DMID Scientific Success Stories Showcase

Point-of-Care Diagnostics for Common Sexually Transmitted Infections

Reported cases of sexually transmitted infections (STIs) in the United States have been increasing at an alarming rate in recent years. According to the Centers for Disease Control and Prevention, there were an estimated 2 million new cases of trichomoniasis, 1.8 million cases of chlamydia, and 616,000 cases of gonorrhea reported in 2019. These numbers represent an all-time high for the sixth consecutive year. People infected with these STIs do not always have symptoms, which makes diagnosing them difficult.

NIAID supported a clinical study of the Visby Medical Sexual Health Test, a palm-sized, rapid point-of-care diagnostic that can detect all three of these infections in women using a self-collected vaginal swab. The Visby Medical Sexual Health Test is a highly sensitive, nucleic acid amplification-based PCR diagnostic that returns results in less than 30 minutes, allowing patients to receive an accurate diagnosis during their initial visit.

Another advantage of the Visby Medical Sexual Health Test is that a rapid diagnosis can help avoid inappropriate use of antibiotics. This is particularly important for gonorrhea, because the bacteria that causes the disease, Neisseria gonorrhoeae, has developed resistance to many of the antibiotics that are used to treat infection. Reducing the unnecessary use of antibiotics can help slow the emergence and spread of resistant bacteria.

The Visby Medical Sexual Health Test received 510(k) clearance and was granted a CLIA waiver from the Food and Drug Administration (FDA) on August 30, 2021. The CLIA waiver allows the tests to be administered in healthcare settings rather than being sent to a laboratory.

Visby Medical also developed a second device based on the platform of their Sexual Health Test, which determines the susceptibility of N. gonorrhoeae to the antibiotic ciprofloxacin. This diagnostic won the federal Antimicrobial Resistance Diagnostic Challenge in 2020. While not yet approved for general use, this device would allow for resistance-guided treatment of gonorrhea infections, helping to preserve frontline antibiotics.

The First Approved Treatment for COVID-19

One of the biggest challenges in addressing a novel disease is the lack of vetted treatments that can be used when people fall ill. After the emergence of SARS-CoV-2, NIAID efforts played a critical role in accelerating the development of new therapeutics and other countermeasures. In January 2020, the first cases of COVID-19 were reported in the United States. One month later, the Adaptive COVID-19 Treatment Trial (ACTT) began. Sponsored by NIAID, this was one of the first clinical trials for an experimental COVID-19 treatment in the United States. The study evaluated the novel antiviral remdesivir in patients hospitalized with COVID-19.

Remdesivir, developed by Gilead Sciences, Inc., is an antiviral medication that targets a range of viruses. It was originally developed as a treatment for hepatitis C and respiratory syncytial virus (RSV), but also showed promise against other viruses. Remdesivir was previously tested in humans with Ebola virus disease and has shown promise in animal models for treating coronaviruses, including Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). These studies are part of why the drug was able to be advanced into clinical studies for treating COVID-19 so quickly after the outbreak was first discovered.

The first iteration of ACTT was initiated to evaluate remdesivir as a treatment option for COVID-19. Results showed that hospitalized patients with COVID-19 who received remdesivir recovered faster than similar patients who received placebo. The study also suggested that remdesivir treatment may prevent patients from progressing to more severe respiratory disease. Remdesivir appeared to most benefit patients who were receiving supplemental oxygen.

Based on the ACTT study and two other trials sponsored by Gilead, the Food and Drug Administration (FDA) granted Emergency Use Authorization for remdesivir in May 2020, and the drug received full approval on October 22, 2020, under the commercial name Veklury. The drug is specifically approved for use in hospitalized adult and pediatric patients (12 years and older) and is the first drug approved in the United States for COVID-19.

In addition to remdesivir, NIAID continues to support additional preclinical and clinical research efforts to identify and develop treatments for COVID-19. For more information on current treatment options for COVID-19, visit: https://www.covid19treatmentguidelines.nih.gov/

Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.
Credit: NIAID

An Antibody Test for COVID-19

Since the start of the pandemic in 2019, COVID-19 has claimed almost 5 million lives worldwide, making it the deadliest infectious disease of our generation. When the pandemic began, testing for active infections was not widely available. Thus, it was impossible to know how many people had been infected. 

NIAID provided support for one of the first serologic tests for COVID-19, a two-step Enzyme-Linked ImmunoSorbent Assay (ELISA) which was developed by researchers at the Icahn School of Medicine at Mount Sinai. Serologic tests can determine if someone was previously infected by testing for the presence of antibodies using an antigen, which is the part of the virus to which the antibody binds. In the case of SARS-CoV-2, the antigen is the spike protein. The Mount Sinai ELISA is highly specific and sensitive, making it an ideal research and public health tool. 

Using this tool, Mount Sinai researchers have been able to understand when local COVID-19 outbreaks started and how widespread they became. The test has also been used to study how long neutralizing antibodies to SARS-CoV-2 persist after infection, and to provide population-level data on how many people might have some immunity. More recent studies have used the test to characterize people’s antibody responses to vaccination, and to assess whether vaccine-induced immunity can protect against emerging variants. The protocol for the ELISA was shared openly with over 200 labs worldwide so that they can use the test in their own research.

The Mount Sinai ELISA received FDA Emergency Use Authorization in April 2020. It has since been developed as the commercial product ‘COVID-SeroKlir’ by the spin-out company Kantaro Biosciences, a joint venture between Mount Sinai and RenalytixAI. 

A New Rapid Diagnostic for Melioidosis

NIAID-funded researchers have developed a new rapid diagnostic for the tropical disease melioidosis, a disease caused by the bacterium Burkholderia pseudomallei. Melioidosis affects approximately 165,000 people worldwide, mainly in Southeast Asia and northern Australia, and causes 89,000 deaths annually. It is primarily contracted through direct contact with contaminated water or soil.

Symptoms of melioidosis overlap with other viral and parasitic diseases which has made it difficult to diagnose, and, in turn, hindered treatment efforts. Melioidosis is frequently misdiagnosed as sepsis, and the standard therapies used to treat sepsis are ineffective for B. pseudomallei.

A new diagnostic for melioidosis, called Rapid Melioidosis, takes only 15 minutes and can be administered in a point-of-care (POC) setting. The test can detect infection at a very early stage from just one drop of blood or serum. Instead of a lengthy lab test that requires the bacteria to be isolated from a clinical specimen and cultured, the new test yields rapid results. Rapid Melioidosis is an immunochromatography test that uses an antigen for hemolysin-coregulated protein (Hcp1) to detect antibodies against Hcp1 in the blood. Hcp1 is a protein secreted by the bacteria that plays a role in its intracellular functions. Studies have shown that this new melioidosis test kit is highly sensitive and specific. The test was developed by researchers at Mahidol University in Bangkok, Thailand and at the University of Washington in Seattle, Washington. The test is currently licensed and available for commercial use in Thailand under the name Active Melioidosis Detect.

Researchers hope the newly developed diagnostic test will greatly accelerate diagnosis and treatment of melioidosis, improve the quality of patient care, and illustrate the importance of increased availability of rapid, POC diagnostics.

 A culture of Burkholderia pseudomallei bacteria, the pathogen that causes melioidosis.
Credit: CDC

Intravenous Fosfomycin to Treat Multidrug-Resistant Infections

Since the introduction of penicillin in the 1940s, a complex array of factors has led to an era in which some bacterial infections no longer respond to any approved antibiotics. The Centers for Disease Control and Prevention estimate that antibiotic-resistant bacteria cause at least 35,000 deaths and 2.8 million illnesses annually in the U.S. alone.

To improve therapeutic options for resistant infections, NIAID provided support to Zavante Therapeutics, Inc. (now Nabriva Therapeutics) for the clinical development of the intravenous (IV) form of the antibiotic fosfomycin (ZTI-01). Fosfomycin is a broad-spectrum antibiotic active against many Gram-positive and Gram-negative bacteria, including multi-drug resistant strains. However, unlike in Europe, where both oral and IV formulations are approved, this therapeutic is only available in oral form in the U.S. IV delivery allows the antibiotic to be delivered directly into the bloodstream, acting much faster than the oral form and reaching the concentrations needed to treat complicated hospital-acquired infections. A NIAID-supported Phase I clinical trial demonstrated the safety of IV fosfomycin in healthy adults and provided insight into the concentrations of fosfomycin reached in blood and urine using different doses of oral and IV fosfomycin.

Following the success of the Phase I trial, Zavante Therapeutics sponsored a Phase II/III clinical trial evaluating the efficacy of IV fosfomycin in treating complicated urinary tract infections (cUTIs). The study compared IV fosfomycin against the standard treatment (piperacillin/tazobactam) and found that IV fosfomycin was safe and worked equally as well in these patients. The U.S. Food and Drug Administration granted Fast Track designation and Qualified Infectious Disease Product designation for the investigation of fosfomycin for cUTIs, hospital-acquired bacterial pneumonia (HABP), and ventilator-associated bacterial pneumonia (VABP), among others. NIAID is now supporting a Phase I trial in healthy volunteers to establish the right dosage for the use of this important investigational antibiotic in patients with HABP and VABP.

VRE: Vancomycin-resistant enterococci in purple
Credit: NIAID

Treating Bed Nets to Prevent Malaria

NIAID-funded researchers are investigating an innovative approach to stop malaria – killing the parasites inside mosquitoes before they can be transmitted to humans. According to the World Health Organization, there were an estimated 228 million cases of malaria and 405,000 deaths from the disease in 2018. With no approved vaccines, insecticide-treated bed nets have been a critical tool for preventing malaria infections. However, mosquitoes have developed widespread resistance to insecticides, threatening the continued success of the intervention.

Researchers are exploring a new a way to enhance the use of bed nets. Instead of treating the bed nets with insecticides, investigators are examining whether coating bed nets with an antimalarial drug can prevent the development of parasites inside mosquitoes.

A NIAID-funded research team, led by scientists at Harvard University, exposed Anopheles gambiae mosquitoes, the main vectors of malaria in Africa, to low concentrations of atovaquone (a malaria drug). The team coated the surface of a petri dish with atovaquone, then allowed female A. gambiae mosquitoes to land on the surface before feeding them a blood meal infected with Plasmodium falciparum, the parasite responsible for malaria. The study found that the antimalarial drug, when absorbed through the mosquito cuticle, was able to reach the mosquito stomach and completely blocked parasite development.

When incorporating the results of this work into a malaria transmission model, findings indicated that treating bed nets with an antimalarial, such as atovaquone, could significantly counteract mosquito insecticide resistance as well as transmission of malaria to humans. Research is ongoing to determine the feasibility of this approach.

An Anopheles gambiae mosquito 
Credit: NIAID

Rapid Diagnostics to Combat Antimicrobial Resistance

The development of rapid, point-of-care diagnostics that can specifically identify the bacteria, fungi or virus causing an infection is an important step in combatting antibiotic resistance priority for NIAID. Currently, broad spectrum antibiotics, which target a wide range of bacteria, are often prescribed when a diagnosis cannot be made prior to starting treatment. Diagnostics that identify the cause of an infection, as well as the susceptibility of that pathogen to specific antibiotics, can inform appropriate treatment, promote antibiotic stewardship, and ultimately, help fight antibiotic resistance.

NIAID has supported and continues to support a number of diagnostics to combat antibiotic resistance, including multiplex platforms such as the FilmArray Blood Culture Identification Panel by BioFire Diagnostics LLC, an affiliate of Biomérieux. Through small business grants and partnerships grants, NIAID supported the development of this polymerase chain reaction (PCR)-based system, which has been cleared by the Food and Drug Administration, to simultaneously detect several pathogens in patient samples in around one hour. This panel tests for 24 Gram-positive bacteria, Gram-negative bacteria, and yeast microbes that cause bloodstream infections (sepsis).. The future assay under development will simultaneously tests for 24 pathogens; Gram-positive bacteria, Gram-negative bacteria, and yeast microbes that cause bloodstream infections (sepsis) within 2 hours of sample draw.

Recently, in addition, NIAID has also provided support for other novel approaches to diagnostics, including using digital imaging to rapidly detect Methicillin-resistant Staphylococcus aureus (MRSA), as well as and using a technique known as surface-enhanced Raman spectroscopy as a diagnostic platform to detect bacteria and antibiotic susceptibility. Ongoing work from the NIAID-supported Antibacterial Resistance Leadership Group (ARLG) includes developing and validating new diagnostics and evaluating the effectiveness of existing platforms. Through the RADICAL study, ARLG investigators are exploring the potential of host biomarker signatures to differentiate between viral and bacterial respiratory infections. Furthermore, NIAID recently awarded several grants under the Partnerships for Development of Clinically Useful Diagnostics for Antimicrobial-Resistant Bacteria program.

This scanning electron microscope image shows SARS-CoV-2 (orange)—also known as 2019-nCoV, the virus that causes COVID-19—isolated from a patient in the U.S., emerging from the surface of cells (green) cultured in the lab.
Credit: NIAID-RML

Designer Flu Proteins: A New Approach to Universal Influenza Vaccines

The influenza virus causes annual epidemics, which result in millions of cases of severe illness worldwide. High-risk groups, including pregnant women, the very young or elderly, and chronically ill individuals, are more likely to experience complications from influenza infection, such as pneumonia or bronchitis. Current influenza virus vaccines are effective, but they have to be reformulated and administered annually to target the influenza virus strains predicted to circulate each year.

To address these issues, NIAID is supporting research to promote the development of universal influenza vaccines, which would provide broader protection against multiple strains of influenza viruses. In 2018, NIAID published a strategic plan for addressing the research areas essential to creating a safe and effective universal influenza vaccine.

One important objective outlined in the strategic plan is the design of new immunogens that elicit a wider breadth of protection. Influenza vaccines induce antibodies that target the viral protein hemagglutinin (HA), which is important for virus entry into host cells. This protein is made up of a head and a stalk domain. Most antibodies elicited by vaccines target the immunodominant head domain, but some antibodies do target the stalk. The head domain can vary widely between different virus strains and is subject to genetic changes with time, which is why new vaccines are required annually. However, the stalk domain of the HA protein is more constant, or conserved.

NIAID has been supporting a universal vaccine strategy which uses vaccine constructs that are made of combinations of conserved HA stalk domains with variable HA head domains derived from different virus strains. Sequential vaccination with these constructs allows an enhanced antibody response to form against the conserved stalk; these antibodies have been shown to provide broad protection against many influenza virus strains.

NIAID has provided support for this universal influenza vaccine strategy, allowing the work to advance from basic research and proof-of-concept studies in animals through clinical development. This work has facilitated major advances in the development of a universal influenza vaccine.

A 3-D print of hemagglutinin (HA), one of the proteins found on the surface of influenza virus that enables the virus to infect human cells.
Credit: NIH

Rapid, Accurate Diagnostics for Ebola

Early symptoms of Ebola virus disease (EVD), including fever, muscle pain, headache, and diarrhea, are often indistinguishable from symptoms of other diseases. However, EVD can progress to impaired kidney and liver function and internal and external bleeding. Because of the severity and high fatality rate, rapid and accurate diagnosis of Ebola infection is critical.

NIAID has supported the development of improved diagnostics to detect Ebola virus infection, including those that can provide rapid identification and can be deployed at the point-of-care where Ebola outbreaks occur. Two of these diagnostics became available under Emergency Use Authorization (EUA) by the Food and Drug Administration for detection of the Ebola Zaire strain during the 2014 West Africa outbreak.

The FilmArray Biothreat-E test, developed by BioFire Defense LLC, and the Xpert Ebola Test, manufactured by Cepheid, are polymerase chain reaction (PCR)-based tests that can detect viral nucleic acid in patient samples in less than two hours.

NIAID has provided support for FilmArray since 2005, with an initial focus on respiratory pathogen detection. From 2009 - 2012, NIAID supported the development of a biothreat panel, which included an Ebola diagnostic test. For the Xpert technology platform, NIAID initially funded basic science research for technology required for this diagnostic, supported the development of the Xpert for use as a diagnostic for tuberculosis, and provided funds to support an Xpert diagnostic for Ebola. The Biothreat E-test and Xpert Ebola Test received EUA in October 2014 and March 2015, respectively.

NIAID also is advancing development of other types of diagnostics, including those using novel technologies, such as microfluidics, optofluidics, and nanophotonics, which are capable of detecting an array of viruses, including Ebola viruses. As a possible alternative to PCR-based tests, which require specialized equipment and personnel, NIAID is supporting development of sensitive lateral flow assays (LFA) for Ebola diagnosis. Lateral flow technology, which is also used in at-home COVID-19 antigen tests, is low cost and easy to use. With NIAID support, scientists are making progress developing highly sensitive rapid LFA-based tests for Ebola viruses that could be deployed in resource-constrained settings for surveillance, early diagnosis of infections, and contact tracing.

Colorized scanning electron micrograph of Ebola virus particles in extracellular space between infected African green monkey kidney cells.
Credit: NIAID

NIAID Enables Approval of Novel Anti-TB Drug

The U.S. Food and Drug Administration (FDA) recently approved a new anti-tuberculosis (TB) drug, pretomanid (PA-824). Pretomanid is only the third anti-TB drug approved by the FDA in the past 40 years, and is approved for use in combination with bedaquiline and linezolid for people with the most serious TB infections, extremely drug-resistant TB (XDR-TB) and treatment-intolerant/non-responsive multidrug-resistant (MDR-TB) TB. Pretomanid was originally discovered in 2000 by the Pathogenesis Corporation in collaboration with NIAID's Division of Intramural Research (DIR). It was developed by the TB Alliance, which was formed as a non-profit development partnership positioned to leverage a global network of public and private partners.  NIAID's DIR elucidated the mechanism of action, evaluated pretomanid in an animal model and tested it in combination with other drugs to assess safety. NIAID's Division of Microbiology and Infectious Diseases (DMID) and Division of AIDS (DAIDS) conducted multiple preclinical animal and safety/toxicology studies on the drug, alone and in combination with other compounds. DMID contributed project management support and conducted clinical studies to advance pretomanid's development. Pretomanid was approved in 2019 under the Limited Population Pathway for Antibacterial and Antifungal Drugs on the basis of promising clinical data from the TB Alliance's NixTB Phase 3 trial in South Africa.  NIAID's support was critical in helping advance this important new drug to licensure. 

Scanning electron micrograph of Mycobacterium tuberculosis bacteria, which cause TB. 
Credit: NIAID

Synthetic Tetracyclines To Combat Bacterial Infections

Tetracyclines are a group of broad-spectrum antibiotics used to treat several different types of bacterial infections, including those caused by both gram-positive and gram-negative bacteria. Unfortunately, many bacteria are developing resistance to this valuable treatment. To address this growing issue, NIAID is supporting the development of novel tetracyclines. Prepared using state-of-the-art chemistry developed by an NIAID-supported scientist at Harvard University, these synthetic compounds are not subject to existing tetracycline resistance mechanisms and therefore represent important new tools for the treatment of multidrug-resistant (MDR) bacterial infections.

NIAID support has enabled the chemical synthesis of over 2,000 novel tetracyclines, several of which are at various steps in the product development pathway. One new tetracycline called eravacycline (TP-434) from Tetraphase Pharmaceuticals was recently approved by the FDA for the treatment of complicated intra-abdominal bacterial infections. In addition, NIAID supported the development of TP-271, a novel tetracycline also created by Tetraphase, which has advanced from proof-of-concept through completion of Phase I trials. With the same chemistry that created TP-434 and TP-271, TetraPhase has synthesized TP-6076, another broad-spectrum antibacterial of the tetracycline class, and developed it for the treatment of serious bacterial infections including carbapenem-resistant Enterobacteriaceae and multidrug resistant Acinetobacter baumannii. TP-6076 has been advanced to clinical Phase I trials. These compounds are being developed for numerous bacterial indications, including community-acquired bacterial pneumonia, MDR gram-negative bacteria, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus anthracis, Fransicella tularensis, and Yersinia pestis.

Colorized scanning electron micrograph of a white blood cell interacting with an antibiotic resistant strain of Staphylococcus aureus bacteria.
Credit: NIAID

Vaccine Candidate Active Against Candida and Staphylococcus aureus: NDV-3

Currently, there are no licensed vaccines to prevent Candida or Staphylococcus aureus infections. With NIAID support, a vaccine candidate is being developed to protect against both infections.

Candida can cause fungal infections in humans. These infections, known as candidiasis, occur most frequently in individuals with risk factors such as weakened immune systems, certain medical conditions, and prior antibacterial use. In some cases, the fungus can escape from the gut to enter the bloodstream and cause more invasive disease known as candidemia, which is one of the most common bloodstream infections.

The bacterium S. aureus is one of the leading causes of healthcare-associated infections. Increased hospitalizations related to drug-resistant S. aureus infections have a significant human and economic impact, including increased mortality, longer hospital stays, and more complicated treatment.

A vaccine to prevent Candida and S. aureus infections could greatly benefit patients, especially those at high risk for infection such as people with weakened immune systems and individuals with high incidence of recurrent infections. NIAID has provided funding and support throughout basic research, discovery, and development of a vaccine candidate: NDV-3. In the early 1980s, NIAID funded studies at Harbor UCLA Medical Center to investigate how Candida adheres to and penetrates endothelial cells. This research led to the discovery of several adhesion proteins that conferred protection in mice. NDV-3 emerged as a lead vaccine candidate. NIAID preclinical services supported scale up, manufacture, and stability testing of this experimental Candida vaccine that also protects against S. aureus infection. In animal models, NDV-3 was found to be protective against several strains of S. aureus, including methicillin-resistant S. aureus (MRSA) strains and the newly emerging multi drug resistant Candida auris. NDV-3 is the first vaccine candidate to provide protective efficacy across kingdoms, as it works against fungi and bacteria.

In Phase I clinical trials sponsored by NovaDigm Therapeutics, the cross-protective vaccine was well tolerated, safe, and induced strong antibody and T-cell responses. The company also supported a Phase IB/IIA clinical trial evaluating the ability of NDV-3 to prevent vaginal candidiasis in women with recurrent vulvovaginal candidiasis.  The investigational vaccine was found to be safe, well-tolerated, immunogenic and efficacious against recurrent vulvovaginal candidiasis.  In collaboration with the Department of Defense, in 2018, NovaDigm Therapeutics launched a Phase II clinical trial testing NDV-3A’s ability to reduce colonization of S. aureus among military recruits. NDV-3A is a newer formulation of the NDV-3 vaccine.

Fluorescent antibody stain revealing the oval budding yeast cells of Candida albicans fungal organisms.
Credit: CDC/Maxine Jalbert, Dr. Leo Kaufman

Second-Generation Smallpox Vaccine: Modified Vaccinia Ankara (MVA)

Smallpox is a disfiguring and deadly disease caused by Variola major. In 1980, the World Health Organization declared that smallpox had been eradicated worldwide. However, smallpox continues to concern public health officials as a potential biological weapon.

A vaccine known as Dryvax was used in smallpox eradication, and the United States has enough of its successor, Acam2000, on hand to vaccinate the population in case of a terrorist attack. However, people with weakened immune systems or skin conditions like atopic dermatitis are at increased risk for serious side effects from these vaccines.

NIAID recognized the need for a safer smallpox vaccine than Dryvax and ACAM2000 that could be used to protect patients with weakened immune systems, like those with HIV or cancer. With this goal, NIAID invested in the development of a second-generation vaccine using Modified Vaccinia Ankara (MVA)-a highly weakened vaccinia virus that does not replicate well in humans. MVA vaccine is being developed by Bavarian Nordic and holds promise as a safer alternative to Dryvax and ACAM2000 to make the nation safer in the event of a biological terrorist attack.

NIAID supported early advanced development work for this important vaccine. This included toxicology and efficacy studies to enable investigational new drug (IND) status and clinical trials in individuals infected with HIV and atopic dermatitis. Preclinical services such as studies on animal model development, natural history, virulence, and vaccine efficacy, contributed to the successful development of MVA.

In 2013, Canada and the European Union approved MVA (under the trade names IMVAMUNE® and IMVANEX®) for use in the general population, including people with weakened immune systems or atopic dermatitis. As of 2013, 20 million doses were delivered to the U.S. Strategic National Stockpile for use among these groups. Studies to support FDA approval for use of the vaccine in the entire population have been concluded and approval was granted in September 2019. 

A transmission electron micrograph of smallpox viruses.
Credit: CDC/Dr. Fred Murphy

Anthim: A New Treatment for Inhalation Anthrax: Anthim

Inhalation anthrax is the deadliest form of infection caused by the bacteria Bacillus anthracis. When a person breathes in anthrax spores, infection begins in the chest lymph nodes and spreads throughout the body, causing severe breathing problems and shock. Immediate treatment is crucial to survival. Without treatment, only about 10 to 15 percent of patients with inhalation anthrax survive.

New treatment options for inhalation anthrax are needed. NIAID, in coordination with the HHS Biomedical Advanced Research and Development Authority (BARDA), supported preclinical and clinical research to develop several antibody-based therapeutics as anthrax antitoxins. One such product is Anthim, a human monoclonal antibody produced by Elusys Therapeutics, Inc. Anthim is intended to be used as an intravenous treatment for patients with inhalation anthrax and to prevent disease after exposure to inhaled anthrax spores.

NIAID supported the preclinical and clinical development of Anthim through both grants and contracts several resources. Initially, NIAID worked with Elusys to develop a scalable process and produce a large quantity of a stable formulation of Anthim. The antibody was evaluated in animal models and demonstrated efficacy and, in small-scale clinical trials, was shown to be safe for humans. NIAID then advanced the development of Anthim by supporting the manufacture of several pilot lots. Following the success of these efforts, BARDA awarded Elusys an advanced development contract to support final development stages.

In 2016, the Food and Drug Administration approved Anthim for the treatment of inhalational anthrax in combination with appropriate antibacterial drugs, and for the prevention of inhalational anthrax when alternative therapies are not available or not appropriate.

Color-enhanced scanning electron micrograph shows inhalational anthrax; featured are rod-shaped bacilli (yellow) and an erythrocyte (red).
Credit: NIAID

Fighting Fire With Fire: Healthy Bacteria May Help Combat Infection

There are many types of bacteria in and on the human body: some cause illness while others have positive effects like aiding our digestion or producing anti-inflammatory compounds. In the vagina, healthy bacteria are thought to provide a protective barrier against unwelcome pathogens, and researchers are currently working on defining the other roles these bacteria might play.

Although there is still much to be learned about healthy vaginal flora, we do know that an infection called bacterial vaginosis (BV) can occur when the normal balance of bacteria in the vagina is disrupted. Many women with BV do not have any symptoms, but some women experience pain, itching, odor, or burning of the vagina. Once diagnosed through laboratory tests, BV can be treated with antibiotics. Unfortunately, BV can recur in many women even after successful treatment. In addition, antibiotics can destroy healthy bacteria and therefore may eliminate the microbial defense system that healthy bacteria provide. This means that women with BV have an increased risk for contracting sexually transmitted infections, such as chlamydia, gonorrhea, and HIV. Pregnant women with BV are also at higher risk of preterm birth and other obstetric complications.

In order to reestablish healthy vaginal flora, an NIAID-supported research company called Osel has developed a novel product called LACTIN-V. LACTIN-V consists of a selected strain of Lactobacillus crispatus, one of the bacteria that protect the vagina from invading pathogens, that has been freeze-dried and formulated as a powder. When inserted into the vagina using a specially designed applicator, LACTIN-V helps reestablish the population of these beneficial bacteria. In early studies, LACTIN-V was shown to be safe and well-tolerated. Women who used LACTIN-V and became vaginally colonized with Lactobacillus crispatus had a lower rate of BV reinfection than those who didn't. LACTIN-V has also been shown to reduce the recurrence of urinary tract infections (UTIs) in women with a history of UTIs. Further clinical trials are currently underway and are helping to build toward FDA approval. If successful development continues, this new product could be a significant advance in BV treatment and in women's health overall.

Fluorescent photomicrograph of a human vaginal biopsy from a healthy individual showing Lactobacillus (rods stained green) adhering to epithelial cells (nuclei stained red).
Credit: Mark Pasmore and William Costerton/ Montana State University. Reproduced with permission from The Journal of Clinical Investigation.

A Novel Vaccine and Therapeutic for Hendra and Nipah Viruses

Hendra virus is an emerging virus that was first discovered in 1994 in Australian horses. Hendra occurs naturally in bats, which can transmit the virus to horses. All human cases of Hendra viruses have occurred following direct exposure to infected horses. Although Hendra infection is rare in people, 57 percent of individuals with confirmed Hendra infection have died, and some survivors have lasting neurological effects.

Nipah virus is a close relative of the Hendra virus and also causes fatal infections in animals and humans. Like Hendra, Nipah is carried by bats, which can transmit the virus to pigs and humans. Nipah has infected humans who have had close contact with infected pigs or bat secretions and can spread from person to person through close contact. There have been more than a dozen Nipah virus outbreaks to date, with most occurring in Bangladesh. Human case fatality rates have been between 40 and 100 percent. Due to the high mortality rate of Hendra and Nipah infection, and the sporadic and unpredictable nature of outbreaks, effective therapeutics and vaccines are needed.

NIAID-funded researchers at the Uniformed Services University of the Health Sciences (USU) and their collaborators at the National Cancer Institute discovered a potential antibody treatment for Nipah and Hendra virus. The researchers developed a human monoclonal antibody (mAb) known as m102.4 that targets the G glycoprotein of both viruses and found that the mAb effectively protected ferrets after exposure to Nipah or Hendra virus. The mAb was also effective in protecting nonhuman primates after exposure. This nonhuman primate model for Nipah and Hendra was developed with NIAID support by the United States Army Medical Research Institute for Infectious Diseases (USAMRIID), the NIAID Rocky Mountain Laboratories, and the University of Texas Medical Branch. NIAID preclinical services have been used to evaluate m102.4 in tissue culture, create a method to produce the mAb, and improve mAb formulation and stability.

After exposure to Hendra through infected horses, several people in Australia received the therapeutic (under emergency use authorization) with no adverse effects. The Australian government is currently manufacturing and stockpiling mAb m102.4 to use during future outbreaks, and has recently evaluated it in a Phase I clinical trial. The results of this trial showed that m102.4 was safe and well-tolerated, supporting the use of this mAb in humans following high-risk exposure to Nipah or Hendra viruses.

NIAID’s Partnerships program has also supported the development of a Hendra vaccine for horses. Vaccinating horses against Hendra will help to prevent them from becoming infected with the deadly virus and is expected to prevent horse-to-human virus transmission. NIAID-funded researchers at USU created the vaccine using one of the Hendra virus proteins (sG) that is essential for infection. The vaccine was evaluated using the same nonhuman primate model supported by NIAID and used to test the mAb. After further testing in animal models, USU researchers partnered with Pfizer Animal Health and Australia's Commonwealth Scientific and Industrial Research Organization to produce the vaccine for horses. In November 2012, Equivac® HeV became the world's first commercially available Hendra vaccine for horses and has been shown to protect experimentally infected cats, ferrets, and monkeys against Nipah virus.

Ongoing studies funded by the NIAID Centers of Excellence for Translational Research involve extending the therapeutic window of m102.4, isolation of pan-henipavirus mAbs and antibody cocktails which neutralize both Nipah and Hendra viruses, and the development of a vaccine for use in humans. NIAID-funded researchers have demonstrated that the vaccine protects monkeys from Nipah and Hendra virus infection, an important first step for future use in humans

Bats, such as the flying fox, have been identified as reservoirs of several infectious diseases.
Credit: J. Epstein copyright EcoHealth Alliance 2013