Develop Tools to Tackle Antibiotic-Resistant Gram-Negative Bacteria

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In response to the alarming increase of drug-resistant Gram-negative bacteria, NIAID has put out a notice of funding opportunity (NOFO) Partnerships for the Development of Tools to Advance Therapeutic Discovery for Select Antibiotic-Resistant Gram-Negative Bacteria (R01, Clinical Trial Not Allowed)

Gram-negative bacterial pathogens such as carbapenem-resistant Acinetobacter, carbapenem-resistant Enterobacterales (CRE), and multidrug-resistant (MDR) Pseudomonas aeruginosa pose grave risks to public health, especially due to the lack of effective therapeutic options to treat some of these infections—an issue that’s exacerbated by the scarcity of novel compounds effective against antimicrobial resistant (AR) and MDR Gram-negative bacteria in the discovery and development pipeline.  

Research Objectives and Scope 

The objective of this NOFO is to support milestone-driven projects focused on developing and utilizing novel predictive models, assays, tools, or platforms aimed at gaining a better understanding of the rules and compound properties that govern the penetration and efflux of drug-like small molecules into Gram-negative bacterial pathogens. This NOFO also encourages the preclinical development of novel Gram-negative antibacterial therapeutics based on the tools and models hereby developed. 

Note that applications must focus on one or more of the following Gram-negative bacterial pathogens: carbapenem-resistant Acinetobacter, CRE, and MDR Pseudomonas aeruginosa. Projects should complete assay/tool/model development prior to the end of the third year of the project period and initiate discovery activities to demonstrate its utility in supporting a corresponding medicinal chemistry program to generate a lead chemical series with demonstrated activity against one or more targeted Gram-negative bacteria. This NOFO also encourages subsequent preclinical development of a promising lead antibacterial. 

Given the complex challenges of this research, this initiative encourages applications from multidisciplinary teams composed of relevant experts in areas such as bacterial physiology, microbiology, bacterial membrane biology, medicinal chemistry, pharmacology, computation, and specialized technologies. It also encourages close collaboration between academic and industry partners to optimally combine innovative basic science with drug discovery expertise and proper access to compound libraries more typically available from industry. In addition, we recommend collaboration with the NIAID Chemistry Center for Combating Antibiotic-Resistant Bacteria (CC4CARB) for completion of project relevant medicinal chemistry tasks. 

Refer to the NOFO for examples of assay and model development activities.  

NIAID will consider applications including the following to be nonresponsive and not review them: 

  • Projects that do not focus on at least one select Gram-negative pathogen (carbapenem-resistant Acinetobacter, carbapenem-resistant Enterobacterales, or MDR Pseudomonas aeruginosa). 
  • Projects focused only on Gram-positive bacteria or Mycobacterium tuberculosis.
  • Projects that do not focus on penetration and efflux of small molecules.
  • Applications not containing a Milestone and Timeline attachment.
  • Applications proposing clinical trials.
  • Research on HIV/AIDS. 

Award and Deadline Information 

The application due date for this NOFO is August 20, 2024. NIAID plans to fund seven to nine awards.  

Application budgets are not expected to exceed $750,000 in annual direct costs. The scope of your project should determine the requested project period, but note that the maximum project period is 5 years.  

Applications must also include a “Milestones and Timeline” attachment under “Other Attachments”. This attachment must not exceed five pages and should provide: 

  • A clear description of all interim objectives (research and/or developmental milestones) to be achieved during the project. Applicants should highlight potential impediments that could require a revision in the work plan or milestones, with a discussion of alternative approaches. 
  • Detailed quantitative criteria by which milestone achievement will be assessed. 
  • A detailed schedule or timeline for the anticipated attainment of each milestone and the overall goal(s). 

Applicant organizations may submit more than one application, provided each application is scientifically distinct.  

Contacts 

For questions related to your application, contact Dr. Zuoyu Xu at xuzuoyu@niaid.nih.gov or 240-627-3394. For peer review questions, contact Dr. Maryam Feili-Hariri at haririmf@niaid.nih.gov or 240-669-5026.

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Championing Asthma Research to Reduce the Burden of Disease

NIAID Now |

Nearly 25 million people in the United States have asthma, including 4.7 million children and adolescents. Almost 10 percent of these individuals had one or more asthma attacks within the past 12 months. Asthma can cause coughing, wheezing, chest tightness, and shortness of breath. In severe cases, breathing becomes extremely difficult. Worsening asthma can lead to missed time at school and work, emergency room visits, and even death.

Today on World Asthma Day, NIAID reaffirms its commitment to reducing illness from this chronic lung syndrome and improving quality of life for people with asthma through research that informs the development of new asthma prevention and treatment strategies. NIAID-funded studies in children and adolescents recently uncovered new risk factors for asthma and a previously unreported cause of frequent, severe asthma attacks. In addition, two new NIAID-supported studies aim to further asthma therapeutics development by shedding light on the behavior of airway-cell genes and proteins involved in regulating asthma severity and by defining poorly understood causes of airway inflammation in underserved youth with the disorder. Learn more about these recent research highlights below.

Asthma Risk Factors 

Nearly a third of infants who are hospitalized with a severe form of a common childhood lung infection called bronchiolitis develop asthma later in childhood. Predicting which infants with severe bronchiolitis are at highest risk for asthma, understanding why, and developing effective interventions remain challenges. Investigators from the NIAID-supported 35th Multicenter Airway Research Collaboration (MARC-35) recently identified genetic factors that may underlie the bronchiolitis–asthma link.

  • Environmental exposures such as tobacco smoke are known to modify the function of certain genes in people, potentially resulting in long-term health effects. In one study, MARC-35 researchers examined such modifications by analyzing DNA in nasal swabs from 625 infants hospitalized with bronchiolitis. The scientists found that the genomes of some infants with severe bronchiolitis had modifications potentially caused by environmental exposures in the uterus or after birth, and these changes were associated with increased risk for asthma later in childhood. Now investigators want to identify which exposures had this detrimental effect.
  • In a second study, MARC-35 researchers focused on small molecules called microRNAs, which derive from DNA and help control the genetic information that directs the building of proteins. The scientists analyzed microRNAs in nasal-swab DNA from 575 children who were hospitalized with bronchiolitis in infancy and followed until 6 years of age. The investigators identified 23 microRNAs that were turned on or off to different extents in the children who developed asthma by age 6 compared to those who did not. Now scientists want to identify what is triggering these differences and how to block them to reduce asthma risk.

Other investigators from the NIAID-funded Urban Environment and Childhood Asthma (URECA) study linked the composition of all the microbes found in the nose—the nasal microbiota—at age 3 years to respiratory health profiles ranging from high to low risk for developing asthma by age 7 years. The scientists also found that both exposure to certain microbes in house dust during infancy and a genetic predisposition to developing allergic diseases later in childhood influence how the airway microbiota develops. 

Therapeutic Insights

Scientists in NIAID’s Laboratory of Allergic Diseases recently demonstrated that a protein called RSG4 in smooth muscle cells of airway walls affects asthma severity in part by regulating airway inflammation independent of so-called G proteins. This finding builds on the lab’s 2020 discovery that blocking RSG4 in a mouse model of asthma reduced a key feature of the disease called airway hyper-responsiveness. This is a heightened sensitivity to molecules that activate smooth muscle cells in airway walls, leading to excessive airway constriction. Together the findings suggest that RSG4 in these cells could be a therapeutic target for asthma.

NIAID-supported researchers discovered recently that structural changes to nerve-cell networks in upper-airway tissues underlie asthma attacks in children who are hospitalized due to these attacks more than once a year. This contrasts with asthma attacks in children who are hospitalized less frequently, as those attacks are characterized by immune-system activity like allergic inflammation and responses to infections. The new findings, reported by the Ohio site in the NIAID-funded Childhood Asthma in Urban Settings (CAUSE) network, suggest that preventing and treating frequent severe asthma attacks in children may require an untraditional approach that targets the nervous system.

The CAUSE network also launched a new study in April 2024 to improve understanding of how airway inflammation influences asthma severity at a cellular and molecular level in children and adolescents who live in low-income urban communities. Airway inflammation in asthma may be categorized as related to a “type 2” immune response, which also plays a role in allergic diseases, or a non-type 2 immune response. The new study aims to define the cellular and molecular mechanisms associated with each type of airway inflammation in severe asthma to identify potential targets for new therapies.

NIAID thanks the hundreds of study participants and their caregivers who made these research advances possible and who help scientists continue to illuminate the complex and varied nature of asthma to reduce the burden of this disease.

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Examine Impact of Hormone Regimens on Treatment and Prevention for HIV and Co-Infections

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NIAID, alongside several partnering NIH institutes and centers (ICs), will support studies that examine the impact of hormone therapy and antiretroviral drugs (ARVs) on treatment and prevention methods of HIV and other sexually transmitted infections (STIs) through the notice of funding opportunity (NOFO) Interaction Between ARVs and Hormones in HIV and Co-Infections (R01, Clinical Trial Optional).  

While data increasingly suggests that gender-affirming hormone therapy (GAHT) may impact the effectiveness and implementation of these treatments, several factors in transgender populations such as variability in GAHT regimens, use of auxiliary drugs, and access to participants and datasets present research challenges. However, recent studies showing the recruitment and retention of participants undergoing GAHT offer a chance to expand on this research. 

NIAID Research Objectives and Scope 

NIAID will support projects investigating the following in participants 18 years of age and above: 

  • The impact of GAHT on biomedical regimens used for HIV prevention or treatment and/or co-infections with other STIs. 
  • Studies of pharmacokinetics/pharmacodynamics, including metabolism, and drug-drug interactions between GAHT and ARVs. 
  • Development of new models (in vitro, ex vivo, in vivo, and in silico) to study the impact of GAHT on the immunology, pharmacology, and safety/efficacy of HIV prevention and treatment regimens and/or co-infections with other STIs. 
  • The impact of feminization and masculinization regimens on the gastrointestinal (GI) and urogenital mucosa and their role in HIV and STI susceptibility, infection, and acquisition. 
  • Hypothesis-driven “omic” studies (e.g., metabolomic, proteomic, transcriptomic, microbiome) and the use of systems biology tools to characterize the impact of the feminizing and masculinizing hormones on HIV susceptibility, risk, and transmission including in the GI and urogenital tracts. 
  • Studies on the determination of active levels of GAHT to address potential variations related to diverse sources of external hormones and various physiological as well as pathophysiological conditions. 

NIAID will support clinical studies to evaluate how GAHT impacts the effectiveness of biomedical HIV prevention or treatment strategies or co-infections with other STIs. Such studies should include appropriate sampling and pharmacokinetic (PK) analysis to determine potential drug-drug interactions that may alter the preventive or therapeutic threshold for treatment or prevention. 

Review the NOFO to learn more about the priority research areas of our partnering ICs.  

We will consider nonresponsive and not review applications including the following types of studies: 

  • Focused solely on prevention/treatment of STIs (do not include HIV). 
  • Do not address the intersection of GAHT on prevention or treatment of HIV. 
  • “omic” surveys of mucosal tissues in the absence of GAHT. 
  • New drugs or drug delivery systems to prevent infection of HIV or STIs. 
  • Efficacy of regimens to achieve gender reassignment. 
  • Development of new drugs or surgical processes to achieve gender reassignment. 
  • Focused solely on the role of social and behavioral factors in susceptibility to HIV and STIs. 
  • Early phase clinical trials for new prevention, therapeutic, or diagnostic products in adults (i.e., clinical studies to support a new drug application). 
  • Studies that have safety, clinical efficacy, clinical management, and/or implementation goals in adults. 

Award and Deadline Information 

The application due date is July 30, 2024.  All applications are due by 5:00 p.m. local time of applicant organization.  

While application budgets are not limited, they will need to reflect the actual needs of the proposed project. Similarly, scope of the project should determine the project period, but note that the maximum requested project period is 5 years.  

Contacts

For questions related to your application, contact Cherlynn Mathias at cmathias@mail.nih.gov. For peer review questions, contact Dr. Vishakha Sharma at vishakha.sharma@nih.gov.

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The HIV Field Needs Early-Stage Investigators (VIDEO)

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by Jeanne Marrazzo, M.D., M.P.H., NIAID Director

The HIV research community is led by scientists with deep personal commitments to improving the lives of people with and affected by HIV. Some researchers, like me, have pursued this cause since the start of the HIV pandemic, growing our careers studying HIV from basic to implementation science. Our collective decades of work have generated HIV testing, prevention and treatment options beyond what we could have imagined in the 1980s. Those advances enable NIAID to explore new frontiers: expanding HIV prevention and treatment modalities, increasing understanding of the interplay between HIV and other infectious and non-communicable diseases, optimizing choice and convenience, and building on the ever-growing knowledge base that we need to develop a preventive vaccine and cure. The next generation of leaders will bring these concepts to fruition, and we need to welcome and support them into the complex and competitive field of HIV science.

Click below for a video in which NIAID grantees and I discuss the value and experience of early-stage HIV investigators (the audio described version is here):

NIAID wants to fund more new HIV scientists and we have special programs and funding approaches to meet that goal. This week, the NIH Office of AIDS Research will host a virtual workshop on early-career HIV investigators tomorrow, April 24, and NIAID will host its next grant writing Webinars in MayJune, and July.

For more information about programs and support for new and early-stage investigators as well as people starting to implement their first independent grant, visit these NIAID and NIH resources: 

Information for New Investigators (NIAID)

HIV/AIDS Information for Researchers (NIAID)

OAR Early Career Investigator Resources (NIH)

Resources of Interest to Early-Stage Investigators (NIH)

Early Career Reviewer Program (NIH)

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Sexually Transmitted Infections—A Closer Look at NIAID Research

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Sexually transmitted infections (STIs) are caused by bacteria, viruses, or parasites. STIs have a devastating impact on adults and infants and annually affect millions of people in the United States. Certain STIs can increase a person’s risk of developing cancer and increase the likelihood of acquiring or transmitting HIV. In addition, STIs can cause long-term health complications, especially in the reproductive and central nervous systems. In rare cases, they can lead to serious illness or death. 

NIAID supports research across the spectrum from basic to clinical science to develop effective diagnostic, preventive and therapeutic approaches to STIs in alignment with the National STI Strategic Plan. In recognition of National STI Awareness Week, NIAID shares a snapshot of new projects and recent scientific advances in STI research. 

Improving treatment for syphilis and trichomoniasis

New reports of syphilis and congenital syphilis are increasing at an alarming rate in the United States. Syphilis is caused by the bacterium Treponema pallidum. Benzathine penicillin G (BPG) is one of only a few antibiotics known to effectively treat syphilis. There is currently a shortage of BPG, and some people are allergic to penicillin antibiotics. In February 2024, NIAID convened a workshop with a wide range of experts on alternative therapies to BPG for the treatment of adult syphilis, neurosyphilis, and syphilis in pregnant persons and infants. The workshop addressed preclinical evaluation of candidate drugs, the potential need for studies on how candidate drugs are processed in the body during pregnancy, and how to approach clinical trials of treatment for congenital syphilis. This work is part of NIAID’s comprehensive portfolio of syphilis diagnosis, prevention, and treatment research. 

Trichomoniasis is the most common parasitic STI, caused by Trichomonas vaginalis. Trichomoniasis can increase the risk of getting or spreading other STIs, including HIV. The parasite can also cause inflammation of the cervix and the urethra. T. vaginalis is treated with an antibiotic drug class called nitroimidazoles. The currently recommended nitroimidazole, called metronidazole, cures 84-98% of T. vaginalis cases but does have high rates of breakthrough infection. A new project led by Tulane University will examine a single dose of secnidazole, a medicine in the same drug class, as a more effective and cost-effective treatment option for women and men. 

Developing a vaccine for herpes simplex virus 2

Herpes simplex virus 2 (HSV-2) is a common subtype of herpes simplex virus that is transmitted through sexual contact. The Centers for Disease Control and Prevention estimates that 18.6 million people aged 15 years and older United States live with HSV-2. In severe cases, HSV-2 may lead to life-threatening or long-term complications. There is no licensed preventive HSV-2 vaccine, and there is no cure. A new project led by the University of Pennsylvania seeks to define correlates of protection for HSV-2, meaning they intend to identify immune processes involved in preventing HSV-2 disease. They will do this by analyzing laboratory samples from animal studies of a promising preventive vaccine candidate that they developed with prior funding. That vaccine candidate is also now in an industry-sponsored early-stage clinical trial. The same project will expand on the HSV-2 targets in the preventive vaccine to develop a therapeutic vaccine concept to reduce recurrent outbreaks. This research responds to the scientific priorities in the NIH Strategic Plan for Herpes Simplex Virus Research.

Increasing fundamental knowledge of bacterial vaginosis 

Bacterial vaginosis (BV) results from an imbalance in the vaginal microbiome. BV can be caused by sexual activity, douches and menstrual products. BV can increase women’s biological susceptibility to HIV and other STIs and can cause premature birth or low birthweight if untreated in pregnant people. In a recent publication, NIAID-supported researchers, led by researchers at the University of Washington and University of California San Diego, shared findings on how damage to the vaginal skin barrier occurs during bacterial vaginosis. Those skin barrier cells, called epithelial cells, are covered in carbohydrate molecules called glycans. The research team found that people with BV had damaged glycans on their vaginal epithelial cells. They suggested that future work should examine the relationship between treatment and restoration of normal glycans. If an association is detected, it could help healthcare providers monitor for successful treatment outcomes to reduce the likelihood that BV will return after a course of treatment. The findings were published in Science Translational Medicine

These activities are among the research investments in NIAID’s STI portfolio. For more information on STIs, please visit:

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NIH Ending the HIV Epidemic Projects Bridge Gaps Between HIV Research and Public Health Practice (VIDEO)

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The National Institutes of Health recently issued $26M in awards to HIV research institutions in its fifth year supporting implementation science under the Ending the HIV Epidemic in the U.S. (EHE) initiative. These awards are the latest investments in a program that is rapidly and rigorously generating evidence to inform the unified domestic HIV response by agencies in the Department of Health and Human Services. 

The EHE initiative aims to achieve a 90% reduction in the number of new HIV infections in the United States by 2030. Since the initiative was announced in 2019, NIH has contributed by supporting implementation science projects through its network of Centers for AIDS Research (CFAR) and the National Institute of Mental Health (NIMH) AIDS Research Centers (ARC). CFARs are co-funded by 11 NIH institutes and centers (ICs), including the National Institute of Allergy and Infectious Diseases (NIAID). NIH ICs provide scientific stewardship to participating institutions in collaboration with the Fogarty International Center and the NIH Office of AIDS Research, which coordinates the NIH HIV research program across the agency. CFAR and ARC-affiliated investigators conduct research in jurisdictions that are disproportionately affected by HIV, and many of the CFAR and ARC member institutions are based in these communities. 

VIDEO: Jeanne Marrazzo, M.D., M.P.H., NIAID Director, discusses NIH’s role in the EHE (audio description version here):

NIH EHE projects enable academic institutions to partner with state and local leaders to jointly translate implementation research findings into improved delivery of HIV testing, prevention, treatment, and response services for priority populations and in priority geographic areas. Projects funded this year are designed to increase and share available knowledge on locally appropriate strategies to: 

  • detect and respond to HIV “clusters,” i.e., groups of people and communities experiencing rapid HIV transmission;
  • leverage pharmacies as HIV service locations; 
  • ensure uninterrupted HIV care for people returning to their communities following incarceration; and
  • develop approaches that address intersecting diseases and conditions that exacerbate health inequities and impact HIV outcomes, including such as viral hepatitis, sexually transmitted infections, and substance use and mental health disorders.

Since Fiscal Year 2019, NIH has funded 253 projects across 50 geographic areas prioritized by EHE. The latest EHE awards to CFARs and ARCs support 47 projects, 8 implementation science hubs, and 1 coordinating center. Hubs provide technical support, coaching, training, and consultative services to funded EHE research teams. The coordinating center provides infrastructure for collaboration and sharing best practices in HIV implementation science. In addition to the CFAR/ARC supplements, NIH supported multiple larger research projects in 2023, including 3 R01 awards, 2 R34 awards, and 1 coordinating center. In September 2023, NIH released a Notice of Special Interest to solicit project proposals from independent investigators for Fiscal Year 2024.

EHE Project Spotlights

The knowledge generated by NIH EHE projects is reviewed with HHS EHE partners to accelerate learning and program improvement. Two projects below illustrate how EHE implementation science projects have already enhanced locally tailored HIV service delivery:

Miami, Florida

Miami-Dade County, Florida has one of the highest rates of HIV incidence in the United States, and yet use of pre-exposure prophylaxis (PrEP) to prevent HIV acquisition remains relatively low. Researchers at the University of Miami, in collaboration with the Florida Department of Health (DOH) and a local community-based organization called Prevention305, developed a process to apply real-time DOH epidemiologic data to prioritize new geographic locations for placement of their mobile PrEP clinics. In collaboration with community partners, the project developed a new outreach approach: “Test-to-PrEP,” in which people using PrEP are engaged to distribute free HIV self-tests and PrEP referrals through their social networks. They have worked with 100 current PrEP clients to engage members of their social network with information about PrEP provide them with HIV self-tests. More than one third of the 117 HIV self-test kit recipients who confirmed they used the test reported they had not previously known about PrEP. Self-reported knowledge and likelihood to use PrEP increased significantly after kit receipt. PrEP clients also reported feeling comfortable with the distribution and enthusiastic about the strategy. Their work has provided a blueprint for mobile HIV prevention and related services as a strategy to interrupt further transmission.

Group of people standing together looking at the camera, under a large tent.

Mobile clinic service team in the Liberty City neighborhood of Miami, Florida

Credit: University of Miami

Shelby County, Tennessee

Rural areas like Shelby County pose distinct challenges to HIV service delivery, including a lack of outpatient providers and fragmented health care and social services, as well as stigma and medical mistrust. To overcome these barriers, researchers from University of Massachusetts, Lowell, in collaboration with the University of Memphis and the Shelby County Health Department, used an implementation research approach to adapt and provide an evidence-based training and capacity-building program in HIV care for existing community health workers (CHWs), with input from HIV care providers, people with HIV, and CHWs. CHWs are frontline public health workers who are also members of the community they serve. The team has trained 67 CHW to support HIV care across eight agencies and has provided coaching sessions to supervisors around how to sustain this workforce. They are assessing the sustainability and effectiveness of this program in addressing service gaps and improving health outcomes through follow-up surveys with health care agency staff and county health leaders. 

A person stands next to a large paper with handwritten text that has been posted on a wall, and points to the text while speaking.

Community health worker Michelle Anderson discussing culturally relevant care HIV care with colleagues in Memphis, Tennessee.

Credit: University of Massachusetts, Lowell

In addition to NIH, HHS agencies and offices participating in EHE include the Centers for Disease Control and Prevention; the Health Resources and Services Administration; the Indian Health Service; the Office of the Assistant Secretary for Health; and the Substance Abuse and Mental Health Services Administration. 

To view a complete list of NIH research projects supported with EHE initiative funding, please visit the awards page

To learn more about EHE, please visit HIV.gov.

 

Reference: 

Butts, SA et al. Addressing disparities in Pre-exposure Prophylaxis (PrEP) access: implementing a community-centered mobile PrEP program in South Florida. BMC Health Services Research. DOI 10.1186/s12913-023-10277-1 (2023).

Johnson, AL et al. “Test-To-PrEP”: Assessing Reach and Adoption of a New Approach to Increase HIV Testing and PrEP Knowledge Using HIV Self-Test Kit Distribution Through PrEP Clients' Social Networks. Journal of Acquired Immune Deficiency Syndromes. DOI 10.1097/QAI.0000000000003294 (2023). 

Rajabiun, S et al. Using Implementation Science to Promote Integration and Sustainability of Community Health Workers in the HIV Workforce. Journal of Acquired Immune Deficiency Syndromes. DOI 10.1097/QAI.0000000000002966 (2023).

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NIAID Renews Consortium for Food Allergy Research in Its 19th Year

NIAID Now |

NIAID has awarded 11 new cooperative agreements to support the Consortium for Food Allergy Research, or CoFAR, in the latest renewal of the program since its establishment 19 years ago. The institute expects to fund the awards with more than $11 million annually for seven years, contingent upon the availability of funds. 

CoFAR’s goal is to conduct groundbreaking clinical research on food allergy prevention and therapy and on the biological mechanisms underlying food allergy. Conducting clinical research with a consortium of multiple study sites enables investigators to pursue questions that can only be answered through the participation of high numbers of study volunteers. Consortia also can potentially recruit a more diverse set of study participants than any single site could. 

Most recently, CoFAR’s OUtMATCH clinical trial found that treatment with omalizumab (Xolair) substantially increased the amount of peanut, tree nuts, egg, milk and wheat that multi-food allergic children as young as 1 year could consume without experiencing an allergic reaction. The Food and Drug Administration approved Xolair for people with food allergy based on the study findings. 

The new awards will support consortium-wide clinical research projects, which may include treatment or prevention clinical trials. The selection process for these consortium-wide projects began in March 2024. The awards also will support local food allergy-related clinical studies conducted by individual CoFAR sites and the completion of the remaining stages of the OUtMATCH trial. 

The awards have been issued to the following institutions as one leadership center and ten clinical research centers:

Leadership Center

Johns Hopkins University (JHU) 

Principal Investigators: Robert A. Wood (JHU); Supinda Bunyavanich and Scott H. Sicherer (Icahn School of Medicine at Mount Sinai) 
Grant number UM1-AI182034-01

Clinical Research Centers

Arkansas Children's Hospital Research Institute 

Principal Investigator: Stacie M. Jones 
Grant number U01-AI181962-01

Boston Children's Hospital 

Principal Investigator: Rima Rachid 
Grant number U01-AI181964-01

Cincinnati Children's Hospital Medical Center 

Principal Investigators: Amal Halim Assa’ad, Marc E. Rothenberg 
Grant number U01-AI181966-01

Icahn School Of Medicine at Mount Sinai 

Principal Investigator: Scott H. Sicherer 
Grant number U01-AI181883-01

Johns Hopkins University  

Principal Investigator: Robert A. Wood 
Grant number U01-AI182032-01

Northwestern University at Chicago 

Principal Investigators: Ruchi S. Gupta, Maria Cecilia Berin 
Grant number U01-AI181897-01

Stanford University 

Principal Investigators: Sayantani B. Sindher, R. Sharon Chinthrajah  
Grant number U01-AI182039-01

University of Michigan at Ann Arbor 

Principal Investigators: James R. Baker, Johann Eli Gudjonsson, Charles F. Schuler 
Grant number U01-AI181882-01

University of North Carolina Chapel Hill 

Principal Investigators: Edwin Kim, Corinne Keet 
Grant number U01-AI182033-01

Vanderbilt University Medical Center 

Principal Investigators: Leonard B. Bacharier, Rachel Glick Robison 
Grant number U01-AI181927-01

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Portia Gough, Ph.D.

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Host Microbe Symbiosis Unit
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Program Description

It is well known that the microbiome plays a role in almost every aspect of human physiology, yet much remains to be understood about the specific mechanisms of how commensal microbes affect human cellular function. The Host Microbe Symbiosis unit focuses on such mechanisms, with a particular focus on innate immune signaling and homeostasis at barrier sites such as the skin. Although the immune system likely expends most of its energy interacting with the multitude of organisms that occupy the human body, our knowledge of these interactions and how they influence the function of the immune system remains fairly limited. 

As allergic and autoimmune diseases and antibiotic-resistant infections become more common, it becomes increasingly necessary for us to better understand how commensal microbes shape immunity and homeostasis. The overarching principle of our research is that commensal organisms influence innate immune signaling at barrier sites via interactions with epithelial and immune cells and direct competition with pathogens. Therefore, understanding both the signaling between commensals and human cells and microbial interspecies interactions can lead to the development of targeted microbial therapeutics that reduce susceptibility to infection and maintain optimal function of barrier sites in the body. 

One such targeted microbial therapeutic is Roseomonas mucosa. This commensal skin bacteria was developed as a topical probiotic for atopic dermatitis by Dr. Ian Myles, also of the Laboratory of Clinical Immunology and Microbiology. R. mucosa serves as a model for how microbes can be used to effectively treat dysbiotic disease and restore optimal function to the skin, and it is the focus of our research thus far in the Host Microbe Symbiosis Unit. Our research is defining the mechanisms by which R. mucosa mediates immune regulation and supports homeostasis of the skin, particularly through its interaction with TLR5 and its bacteriostatic effects on Staphylococcus aureus. These studies provide a framework for future studies of other host-commensal interactions.  

The main techniques utilized in our study of host-commensal interactions are in vitro modeling with primary human cells, mouse models, quantitative proteomics, and various immunoassays to evaluate the interaction in three areas: initial contact of the microbe with host tissue (adhesion), downstream signaling from the activated receptor (e.g., TLR5), and the outcomes of the activated signaling pathway (cytokine, chemokine, antimicrobial peptide production, cell proliferation). A particular focus of the lab is that the downstream effects of interaction between commensal bacteria and TLRs appear to differ from the activation of TLRs by pathogen-derived ligands in a way that likely fine-tunes inflammatory responses for the host.  

Selected Publications
Major Areas of Research
  • Host-microbe interactions
    • Role of commensal bacteria in homeostasis 
    • Toll-like Receptor (TLR) signaling in interactions with commensal bacteria 
    • Effects of microbiota in innate immune regulation at barrier sites 
    • Protective effects of microbiota during infection

A Change in Drug Regimen is Associated with Temporary Increases in Dormant HIV

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Switching to an antiretroviral therapy (ART) regimen containing the drug dolutegravir was associated with a significant temporary increase in reservoirs of latent HIV, according to a new analysis from a study in Uganda. HIV reservoirs are cells where HIV lies dormant and cannot be reached by the immune system or ART. They are central to HIV’s persistence, preventing current treatments from clearing the virus from the body. The findings were published today in eBioMedicine.

When taken as prescribed, ART can stop HIV from replicating. The different classes of available antiretroviral drugs (ARVs) interrupt different stages of HIV replication. People are often prescribed drug regimens composed of multiple drug classes to increase the likelihood that ART will fully suppress HIV replication. In 2018, many countries began using dolutegravir-based ART regimens following studies that showed the drug had higher efficacy and fewer side effects than the drugs that had been in use previously. Uganda was among these countries and recommended dolutegravir together with the ARVs tenofovir and lamivudine for all people whose HIV was treatable with those drugs.

In 2015, NIH scientists and researchers from the Rakai Health Sciences Program in Uganda began a longitudinal study of reservoirs among people with HIV in the Rakai and Kyotera Districts in Uganda. Study participants were people whose HIV was suppressed by ART and had agreed to provide blood samples and receive a routine physical examination annually. People meeting study entry criteria continued to enroll each year. As part of this study, the team examined whether the introduction of dolutegravir-based regimens in 2018 had any effect on the makeup of HIV reservoirs in study participants. At the time of the published analysis, 63% of participants were female. The study observed that HIV reservoir size was generally decreasing as participants remained virally suppressed for longer periods. In the analysis of samples provided post-dolutegravir introduction, they observed a surprising 1.7-fold average increase in HIV reservoir size above pre-dolutegravir levels, which lasted for approximately a year, then returned to normal. This effect was consistent across the majority of study participants regardless of how long they had been living with HIV. 

According to the study authors, no other study has found significant differences in HIV reservoir characteristics due to ART regimen changes, but previous research has identified changes in immune characteristics and cardiovascular disease risk, as well as other effects in the period after dolutegravir initiation, suggesting the body goes through a period of adjustment when switching to use the new drug. The authors state that it is important to explore whether other populations experience the same temporary reservoir increase post-dolutegravir initiation, and that more research is needed to understand the mechanism causing the increase, especially if it is starting dolutegravir or stopping the previous ARV. They further suggest that these findings may inform HIV cure research, including approaches referred to as “Shock and Kill” that attempt to stimulate HIV reservoirs to resume activity, then promptly remove them. The authors did not observe any negative clinical ramifications, such as loss of viral control, associated with this finding.  

Most HIV reservoir research has been conducted among predominantly male study populations in Europe and North America, unlike the primarily female participants in this study. The authors highlight the importance of exploring sex-based differences in HIV reservoir characteristics and the inclusion of representative populations in HIV studies.

This research was conducted by NIAID, Western University, and the Rakai Health Sciences Program and with co-funding from other NIH institutes, the Gilead HIV Cure Grants Program, the Canadian Institutes of Health Research, and the Ontario Genomics-Canadian Statistical Sciences Institute.

Reference:

RC Ferreira, et al., Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen. eBioMedicine DOI: 10.1016/j.ebiom.2024.105040 (2024)

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Centering Women and Girls’ Health in HIV Research

NIAID Now |

Women account for approximately 23 percent of people with HIV in the United States. In recent years, women aged 25 to 34 comprised the highest number of new diagnoses. Furthermore, Black women, transgender women, and women aged 13 through 24 are more likely to experience health disparities associated with lack of access to HIV testing, treatment, and prevention resources. This weekend marked National Women and Girls HIV/AIDS Awareness Day. NIAID supports research programs that focus on HIV and other health outcomes in women to inform and enable more targeted and effective HIV prevention, care, and treatment.

American Women: Assessing Risk Epidemiologically (AWARE) 

The AWARE project aims to explore the multiple risks and vulnerabilities that lead to higher rates of HIV and other sexually transmitted infection (STI) acquisition in women, including transgender women. In the United States, the rate of new HIV diagnoses in Black women is about 14 times higher than their non-Black counterparts, and AWARE is designed to engage diverse racial and ethnic minorities, including Black women. AWARE is a national digital cohort with a primary goal of identifying women with greater likelihood of acquiring HIV and investigating contributing factors. The research group also seeks to design tailored and effective approaches to reaching women who reside in rural and underserved communities of color with HIV prevention and awareness resources. 

CAMELLIA Cohort: A Longitudinal Study to Understand Sexual Health and Prevention Among Women in Alabama 

The CAMELLIA Cohort supports cisgender and transgender women in Alabama who had a recent STI acquisitions and are impacted by disparities surrounding the lack of access to and the utilization of PrEP. The research program also uses a population-based approach to better understand how the quality of HIV and STI testing, in addition to HIV PrEP access, can be improved. CAMELLIA is sponsored by the University of Alabama at Birmingham in collaboration with NIAID and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

HIV and Women at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI)

At CROI 2024, NIAID-supported studies reported results on women-controlled HIV prevention and cardiovascular health in women with HIV:

  • Pregnant people are three times more likely to acquire HIV than those who are not pregnant. The NIAID-sponsored DELIVER study, conducted by the Microbicide Trials Network, showed that the dapivirine vaginal ring and oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine- were each safe for HIV prevention throughout pregnancy. The large clinical study was conducted in Malawi, South Africa, Uganda and Zimbabwe. Learn more about the DELIVER results presented at CROI. 
  • A new analysis from the NIH-supported REPRIEVE trial found that the elevated cardiovascular disease risk among people with HIV is even greater than predicted by a standard risk calculator in several groups, including Black people and cisgender women. The study team concluded that updated tools are needed to facilitate precision, high-quality care of the diverse population with HIV. REPRIEVE enrolled 7,769 people with HIV across 12 countries, of whom 31% were women. Learn more about the REPRIEVE analysis presented at CROI, and the primary analysis that found pitavastatin reduced the risk of major adverse cardiovascular events by 35% in people with HIV. 

 

The NIH Office of AIDS Research (OAR) and Office of Research on Women’s Health (ORWH) jointly lead NIH’s HIV and Women Signature Program. The cornerstone of this new program is an intersectional, equity-informed, data-driven approach to research on HIV and women. The Signature Program advances the NIH vision for women's health, a world in which all women, girls, and gender-diverse people receive evidence-based care, prevention, and treatment tailored to their unique needs, circumstances, and goals. A new position paper, published February 26 in The Lancet HIV, outlines the framework for NIH's approach to research on HIV and women and highlights selected topics of relevance for women, girls, and gender-diverse people with or affected by HIV. The program also supports women in science careers to meet their full professional potential. From March 21-22, the OAR and ORWH will host the NIH HIV & Women Scientific Workshop: Centering the Health of Women in HIV Research. The workshop will review the state of the science on HIV and women to inform the future research agenda. Learn more.

 

The 2024 U.S. government theme for National Women and Girls HIV/AIDS Awareness Day is “Prevention and Testing at Every Age. Care and Treatment at Every Stage.” NIAID remains committed to advancing HIV research and prevention efforts for cisgender and transgender women alike. 

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