of extramural researchers are also working on novel approaches to develop a vaccine which is broadly reactive with multiple influenza subtypes by targeting conserved internal proteins of the virus as well as less variable regions of the hemagglutinin protein.

NIAID investigators initiated collaborations with Mexican health authorities to address the impact and epidemiology of the 2009 pandemic H1N1 influenza in that country. In addition, during the course of the 2009 H1N1 influenza outbreak, NIAID conducted 12 clinical trials through its longstanding Vaccine Treatment and Evaluation Units (VTEUs), six of which provided information that helped build the foundation for the nationwide 2009 H1N1 immunization campaign. Trial data offered key scientific evidence essential for public health decision-making, including optimal dosage and number of doses for individuals in different age brackets and for specific high-risk groups of particular concern such as pregnant women. Studies on concurrent administration of H1N1 vaccine and seasonal influenza vaccine demonstrated that two influenza vaccines could be safely administered at the same time. NIAID-sponsored clinical trials also provided data on the use of the vaccine in selected populations with underlying health conditions, including HIV and asthma, and also examined the use of an adjuvant with H1N1 vaccine, which showed that the adjuvant was safe and could be used to stretch the vaccine supply. The information and experience that was gained from all of these clinical trials will apply well beyond the 2009 H1N1 influenza.

NIAID continues to support the Centers for Excellence in Influenza Research and Surveillance (CEIRS) Program. The CEIRS Program is an integrated network of five centers that was established in 2007, building upon an NIAID-funded program begun at St. Jude’s Children’s Hospital in 1999. The Program brings together multidisciplinary teams of researchers to expand the NIAID influenza virus surveillance program, both internationally and in the United States, and to study host immune responses, pathogenesis, the factors that control the emergence and transmission of influenza viruses among animal reservoirs, and the immunological factors that determine whether an influenza virus causes only mild illness or causes death. The CEIRS Program continually monitors cases of animal and human influenza worldwide to rapidly detect and characterize viruses that may have pandemic potential and to create pandemic vaccine candidates. Ultimately, the CEIRS network will lay the groundwork for new and improved control measures for emerging and reemerging influenza viruses.

NIAID supported the development of the FilmArray Respiratory System, which is capable of simultaneously detecting 15 respiratory viruses (including several influenza strains) in one hour. The initial FilmArray system was approved by the FDA in 2011. Since 2005, NIAID has awarded small business grants and NIAID partnerships to Idaho Technology, Inc., to support development of this multiplex diagnostic platform from initial prototype through the current version. This support was essential for Idaho Technology to develop the FilmArray Respiratory Panel. NIAID's preclinical resources also played a role in developing the HT-FilmArray. Influenza sequences generated by NIAID's Genomics Sequencing Centers and made available through the Influenza Research Database facilitated design of the influenza detection assays included in this platform. Avian influenza strains obtained from the BEI repository were used to validate the assays.

NIAID also supports international collaborations, including through the Southeast Asia Infectious Diseases Clinical Research Network, which has assembled a 17-site network in Thailand, Vietnam, and Indonesia to address issues of emerging influenza viruses and other emerging infections, as well as in Mexico, where five sites in Mexico City address the impact and epidemiology of influenza-like illness in the region.

Antimicrobial resistance is a significant and increasing health concern, and NIH funds research to understand and address it. Infectious microbes have a remarkable ability to evade and resist the actions of antimicrobial drugs. Combined with the overuse of antibiotics, this has led to an increase in the number of drug resistant infections. To that end, NIAID supports and conducts research on many aspects of antimicrobial (drug) resistance, from basic research on how microbes develop resistance, to clinical trials that translate research from lab findings to potential treatments. Several new research initiatives will advance this important research effort.
The NIAID-sponsored Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance program308 explores improved treatment strategies to help reduce the risk of antimicrobial resistance and preserve the effectiveness of existing drugs. NIAID now supports eight large-scale clinical trials to evaluate treatment alternatives for diseases where antibiotics are prescribed most often, including acute otitis media, community-acquired pneumonia, and skin and soft tissue infections caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA).

The Partnerships for the Development of Therapeutics and Diagnostics for Drug-Resistant Bacteria and Eukaryotic Parasites initiative focuses on advancing the development of diagnostics and therapeutics for drug-resistant pathogens. Nineteen projects were awarded in 2010. In addition, NIAID issued the Partnerships for Development of New Therapeutic Classes for Select Viral and Bacterial Pathogens309 funding announcement in FY 2010 to address the threat to public health presented by drug resistance in the Clostridium difficile bacteria, which causes severe intestinal disease, in Neisseria gonorrhoeae,which causes gonorrhea, and in strains of hepatitis B virus.

In FY 2011, NIAID issued the Targeting Resistance in Select Gram-Negative Pathogens initiative to stimulate innovation in the discovery and development of novel therapeutic approaches for infections caused by resistant Gram-negative bacteria. NIAID also launched the Host-Targeted Interventions as Therapeutics for Infectious Diseases program in FY 2011 aims to discover and develop therapeutics that target host functions required for infection, replication, spread and/or pathogenesis by priority pathogens. Research supported in this program suggests that an intervention that targets the essential host function would have broad-spectrum efficacy. Moreover, targeting a host function reduces selective pressure on the microbe to acquire resistant mutations, making resistance less likely to emerge. When using the knowledge gained to develop drugs targeted against host functions with that known about microbial pathogenesis, significant steps could be made leading to the treatment of many microbial threats, including priority pathogens deemed highly threatening to public health.

Dengue fever, a mosquito-borne flu-like illness that can turn deadly, continues to increase in the tropics and subtropics. It has the potential to spread in temperate zones and appears to be increasing in severity. NIAID dengue research priorities include elucidating the viral/human genetics and immunological factors that contribute to disease severity and the pre-clinical development and clinical evaluation of rapid diagnostics, therapies, and vaccines against dengue. The dengue research program received an important boost from American Recovery and Reinvestment Act, which NIAID used to advance studies of the immune responses to viral infection and the effects of mucosal dengue vaccination and other novel vaccine development strategies. In 2010, NIAID researchers announced they had developed an experimental vaccine against dengue after ten years of research. Clinical trials to evaluate the safety of this vaccine in healthy adults are underway in the United States and trials are planned in dengue-endemic countries. Other NIAID-supported investigators are developing vaccines using a variety of technologies to improve the delivery methods and ability to stimulate an immune response to dengue infection. For example, NIAID recently awarded a contract to develop a novel dengue vaccine that can be delivered through the skin without the use of needles and to evaluate this vaccine for safety and immunogenicity in clinical trials in the United States and abroad. Two other vaccines, whose development was partially supported by NIAID, are currently being tested by companies. Altogether, the Institute supports a wide array of dengue research activities and will continue to do so until the disease is under control or eliminated.

NIH also helps coordinate research to develop safe and effective medical countermeasures against chemical weapons. The NIH Countermeasures Against Chemical Threats (CounterACT) Research Network supports the development of medical countermeasures to prevent, diagnose, and treat conditions caused by chemical agents that might be used in a terrorist attack or released by industrial accidents or natural disasters. The network is a collaboration between the NIH and the U.S. Department of Defense, including the CounterACT Research Centers of Excellence, individual research projects, small business research grants, contracts, and other programs that conduct basic, translational, and clinical research. The CounterACT Research Network solicited proposals from academia, other governmental agencies, and industry. In Fiscal Year 2006, the CounterACT Research Network established four Research Centers of Excellence in Medical Chemical Research. The network enabled the development of therapeutics for cyanide, nerve agents, chlorine, sulfur mustard, and radiation exposures. Training of personnel remains a critical facet of effective response to a release of chemical or nuclear/radiological material. For the past 15 years, NIH has worked with the Service Employees International Union (SEIU) to provide high-quality training for hazardous materials emergency responders.

NIH continues to lead HHS efforts to sponsor and coordinate research to develop medical countermeasures to mitigate and/or treat radiation-induced damage. Many candidate medical countermeasures are in the early stages of discovery, including medical countermeasures for hematopoietic acute radiation syndrome (ARS), gastrointestinal ARS, radiation-induced lung pneumonitis and/or fibrosis, and other radiation-induced injuries. Key efforts underway focus on developing decorporation agents-- specific drugs that remove radioactive isotopes from the body. Three orally bioavailable decorporation agents moving toward Investigational New Drug Application submission will be used to treat victims with internal radionuclide contamination from fallout or “dirty bombs”. At the same time, an IND for an oral decorporation agent has been filed with the FDA and the project is now being funded by HHS/BARDA for advanced development.

NIAID established the Centers for Countermeasures Against Radiation (CMCR) program in 2005 in an effort to develop medical products to diagnose, prevent and treat the short- and long-term consequences of radiation exposure after a radiological or nuclear accident or terrorist attack. The program supported over 100 pilot studies and attracted a number of new investigators from fields outside radiobiology research and developed educational materials in radiation biology for trainees across the United States. The program has yielded include numerous publications, and several patents were filed. The efforts of CMCR helped to revitalize an area of science that had been dormant for many years. To expand on these efforts, NIAID agreed to provide five years of additional funding to the program beginning in fiscal year 2010. Seven academic institutions from across the country participated in the renewed program. A progress report detailing the research priorities for the nuclear/radiation countermeasures program was published in 2012.310

NIH has invested substantially in the intellectual and physical infrastructure needed to build the nation’s capacity for research on biodefense and emerging infectious diseases. The physical and intellectual research infrastructure that NIAID has built over the years is critical to the development of medical countermeasures and has increased the nation’s ability to respond to new and re-emerging infectious diseases. This comprehensive infrastructure includes:

Controlling infectious diseases not only saves lives but is essential for building a strong global economy and maintaining international stability. Through its support for research that underpins intervention programs, NIH participates in several efforts, including the U.S. President’s Emergency Plan for AIDS Relief; the Global Fund to Fight AIDS, Tuberculosis, and Malaria; and other global initiatives. NIH supports networks of U.S. and international scientists, trains U.S. and foreign investigators to work internationally, and enhances basic biomedical, clinical, and behavioral research capacity and facilities around the world.

artnerships, including those with bilateral and multilateral international partners, industry, and host governments, provide extraordinary opportunities for research on vaccines, drugs, and new diagnostics to benefit local populations where the research is done.

NIH funds and partners with institutions and researchers throughout the world and especially in places where diseases such as HIV/AIDS, tuberculosis, malaria, dengue, and neglected tropical diseases remain endemic. The following are selected examples of NIAID’s programs that illustrate the variety of models and platforms made available to support international research.

The International Centers for Excellence in Research (ICER) program was launched in 2002 to develop and sustain research programs in disease endemic countries through partnerships with local scientists. While the ICER program is focused on clinical research in infectious diseases, each center has the capability to address the research and training needs of greatest relevance to the local population. The ICER program builds on experience gained from NIAID’s long-standing malaria research collaboration with scientists in Mali, West Africa. The NIAID Division of Intramural Research, through long-term collaborations with colleagues in country, has developed a core research program at each site and, over time, has provided opportunities to expand the research capabilities and programs. The improvement of laboratory and clinical field site infrastructure and the enhancement of information technology capability have been critical components of this effort. NIAID extramural divisions also have provided support to investigators at these sites and aim to continue to support ICER programs through the extramural scientific community. The current ICER sites are located in Mali, Uganda, and India.

NIAID HIV/AIDS Clinical Trials Networks (comprising leadership groups and trial sites) provide a domestic and international research infrastructure for conducting clinical trials on all aspects of HIV/AIDS. These networks provide multiple opportunities for cross-NIH collaborations, with NIMH, NICHD, NIDA, NINDS, NCI, NIDCR, and OAR providing additional funding for specific networks or studies. NIAID is expanding the scope of the network’s current activities to include the treatment and prevention of tuberculosis and hepatitis, major co-infections with HIV, and has also leveraged this infrastructure for an intramural study testing a new HPIV3 vaccine in infants.

South East Asia Infectious Diseases Clinical Research Network (SEAICRN) was founded in 2005 in response to the global challenge posed by avian influenza to conduct research on human and avian influenza and other infectious diseases of importance to the region. In concert with the World Health Organization, the Wellcome Trust, and the ministries of the respective countries, the SEAICRN is a 17-site network in Thailand, Vietnam, and Indonesia addressing issues of emerging influenza viruses and other emerging infections. A second five-year contract for NIAID support and collaboration is currently being negotiated. The intent of the collaboration is to establish and maintain an independent clinical research network of importance to the region, to the U.S., and to the global community.

The Mexican Emerging Infectious Diseases Clinical Research Network (La RED) is a multisite collaboration between NIAID and the Mexico Ministry of Health that began in September 2009 to conduct clinically relevant and high-quality research on emerging infectious diseases. The five sites in Mexico City include two pediatric sites. Three studies are currently enrolling participants. Future short-term strategic goals include expansion to 1–2 sites outside of Mexico City and the start of an additional flu study. The long-term strategic plan is to promote sustainability and capacity of La Red.

Phidisa is an HIV/AIDS research collaboration with HHS through the NIAID, the U.S. Department of Defense, and the South African Medical Health Services (SAMHS). Launched in 2003, this six-site clinical research project focuses on the management and treatment of HIV infection in the uniformed members of the South African National Defense Force (SANDF) and their dependents, with over 6,000 enrolled patients. Phidisa’s mission is to generate evidence through clinical research to inform policy and improve medical care to benefit members of the SANDF and their families. Phidisa has recently expressed an interest in building capacity within the SAMHS to conduct research on other diseases of critical importance to military force preparedness.

Indo-U.S. Vaccine Action Program (VAP) was initiated under the Gandhi-Reagan Science and Technology Agreement signed in 1985, and implemented in 1987. The VAP is co-managed by the Indian Department of Biotechnology and the NIAID and supports a broad spectrum of research activities aimed at improving vaccines for diseases of importance to India and of interest to the U.S. Diseases and topics funded under the VAP include malaria, TB, dengue, immune enhancement, hepatitis C, rabies, the genetics of respiratory syncytial virus, and vaccine development for rotavirus and HIV. While the VAP will continue to promote translational research and support individual projects proposed by Indian and U.S. collaborating scientists, it will also expand into new scientific areas, such as understanding human immunology and the development of novel vaccine-related technologies.

307 For more information, see http://www.fda.gov/downloads/EmergencyPreparedness/MedicalCountermeasures/UCM283166.pdf.
308 For more information, see http://grants.nih.gov/grants/guide/notice-files/NOT-AI-10-020.html.
309 For more information, see http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-10-010.html.
310 For more information, see http://www.niaid.nih.gov/topics/radnuc/Documents/radnucprogressreport.pdf.