NIH scientists illuminate causes of hepatitis b virus-associated acute liver failure

National Institutes of Health scientists and their collaborators found that hepatitis B virus (HBV)-associated acute liver failure (ALF) — a rare condition that can turn fatal within days without liver transplantation — results from an uncommon encounter between a highly mutated HBV variant and an unusual immune response in the patient’s liver that is mainly sustained by antibody-producing B cells.

This transmission electron microscopic (TEM) image revealed the presence of hepatitis B virus (HBV) particles (orange). The round virions, which measure 42nm in diameter, are known as Dane particles.CDC/ Dr. Erskine Palmer

By applying state-of-the-art technologies, the researchers discovered important new mechanisms about the disease by examining liver samples taken from four patients who developed HBV-ALF. HBV-ALF is one of the most dramatic clinical syndromes in medicine, according to the research team, but so rare that samples of this type are seldom available for study.

Scientists from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) led the project with colleagues from two Italian universities. Their study is published in Proceedings of the National Academy of Sciences.

The investigators used advanced gene sequencing and tissue and cell analysis technologies to determine specific molecular events occurring at the site where HBV replicates and damages liver tissue. They identified processes that are distinct to HBV-ALF cases compared with cases of classic acute HBV infection. Some of these unique events involve a highly mutated virus antigen, the HBV core antigen. The scientists believe that this antigen plays a key role in disease development because it interacts with specific antibodies that are — unusually, they say — already present in these patients. Because of ethical reasons in obtaining liver tissues from patients with classic acute HBV, for their comparison study the scientists used archived liver specimens from two chimpanzees with acute HBV that had been studied many years earlier. They found the mechanism of acute HBV disease to be completely different from that of ALF.

According to the scientists, the HBV-ALF findings were consistent among samples taken from all four patients studied. That is important validation, they say, because virtually no studies have been done on the molecular pathogenesis of HBV-ALF in the liver. They hope their new work provides a model of how the disease develops and will lead to new diagnostic, treatment and prevention strategies.

NIAID-Funded Researchers Predict TB Relapse Risk

Each year, tuberculosis (TB) kills more people than any other single infectious disease. Although tuberculosis can often be treated through a long and grueling course of antibiotics, not everyone is completely cured.

A scanning electron micrograph of Mycobacterium tuberculosis bacteria. Credit: NIAID

Even among patients who are infected with Mycobacterium tuberculosis (Mtb) strains that are considered to be susceptible to the standard treatment regimen, 5 percent of patients relapse within six months of completing standard treatment. Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and through NIAID’s Tuberculosis Research Units Network (TBRU-N), found that a more refined analysis of TB strains collected from volunteers before treatment could accurately predict whether those volunteers would be likely to relapse after standard treatment was completed.

The consequences of TB relapse can reach beyond an individual patient, as any bacteria that remain in the patient after treatment has ended are more likely to be resistant to antibiotics. Multidrug-resistant tuberculosis is often much more difficult to treat, and its spread is a serious concern.

If health professionals could know whether a patient might relapse after standard treatment, they could decide to prescribe a different, or longer, treatment regimen. However, predicting whether a patient will relapse can be difficult. Research published in the New England Journal of Medicine in August sought to determine if identifying the level of drug required to kill the Mtb strains in a new patient’s sputum, a viscous mucus, could predict whether the patient would relapse later, once treatment was complete.

The researchers used data and samples from volunteers who had participated in a prior study run by the Tuberculosis Trial Consortium(link is external) of the Centers for Disease Control and Prevention. Roughly 1,000 adult volunteers from the United States and Canada, all of whom tested positive to drug-susceptible TB, enrolled in the study between April 1995 and February 2001. Before the study began, volunteers gave samples of sputum, which were stored for later testing. Volunteers then underwent both eight weeks of standard antibiotic therapy and an additional 16 weeks of either once-per-week rifapentine and isoniazid treatments, or twice-weekly rifampicin and isoniazid treatments. For two years after treatment completion, researchers followed the volunteers, noting who relapsed.

In this current study, researchers analyzed the TB strains in the volunteers’ stored sputum. They studied Mtb strains collected from all 57 volunteers who relapsed after completion of treatment and whose sputum bacteria could be cultured, and from 68 randomly selected volunteers who were cured as controls. The researchers cultured the bacteria isolated from the sputum of the 125 volunteers before they started TB treatment and tested for the bacteria’s susceptibility to isoniazid and rifampicin at different concentrations. The researchers found that strains collected from volunteers who relapsed required higher concentrations of isoniazid and rifampicin to halt their growth, on average, as compared to strains collected from patients who were cured. Based on these results, researchers developed a model to predict how likely a patient with drug-susceptible TB will relapse.

The researchers then conducted a follow-up study to validate their model using a group of volunteers enrolled in a different study led by NIAID’s Division of Microbiology and Infectious Diseases at sites in Brazil, the Philippines, and Uganda. These volunteers, who had also been diagnosed with drug-susceptible TB, also provided sputum samples prior to undergoing standard treatment with isoniazid, rifampin, ethambutol, and pyrazinamide, followed by two months of isoniazid and rifampin. Some volunteers were randomly assigned to an additional two months of isoniazid and rifampin. Using the model developed in the first study, researchers demonstrated that bacteria in pre-treatment sputum samples from 11 volunteers who experienced a relapse required higher concentrations of drugs to be killed in culture, as compared to bacteria cultured from pre-treatment sputum from 14 volunteers who did not relapse.

The results of this study provide a first step in identifying which patients are likely to relapse after completion of TB standard therapy. This has the potential to improve TB treatment success rates and decrease the development of drug-resistant Mtb.

ARTICLE:

Colangeli, R. et al. Bacterial Factors that Predict Relapse after Anti-Tuberculosis Therapy(link is external). The New England Journal of Medicine. DOI: 0.1056/NEJMoa1715849(link is external) (2018).

Novel antibiotic shows promise in treatment of uncomplicated gonorrhea

An investigational oral antibiotic called zoliflodacin was well-tolerated and successfully cured most cases of uncomplicated gonorrhea when tested in a Phase 2 multicenter clinical trial, according to findings published today in the New England Journal of Medicine. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, sponsored the clinical study.

This illustration depicts a three-dimensional (3D) computer-generated image of a number of drug-resistant, Neisseria gonorrhoeae diplococcal bacteria. U.S. Centers for Disease Control and Prevention – Medical Illustrator

Gonorrhea is a common sexually transmitted disease (STD) that affects both men and women, particularly young people ages 15 to 24 years. Gonorrhea is the second most commonly reported notifiable disease in the United States, with more than 550,000 cases reported in 2017. If untreated, gonorrhea infection can lead to pelvic inflammatory disease, ectopic pregnancy, infertility, and an increased risk of HIV infection. Pregnant women can pass the infection to their babies, who can become blind or develop life-threatening infections as a result.

Gonorrhea is caused by the bacterium Nesseria gonorrhoeae, which has progressively developed resistance to each of the antimicrobials used to treat it. As a result, in 2015, the U.S. Centers for Disease Control and Prevention revised gonorrhea treatment guidelines to recommend dual therapy with injectable ceftriaxone and oral azithromycin to reduce the emergence of resistance to ceftriaxone.

Zoliflodacin (formerly known as ETX0914 and AZD0914), developed by Entasis Therapeutics based in Waltham, Massachusetts, represents a new type of oral antibiotic that inhibits DNA synthesis in a different way than currently approved antibiotics.

“The rate of reported gonorrhea cases in the United States has increased 75 percent since the historic low in 2009, and antibiotic resistance has considerably reduced the number of treatment options for this disease,” said NIAID Director Anthony S. Fauci, M.D. “These encouraging research findings published today suggest that zoliflodacin has the potential to be a useful and easy-to-administer oral antibiotic for treating gonorrhea.”

The study took place from November 2014 through December 2015 and was led by Stephanie N. Taylor, M.D., of Louisiana State University Health Sciences Center in New Orleans. Study investigators recruited patients from sexual health clinics there and in Seattle; Indianapolis, Indiana; Birmingham, Alabama; and Durham, North Carolina. The trial enrolled 179 participants (167 men and12 non-pregnant women) ages 18 to 55 years with either symptoms of uncomplicated urogenital gonorrhea, untreated urogenital gonorrhea or sexual contact with someone with gonorrhea within 14 days before enrollment. Participants were randomly selected to receive either a single 2 or 3-gram dose of oral zoliflodacin or a 500-milligram (mg) dose of injectable ceftriaxone. Among the 117 per-protocol participants who were evaluated six days after treatment, 98 percent (48 of 49 participants) of those who received the 2-gram zoliflodacin dose, 100 percent (47 of 47 participants) of those who received the 3-gram dose, and all (21 of 21) of the participants in the ceftriaxone group were considered cured of their urogenital gonorrhea based on culture results.

Zoliflodacin cured all rectal gonorrheal infections (4 of 4 participants who received the 2-gram dose and 6 of 6 participants who received the 3-gram dose) as did ceftriaxone (3 of 3 participants). However, the investigational drug did not fare as well in treating patients with gonorrhea infections of the throat (pharyngeal): 67 percent of volunteers who received the 2- gram dose (4 of 6 participants) and 78 percent of those who received the 3-gram dose (7 of 9 participants) were cured. All of the participants (4 of 4) in the ceftriaxone group achieved a cure.

The investigational antibiotic was well tolerated with transient gastrointestinal upset the most commonly reported adverse effect. Microbiological evaluation of post-treatment clinical isolates did not demonstrate resistance to zoliflodacin.

In March 2018, NIAID completed a study to evaluate zoliflodacin’s pharmacokinetics, safety and tolerability as a single oral dose to serve as a bridge from the Phase 2 clinical trial formulation to the final formulation for Phase 3 testing. Results from that study have not yet been made public. Additionally, in September 2018 NIAID launched a Phase 1 study to evaluate the investigational drug’s cardiac effects, a standard safety test for new drugs such as this.

Zoliflodacin has been awarded fast track status by the U.S. Food and Drug Administration for development as oral treatment for gonococcal infections. It is expected to begin Phase 3 testing in the Netherlands, South Africa, Thailand and the United States next year.

Experimental Nasal Influenza Vaccine Tested in Kids, Teens

NIAID-Supported Phase 1 Trial of Potential Broadly Protective Vaccine

An early-stage clinical trial testing the safety and immune-stimulating ability of an experimental nasal influenza vaccine in healthy 9- to 17-year-old children and teens has begun enrolling participants at a Vaccine and Treatment Evaluation Unit (VTEU) site at Saint Louis University, St. Louis, Missouri.

Illustration – Influenza viruses. A virus which causes flu. Model shows hemagglutinin and neuraminidase surface glycoprotein spikes, 3D illustration

The VTEU is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Annual vaccination against influenza is recommended for everyone over six months of age. However, because the flu virus changes from year to year, vaccines must be reformulated annually to take account of those changes. When mismatches occur, vaccine effectiveness may suffer.

“We are hopeful that newer kinds of influenza vaccines, such as the candidate being tested in this trial, will provide protection even if their components do not precisely match the currently circulating influenza virus strains,” said NIAID Director Anthony S. Fauci, M.D.

Principal investigator Daniel Hoft, M.D., Ph.D., leads the clinical trial, which will enroll 50 participants. Half will receive the candidate nasal vaccine and the other half will receive a dose of inactive saline solution delivered as nasal spray. Neither the study staff nor volunteers will know whether a participant has received the experimental vaccine or placebo saline solution. All volunteers will receive an intramuscular injection of a licensed, quadrivalent seasonal influenza vaccine three months after receiving the initial nasal vaccine or placebo. An important objective of the study is to determine whether the combination of the licensed and experimental vaccine leads to broader protection against influenza viruses compared with the licensed vaccine alone. Investigators will perform an array of tests on volunteer blood samples at four time points following the first vaccination as well as three weeks after the second vaccination. They will look for evidence of immune responses from antibody-producing cells as well as from the cellular arm of the immune system.

The investigational vaccine, developed by FluGen, Inc. of Madison, Wisconsin, is made from a strain of seasonal influenza virus (H3N2) that has been genetically designed to replicate only once in the body. Studies in animals showed that the “single replication” virus does not cause disease but nevertheless prompted a robust immune response akin to that of a natural influenza infection. Investigators hypothesize that volunteers who receive the candidate vaccine will have a robust immune response not only against H3N2 strains that match those in the vaccine but also against influenza strains that are mismatched to the vaccine strain. A previous Phase 1 trial of this candidate vaccine in healthy adults showed that it was safe and generated a robust immune response and a Phase 2 trial in healthy adults is currently underway (that trial is not supported by NIAID.)

Pregnancy loss occurs in 26 percent of Zika-infected monkeys

Fetal death in utero occurred in more than one-fourth of monkeys infected in the laboratory with Zika virus in early pregnancy, according to new research published in Nature Medicine. The finding raises the concern that Zika virus-associated pregnancy loss in humans may be more common than currently thought, according to the study authors.

Transmission electron microscope image of negative-stained, Fortaleza-strain Zika virus (red), isolated from a microcephaly case in Brazil.National Institute of Allergy and Infectious Diseases (NIAID)

A large team of experts aggregated data on Zika-infected macaques from six National Primate Research Centers (NPRCs)(link is external) in the United States for the new analysis. The study was funded in part by the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy ShriverNational Institute of Child Health and Human Development (NICHD), both components of the National Institutes of Health.

Zika virus is most often transmitted to humans via the bite of an infected Aedes aegypti mosquito. It also is transmitted sexually. Many people infected with Zika virus will not have symptoms; others may have fever, rash, headache, joint pain, red eyes, and muscle pain. Zika virus can be passed from an infected pregnant woman to her fetus and cause a range of birth defects collectively known as congenital Zika syndrome. Although Zika virus was first discovered in 1947, Zika-related birth defects were not reported until 2015 during a large outbreak of Zika in the Americas. No licensed treatments or vaccines for Zika virus are currently available, but many are in various stages of development. For example, NIAID is leading an international Phase 2 trial of an experimental Zika vaccine.

Research recently published in the New England Journal of Medicine(link is external) showed a 5.8 percent miscarriage rate and a 1.8 percent stillbirth rate in a cohort of pregnant women with symptomatic Zika virus infection in French Guiana, Guadalupe or Martinique. Authors of the new nonhuman primate analysis note that the rates from the NEJM study could be an underestimate — the study included only symptomatic pregnant women, whereas many people with Zika infection are asymptomatic.

For the new analysis, experts combined published and unpublished data from various studies of pregnant macaques infected with Zika virus. Fetal death (miscarriage or stillbirth) occurred in 13 of 50 (26 percent) of the animals studied. Macaques infected early in pregnancy had significantly higher rates of fetal death than those infected after gestation day 55. The results track with human data showing more severe fetal outcomes in women infected with Zika in their first trimester compared to those infected later in pregnancy. The rates of fetal death in macaques underscore the need for careful monitoring of fetal loss and stillbirth in Zika-affected human pregnancies, the authors write.

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NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. 

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. 

NIAID-Sponsored Trial of a Universal Influenza Vaccine Begins

A Phase 2 clinical trial of an investigational universal influenza vaccine intended to protect against multiple strains of the virus has begun in the United States.

The study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and is being conducted at four U.S. sites that are part of the NIAID-funded Vaccine and Treatment Evaluation Units (VTEUs).

The trial is testing an experimental vaccine called M-001 for safety and its ability to produce potentially broad protective immune responses, both on its own and when followed by a standard, licensed seasonal influenza vaccine.

Influenza viruses mutate constantly, resulting in the emergence of viruses that may not always match those targeted by seasonal and pre-pandemic influenza vaccines. Seasonal influenza vaccines are made anew each year to match the strains predicted to circulate in the upcoming season. To receive the best protection against influenza, people must be vaccinated annually.

However, if a particular influenza strain changes in an unanticipated way, or a different strain from that included in the vaccine spreads widely, the seasonal influenza vaccine may not be sufficiently protective. Each year, seasonal influenza sickens millions in the United States and results in 140,000 to 710,000 hospitalizations and between 12,000 and 56,000 deaths, according to the Centers for Disease Control and Prevention.

Influenza pandemics occur when a novel influenza strain for which people have little to no protection begins to spread among humans and present a greater public health threat than seasonal influenza. For example, the 1918 influenza pandemic killed at least 50 million people worldwide. An ideal universal influenza vaccine would provide durable protection for all age groups against multiple influenza strains, including those that might cause a pandemic.

“The 2017-2018 influenza season in the United States was among the worst of the last decade and serves as a reminder of the urgent need for a more effective and broadly protective influenza vaccine,” said NIAID Director Anthony S. Fauci, M.D. “An effective universal influenza vaccine would lessen the public health burden of influenza, alleviate suffering and save lives. There are numerous paths of inquiry that the scientific community is pursuing, with each new study yielding more critical information and bringing us closer to our shared goal.”

The new trial is being led by principal investigator Robert L. Atmar, M.D., of Baylor College of Medicine in Houston. The trial will test the M-001 vaccine candidate, developed and produced by BiondVax Pharmaceuticals based in Ness Ziona, Israel. The experimental M-001 vaccine contains antigenic peptide sequences shared among many different influenza viruses. Theoretically, it could protect against many current and emerging strains of influenza. Six previous clinical trials involving a total of 698 participants conducted by BiondVax in Israel and Europe indicated that the vaccine candidate was safe, well-tolerated and produced an immune response to a broad range of influenza strains.

The new study will enroll up to 120 healthy volunteers between the ages of 18 and 49 years. Participants will be assigned randomly to receive either two doses of the experimental vaccine or a placebo. They will be vaccinated twice, receiving one dose (1 mg; 0.4 milliliters) of M-001 or placebo via intramuscular injection on the first day and a second dose 22 days later. Approximately 172 days later, all participants will receive an approved seasonal influenza vaccine. During periodic additional clinic visits throughout the course of the study, blood will be drawn from study volunteers to evaluate their immune responses to both the experimental vaccine and to the seasonal vaccine. Each participant will be followed for approximately seven months.

The trial will take place at four NIAID-funded VTEUs. Patients will be enrolled at the Baylor College of Medicine; the University of Iowa in Iowa City; and Cincinnati Children’s Hospital Medical Center. Laboratory support will be provided by Saint Louis University.

 

NIAID dedicated to helping eliminate tuberculosis

NIH Statement on World Tuberculosis Day 2018

Statement of Christine F. Sizemore, Ph.D., Richard Hafner, M.D., and Anthony S. Fauci, M.D.

In the 130 years since the discovery of Mycobacterium tuberculosis (Mtb) — the bacterium that causes tuberculosis (TB) — at least 1 billion people have died from TB. That death toll is greater than the combined number of deaths from malaria, smallpox, HIV/AIDS, cholera, plague and influenza. Today, in commemoration of World TB Day, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), renews and reinvigorates its commitment to the research needed to end this ancient scourge.

 

Tuberculosis (TB) remains the world’s leading cause of death alongside HIV

Mtb is transmitted through the air and primarily affects the lungs.  TB is the leading killer among infectious diseases and among the top 10 causes of death worldwide.  The World Health Organization (WHO) estimates that in 2016, TB claimed the lives of 1.7 million people, including 250,000 children, and 10.4 million people were newly infected with Mtb. TB is the primary cause of death for individuals co-infected with HIV. According to the WHO, more than 2 billion people globally are “latently” infected with TB, meaning they carry the bacteria but are currently without symptoms, which would include cough, fever, weight loss and night sweats. People with latent TB infection cannot actively transmit TB bacteria to another person. Up to 13 million people in the United States are estimated to have latent TB infection, according to the U.S. Centers for Disease Control and Prevention. Overall, people with latent TB infection have a 5 to 15 percent lifetime risk of developing active TB disease. This risk increases for people with compromised immune systems, such as those living with HIV, people receiving immunosuppressive therapy (such as individuals being treated for cancer), as well as diabetics, smokers and the malnourished.                                                                                                                                                                              WHO’s End TB Strategy envisions an end to TB by 2035. To accomplish this, incremental improvements in understanding the disease and in the tools used to identify, treat, and prevent it will not be sufficient. Rather, accelerated efforts and transformative advances are needed. Recent engagement includes NIAID participation in the first “WHO Global Ministerial Conference on Ending TB in the Sustainable Development Era: A Multisectoral Response” in Moscow. At this November 2017 meeting, the urgent need for a more intensive biomedical research approach to controlling and ultimately eliminating TB was clearly articulated. Specifically, we need a more intensive interdisciplinary systems biology approach (using cutting-edge methods, large data sets, and modeling to understand complex biological systems) to improve our understanding of how Mtb infection causes disease. Additionally, we must work toward improved diagnostics that can detect Mtb in a variety of clinical specimens in addition to sputum. Also, rapid, accurate, and inexpensive “point-of-care” tests to distinguish between drug-sensitive and drug-resistant Mtb must be developed. NIAID investments in research contributed substantially to the WHO-endorsed GeneXpert MTB/rifampicin resistance diagnostic currently in use, and the Institute continues to support the development of next-generation TB diagnostics.

 

Today’s treatment regimens for TB require too many drugs, often with toxic side effects, that must be taken for six months or longer. With the increasing incidence of multidrug resistant TB (MDR-TB), these regimens often become very lengthy (up to 20 months), more complex, costly, and more prone to failure. Extensively drug-resistant TB (XDR-TB) is even more difficult to treat, and for some patients, no effective treatment regimens exist. Despite the urgent need for new and improved TB treatments, there is a paucity of new drugs in the clinical development pipeline. To address this deficit, NIAID-supported investigators have engaged in cross-disciplinary, international collaborations designed to spur basic science and early-stage TB drug discovery. Additionally, NIAID has used its HIV/AIDS clinical trials networks to enhance TB clinical research by conducting key studies of potential TB treatment strategies. For example, a NIAID-led study found that a one-month antibiotic regimen to prevent active TB disease in people with latent TB infection was as safe and effective as the standard 9-month course in people living with HIV.  Additionally, the NIAID-funded HIV/AIDS clinical trials networks have conducted studies of improved regimens for MDR-TB therapeutics geared to treat both HIV-infected and uninfected adults and children.

A broadly effective preventive TB vaccine could avert millions of new Mtb infections; however, critical knowledge gaps have made developing such a vaccine a difficult challenge. The current Bacille Calmette-Guerin (BCG) vaccine, developed in 1921, offers protection against disseminated TB disease and death in children, but this protection does not reliably extend into adulthood.  A recent study suggests that revaccination with the vaccine could potentially prevent Mtb infections in high-risk adolescents. To reliably protect against the transmissible pulmonary form of the disease in adults, a new, more effective intervention strategy is needed. NIAID supports basic, preclinical and clinical research to find and develop new, innovative vaccines to prevent TB infection and disease.

The WHO estimates that 53 million lives were saved between 2000 and 2016 through improved TB diagnosis and treatment. Through an intensified research agenda, a sustained commitment to supporting and conducting TB research, and a renewed effort to work with other agencies and organizations, NIAID is dedicated to helping eliminate this disease and improving and saving the lives of people with TB. In September 2018, the United Nations General Assembly will conduct a high-level meeting on TB—representing an important step forward by governments and other partners from around the world in the fight against TB. On this World TB Day, we stand with global leaders in response to the bold call of action to make history and end TB.

Anthony S. Fauci, M.D., is Director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health in Bethesda, Maryland. Richard Hafner, M.D., is chief of the TB Clinical Research Branch in NIAID’s Division of AIDS; Christine F. Sizemore, Ph.D., is chief of the Tuberculosis and other Mycobacterial Diseases Section in the NIAID Division of Microbiology and Infectious Diseases.

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses.

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About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.