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Genomic Surveillance of Mpox through the Development of a Wastewater Intelligence Model and Data Analytics Platform

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National Institute of Allergy and Infectious Diseases (NIAID)

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A critical challenge in pandemic preparedness is the rapid identification of viral outbreak sources and tracking mutations that lead to new variants. Current public health surveillance methods, relying on resource-intensive laboratory testing of patient specimens, often yield incomplete data due to underreporting. The recent mpox outbreak in the Democratic Republic of the Congo—with over 22,000 suspected cases since January 2023 and the emergence of a new strain (clade 1b)—underscores the need for more effective surveillance tools. To address these limitations, we and others have developed wastewater approaches to screen municipal sewage for viral levels and variants. This method capitalizes on the shedding of pathogens like SARS-CoV-2 and mpox into sewer systems through bodily fluids, providing a comprehensive, real-time snapshot of community infection levels and viral evolution. Over the last five years, our team has built and implemented a comprehensive wastewater COVID-19 surveillance program that includes a community engagement responsive element and serves 2.4 million residents and 50 million annual tourists in Southern Nevada. In Summer 2022, we adapted this program to pilot a study tracking the clade IIb mpox outbreak in Las Vegas. Building on these achievements and developing novel reagents for clades I and II, we have a time-sensitive opportunity to test our central hypothesis: that enhanced wastewater surveillance, coupled with new computational tools, can enable rapid detection of mpox variants from both clades, facilitate assessment of antiviral drug efficacy, and inform strategic prioritization of vaccination sites. This high-risk, high-reward proposal extends our previous successful approaches with SARS-CoV-2, influenza, and drug use in wastewater, potentially breaking new ground in mpox research. Our proposal directly responds to the 2022 and 2024 mpox public health emergency of international concern declarations and aligns with NIAID's 2024 mpox research agenda. The identification of even a single mpox outbreak or treatment-resistant strain through our wastewater studies would significantly advance innovative research in genomic epidemiology and public health surveillance, potentially transforming our approach to managing emerging infectious diseases.

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National Institute of Allergy and Infectious Disease

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Multi Parametric Total-Body Imaging of Immune Activation in Post Acute Sequelae of SARS-CoV-2 (PASC)

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National Institute of Allergy and Infectious Diseases (NIAID)

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Post-acute sequelae of SARS-CoV-2 infection (PASC) is a persisting health challenge characterized by a range of symptoms affecting multiple organ systems, which continues to impact approximately 10% of COVID-19 survivors. Multiple, potentially overlapping, mechanisms have been identified that may play a role in PASC. However, with no effective preventative measures or treatments, there is a critical unmet need for understanding the pathophysiology of PASC; as previous studies, often limited by focus on peripheral blood biomarkers only or confined to single organ systems, have not sufficiently and quantitatively investigated the multisystemic and immune-related complexities of this condition in non-blood tissue. The long-term objective of this project is to bridge this knowledge gap by providing insight into the immune and systemic manifestations of PASC, through the innovative use of total-body dynamic positron emission tomography (PET) with the 18F-AraG radiotracer, which particularly offers selectivity towards activated T cells. To achieve this, we will use the dynamic PET images obtained from a high-sensitivity total-body PET scanner to develop, optimize, and validate a kinetic model for 18F-AraG in different anatomical sites and tissue types for multi parametric quantification of uptake. We expect that this will not only improve the quantification accuracy compared to standard static imaging, but also can shed light on the underlying mechanisms of uptake. The multi parametric imaging will be firstly used to identify sites of immunological perturbation in PASC patients, offering a total-body view of tissue-level manifestations of PASC. For this, we will compare the kinetic parameters of different tissues between symptomatic PASC participants and a control group consisting of individuals with a complete COVID-19 recovery. Second, we will integrate the multiparametric imaging data with peripheral blood assays, aiming to assess the correlations between certain 18F-AraG kinetic parameters and biomarkers of inflammation, immune dysregulation, and endothelial dysfunction in peripheral blood. Particularly, to identify vascular alterations in tissue and their association with endothelial markers in blood, we will use vascular permeability modeling to estimate the blood flow in different tissues from the early frames of the kinetic data. Third, we will employ a longitudinal design to quantify changes in 18F-AraG kinetic parameters and correlate them with evolving PASC symptom profiles over time. We will include two follow-up scans of the PASC participants at 4 months and 8 months after the baseline scans with systematic symptom assessments, focusing on individual patient trajectories. Through this, we expect to establish a direct and meaningful connection between molecular imaging data and clinical manifestations. In summary, the incorporation of cutting-edge imaging technology with quantitative modeling techniques for non- invasive evaluation of total-body immune response, combined with the longitudinal design of the study promises to provide unprecedented insights into this complex condition and would extend well beyond the confines of the PASC condition, offering frameworks and tools that could as well be used for other post-viral conditions.

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Post-Acute Sequelae of SARS-CoV-2 Infection

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Chemical composition-viability relationship of bioaerosols through spatial distribution and size-controlled measurements

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National Institute of Allergy and Infectious Diseases (NIAID)

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Bioaerosols are small airborne particles that can harbor pathogenic microorganisms leading to serious and challenging-to-control diseases such as respiratory syncytial virus (RSV), SARS-CoV-2, and influenza in humans, and porcine reproductive and respiratory syndrome (PRRS) in animals. RSV is particularly hazardous to young children, causing severe lower respiratory tract infections. Unfortunately, there are no effective therapies or vaccines for RSV in the pediatric population. However, by gaining a better understanding of the transmission dynamics of airborne viruses through bioaerosols, we can improve our ability to predict and control their spread through the implementation of administrative and engineering controls such as optimized ventilation designs. The project’s broad and long-term objectives are to understand how the bioaerosol’s microenvironmental conditions, such as size, chemical composition, and phase status, and environmental conditions, such as temperature, relative humidity (RH), and UV light, can impact the pathogen viability and transmission. Towards this goal, this proposed study aims to develop an innovative method for measuring virus distribution in bioaerosols and understanding their viability decay based on chemical compositions that are more relevant to various respiratory generation locations, specifically for sub-5µm and submicron particles that can transmit long distances. This study will be performed in two aims. First, we will determine the spatial distribution of chemicals and pathogens in bioaerosols. We'll use gold nanoparticles to label RSV and visualize it with advanced electron microscopy and spectroscopy to map the chemical distribution of various components such as salt (Na, K, Cl) and protein. This will help us understand how viruses are distributed in bioaerosols and provide insights into their corresponding survival rate and viability. Second, we will study chemical composition's impact on RSV viability decay for sub-5µm and submicron bioaerosol particles from various generation origins. We will generate monodisperse particles using a unique experimental setup in this size range with various chemical compositions from oral to deep lung, and measure RNA and virus viability to obtain virus decay rates. This aim investigates airborne virus decay rates for submicron and sub-5 m virus-laden particles, critical for long-range airborne transmission, and identifies the relationship between pathogen viability decay rates and chemical compositions from various generation locations. This study proposes a novel gold labeling approach to measure the distribution of viruses within bioaerosol particles. It contributes to our long-term goals by providing insights into the relationship between the chemical composition, virus spatial distribution in bioaerosol particles, and the survival of pathogens. This tool can be applied to various pathogens besides RSV. The proposed work aims to provide a better understanding of how pathogens survive and interact with their microenvironment, going beyond the current state-of-the-art.

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Porcine Reproductive and Respiratory Syndrome

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Leveraging the sensitivity of antigen-specific T cells to interrogate disease mechanisms and identify therapeutic targets for Long COVID

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National Institute of Allergy and Infectious Diseases (NIAID)

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Project Summary/Abstract: An estimated 400 million people worldwide have experienced persisting and sometimes debilitating symptoms for months and years after SARS-CoV-2 infection, known as Long COVID (LC). No proven therapies exist to treat LC, and the underlying mechanisms driving disease remain poorly understood. Reactivation of herpesviruses such as Epstein-Barr virus (EBV) and varicella zoster virus (VZV) has been linked to LC, but it is unclear how SARS-CoV-2 infection alters immune responses to these common viruses. Recent studies have also provided emerging evidence for persistence of SARS-CoV-2 in some individuals with LC, but key questions remain unanswered, including how viral reservoirs persist, why the immune system fails to clear virus, whether persisting virus drives ongoing immune stimulation, and how therapies to treat LC will affect immune responses to SARS-CoV-2. Efforts to identify effective treatments for LC depend on answering these questions. Our preliminary data demonstrate elevated activation of SARS-CoV-2-, EBV-, or VZV-specific T cells in 40% of LC patients, providing one of the most sensitive measures of immunopathology in LC to date. Thus, there is an urgent need to investigate virus-specific T cell activation in LC to define underlying mechanisms of disease and identify promising therapeutic targets. The proposed research will respond to this need by testing three working hypotheses: first, that SARS-CoV-2-specific CD8 T cells survey tissue reservoirs of SARS-CoV-2 and sense viral antigens, but fail to clear the virus due to impaired functionality in LC; second, that therapies suppressing SARS-CoV-2 replication will reduce T cell stimulation in LC but may not achieve a durable cure; and third, that immune stimulation by common herpesviruses is associated with disease pathology in LC. These hypotheses will be tested by leveraging custom HLA-I/peptide tetramers to identify and sort rare virus-specific CD8 T cells from hundreds of longitudinal blood and tissue samples from people with LC and people who fully recovered after SARS-CoV-2 infection. Cells will be analyzed using spectral flow cytometry and single-cell sequencing approaches to elucidate the mechanisms driving LC pathology, identify promising therapeutic targets for LC, and investigate how immune stimulation by herpesviruses shapes human disease. This research will be integrated with a comprehensive training plan to develop skills in tissue immunology, single-cell sequencing, and bioinformatics, which will be reinforced with targeted coursework and professional development activities in scientific writing, responsible conduct of research, laboratory management, and mentorship of junior personnel. The research and training plan will take full advantage of the outstanding environment at the University of Pennsylvania and the wealth of expertise in Dr. John Wherry’s lab. Completing the proposed research and training will substantially advance the human immunology field and form the foundation of my research program as I open my independent laboratory, creating a pathway to my goal of being an impactful independent researcher in human infectious disease immunology.

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Development of a monoclonal therapy for neonatal herpes

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National Institute of Allergy and Infectious Diseases (NIAID)

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Neonatal infections caused by herpes simplex virus 1 or 2 (HSV-1, HSV-2) result in significant morbidity and mortality. Current medical treatment of neonatal HSV infections (nHSV) is limited to small molecule antivirals such as acyclovir, but even with high dose treatment, mortality subsequent to disseminated disease remains high (30%), and central nervous system (CNS) disease is associated with ∼70% neurological morbidity and 25% mortality. Monoclonal antibodies (mAbs) offer a class of intervention that provides immediate protection and a well-established development path, with over 200 mAb products licensed by U.S. and European regulatory bodies. Passive immunization with mAbs has been shown to be effective against a wide variety of infectious agent, with mAbs against Ebola virus, SARS-CoV-2, and Respiratory Syncytial Virus (RSV) approved by the FDA. Members of the ZabBio team have previously advanced 3 mAb products to clinical trials, including one which contained the broadly neutralizing HSV mAb, HSV8, which is the focus of this product development Fast Track SBIR proposal for neonatal HSV infection. More recently, ZabBio scientists have collaborated with Drs. Margaret Ackerman and David Leib (Dartmouth) who have demonstrated the utility of HSV8 in a mouse model of nHSV. These data support the hypothesis that HSV8 may be a useful clinical intervention for nHSV in humans. Phase 1 of this proposal contains 2 aims: 1) Assess the neutralization potency of HSV8 against a panel of HSV-1 and HSV-2 isolates from neonatal herpes patients; 2) Test whether HSV8 selects for HSV-1 and HSV-2 escape mutants. These two aims will result in a rigorous Go/No decision for proceeding to Phase 2. In Phase 2, the proposal transitions to traditional product development with 3 aims: 1) Manufacture HSV8 under cGMP in the Nicotiana benthamiana based Rapid Protein Production Platform (RP3) system; 2) Submit pre-IND to FDA; 3) Perform IND-enabling pharmacology/toxicology studies. This work scope will culminate in an Investigational New Drug (IND) submission.

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Small Business Innovation Research Grant

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Assessing the mechanisms underlying female sex-predominance in Long COVID

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National Institute of Allergy and Infectious Diseases (NIAID)

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Long COVID, or post-acute sequelae of COVID-19 (PASC), is estimated to occur after ~10% of COVID-19 cases and affects tens of millions of people worldwide. The mechanisms underlying Long COVID remain poorly understood, which hinders the ability to establish effective evidence-based treatments for the condition. One of the most striking observations in the epidemiology of Long COVID is its female sex predominance: women, particularly pre-menopausal women, are much more likely than men to have the condition. In this proposal, we leverage the Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort (NCT04362150) – which since April 2020 has recruited >1,000 participants with and without Long COVID – to interrogate the mechanistic basis underlying the increased prevalence of Long COVID in women. Our central hypothesis is that in women with Long COVID, there is an elevated and sustained immune type I IFN (T1IFN) response to SARS-CoV-2 (SCV2) gene products, which in turn diminishes the quality of adaptive immune responses against chronic herpesviruses (EBV, CMV) and SCV2 itself, increases the risk of pathogenic autoantibody responses, and results in overall systemic inflammation and immune dysregulation that is characteristic of Long COVID. We further postulate that both incomplete X chromosome inactivation and sex hormones drive the elevated T1IFN responses in women with Long COVID. In Aim 1, we will subject banked longitudinal blood specimens from women and men from LIINC (including both those with and without Long COVID) to assays that will measure the extent of persistent SCV2, T1IFN responses, the features of adaptive immune responses to persistent viruses associated with Long COVID (SCV2, EBV, CMV), autoantibody responses, and the overall state of inflammation. In Aim 2, we will leverage the LIINC Tissue Biopsy program to obtain paired endometrial and gut biopsies from women with Long COVID, to test the hypothesis that the endometrium is a key site of SCV2 persistence and immune dysregulation during Long COVID. This analysis will be compared to a parallel set of studies using gut specimens from matched men with Long COVID. Finally, Aim 3 will analyze specimens from two clinical trials designed to eliminate SCV2 gene products as treatment for Long COVID. The first of these, performed by Resolve Therapeutics, found that administration of RSLV-132, a catalytically active RNase1 intended to degrade SCV2 RNA, improved Long COVID symptoms in women but not men (NCT04944121). The second, occurring within LIINC, is ongoing (enrollment is complete) and testing the effects of AER002, a monoclonal antibody that directly targets and clears SCV2 protein (NCT05877508). Using specimens from both trials, we will test the notion that SCV2 gene products drive sustained T1IFN responses in women that contribute to Long COVID symptoms. Collectively, our aims will improve our understanding of the mechanisms underlying the female-predominance of Long COVID and improve our overall understanding of the disease. This will be a key step in the identification of evidence-based treatments for both women and men who continue to develop and live with this disabling condition.

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Post-Acute Sequelae of SARS-CoV-2 Infection

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Statistical Approaches to Unlock Protein Function from Deep Mutational Scans

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National Institute of General Medical Sciences (NIGMS)

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Understanding how genetic variants impact protein function is essential for unraveling the mechanisms underlying both basic biology and disease, particularly for rare genetic variants. Of the 4.6 million missense variants found in large population studies, only about 2% have clinical interpretations. Due to their rarity, these variants are exceptionally challenging to study through observational methods. However, Deep Mutational Scanning (DMS) offers a high-throughput method for testing thousands of protein variants by generating a mutant library and obtaining a phenotypic readout for each mutation in one sequencing assay. Initially focused on fitness-based readouts, DMS has expanded to include fluorescence-based methods for protein profiling, binding assays, and more. It has been crucial for studying proteins like SARS-CoV-2, BRCA1, and drug-metabolism transporters like OCT1. With over 1,000 protein datasets publicly available, a recent study highlights technical advances by independently assaying over 500 additional proteins in one study.  Unfortunately, the development of statistical methods to interpret and analyze these technologies has not kept pace. For example, DMS with fluorescence-activated cell sorting (DMS-FACS), which has been used for nearly a decade to measure protein abundance and other functional phenotypes, still lacks dedicated analysis methods. As a result, analyses are often ad hoc, and small sample sizes (typically three replicates) make standard statistical methods unsuitable. Our recent work demonstrates that naive approaches miss many real effects and lead to many false discoveries. We propose three statistical areas to improve DMS analysis and interpretation through accurate sample comparisons, epistasis analysis, and causal inference.  First, we will develop methods to analyze DMS-FACS for assessing how genetic variants affect molecular phenotype targeted by FACS, and enabling precise comparisons between experimental conditions. Second, we will develop methods to improve genetic interaction (epistasis) analysis and interpretation within proteins, and thus ask which protein regions are acting in concert. Third, we open a new area of research for DMS, aiming to identify the causal impact of variants through measured pathways, including complex traits.  In summary, we will solve the analysis gap for DMS-FACS, epistasis DMS, and causally link DMS data through structural causal models by leveraging our expertise in DMS data and small sample statistics. Leveraging our expertise in DMS data and small sample statistics, we will create reliable, robust tools for common workflows while also enabling new types of analyses that improve the interpretation of DMS, epistasis, and phenotypic relationships. With strong collaborations with assay developers and DMS experts, along with a proven track record in developing tools for high-throughput sequencing in small sample contexts, we are well-positioned to lead this effort.

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Improving the diagnosis and outcome of diffuse alveolar hemorrhage in systemic lupus erythematosus

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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

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The variable clinical manifestations of SLE patients are largely unexplained. Although severe diffuse alveolar hemorrhage (DAH) with pulmonary capillaritis is unusual in lupus, more than half of patients with this complication die and focal lung hemorrhage occurs in 30-66% of patients. Using a mouse model (pristane-induced lupus) developed in our laboratory, we will ask why C57BL/6 (B6) mice are susceptible to pristane-induced DAH/vasculitis whereas BALB/c and DBA/2 mice are resistant. DAH is initiated by lung endothelial cell (EC) injury followed by recruitment of bone marrow-derived monocytes to the lung. We found that dysregulation of the extrinsic coagulation pathway also is involved and that lung disease is abolished by early treatment with MEK1/2 or ERK1/2 inhibitors. The overall hypothesis is that genetically- determined lung microvascular EC injury evolves into DAH because of monocyte infiltration into the lung and abnormal regulation of the extrinsic coagulation pathway. Aim 1 addresses susceptibility to DAH. We will ask whether EC injury and bleeding are lung-specific and investigate gene expression patterns associated with DAH by single-cell RNA-sequencing. Genes conferring susceptibility/resistance to EC injury and bleeding be mapped in recombinant inbred BXD (B6 X D2) mice. Aim 2 examines the MEK1/2-ERK1/2 pathway in pristane-induced DAH. We will define the sequence of events leading to DAH and develop blood-based diagnostic tests for the diagnosis of incipient DAH prior to the onset of bleeding. This is important, because the disease process is irreversible once hemorrhage begins. We will look for tests that distinguish early DAH (pre-bleeding) from other forms of lung injury, such as sepsis with acute respiratory distress syndrome. Aim 3 translates what is learned in mice to human DAH. We hypothesize that the disease process is similar except that the initial EC injury is caused by respiratory viral infections rather than pristane. We will ask if a predisposition to lung EC injury determines susceptibility, as in mice, and whether diagnostic approaches developed in the mouse model are relevant to human DAH. Lung EC injury will be examined in SLE patients with influenza or COVID infection and the role of mild bleeding disorders will be explored. The ability to diagnose incipient DAH (pre- bleeding) may permit future therapeutic trials using FDA-approved MEK1/2 inhibitors, such as trametinib, which are highly effective in pristane-induced DAH.

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A System to Support Development and Success of NCI-Sponsored Trials for Rare Diseases

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R50 Abstract – Reiss Gastrointestinal maligancies remain lethal and difficult-to-treat, with poor outcomes for many patients. In spite of this, we are in a moment of a scientific and clinical revolution with the development of biomarker-driven therapies for selected patients. With these advances come multiple new questions for the field, many of which the NCTN infrastructure is optimally suited to address. To date, I have demonstrated a strong commitment to clinical and translational research for populations of patients with rare subsets or biomarkers, including via the development and implementation of NCI-trials at my own institution: I am the international study chair and lead accruer for EA2192 as well as the study champion and lead national accruer for SWOG-2001. On the larger scale, I hold leadership roles within the Abramson Cancer Center (ACC) at the University of Pennsylvania and at the NCTN. I serve as the co-chair of the ECOG- ACRIN GI Committee, I am the co-leader of the ACC Cancer Therapeutics Program and I am the co-leader of the ACC Pancreatic Clinical Trial Program. These leadership positions are optimal platforms upon which to spearhead programs that (1) formally and longitudinally assist junior and mid-career oncology faculty in their quests to develop investigator-initiated studies and (2) develop a program at the NCTN that focuses on developing realistic trials for rare populations and then on accruing them successfully. To date, I have demonstrated a persistent and strong commitment to the NCI research enterprise. I have been involved with NCI-related research since my early career, initially attending meetings and later developing my own protocol, EA2192. Based on my steady engagement and input, I was appointed as the co-chair of the GI Committee in 2022 alongside Jordan Berlin (see LOS). Together, we have made a commitment to improving the process of clinical trial development, a mission that will be critical in order for the NCTN to remain competitive in an ever-changing landscape. Over the past three years, we have employed multiple initiatives including boosting the education of our investigators about the NCTN process, leaning on the excellent Working groups chairs to fine-tune concepts prior to Committee Presentation and providing substantial assistance during the submission process. With the support of the R50 Research Specialist award, I will build further on this approach in two ways: At the ACC, I will develop a sustainable program for early and mid-career investigators to provide longitudinal support in the development of investigator-initiated trials, with a particular focus on rare disease studies that can be best executed via the ECOG-ACRIN system. Within the NCTN, I will employ a novel program assisting investigators in the development and successful enrollment of trials for rare disease populations, a subset of studies that have lost ground since the COVID pandemic. Specifically, I will create a living resource for NCTN investigators that focuses on methods to design practical, feasible studies and will provide longitudinal support to those across the NCTN who are developing studies in this space. My ultimate goal is to develop and implement pragmatic clinical trials that address key questions in the field of gastrointestinal malignancies, particularly for patients with rare subsets of disease.

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Abramson Cancer Center at the University of Pennsylvania

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American College of Radiology Imaging Network

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Malignant neoplasm of gastrointestinal tract

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SCH: A structural causal framework for adaptive experiments

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Adaptive randomized clinical trials are critical in infectious disease research, offering flexibility to adjust sample sizes, introduce new interventions, discontinue ineffective treatments, and target specific subgroups to enhance treatment efficacy. This adaptability is particularly valuable in rapidly evolving public health crises, such as the development of treatments for emerging infectious diseases like COVID-19. However, adaptive trials present significant challenges, including unclear inferential targets, statistical biases from temporal and spatial variability, complexities in handling dynamic data structures, and an increased risk of false-positive findings. These concerns are reflected in recent FDA guidance on estimands, which emphasizes the need for clearly defined inferential targets, and on adaptive designs, which acknowledges that statistical bias in adaptive trials remains an understudied issue. Despite these recognized challenges, current research lacks a principled framework for structurally representing and unbiasedly estimating causal effects in adaptive trials. This project will develop a structural causal framework for adaptive trials, leveraging modern causal inference and statistical techniques alongside secondary data from the Adaptive COVID-19 Treatment Trial (ACTT)—an adaptive trial evaluating novel therapeutics in hospitalized COVID-19 patients—to enable transparent, efficient, and statistically unbiased estimation of causal effects. To achieve this, we propose the following specific aims: Aim 1: Develop a structural causal approach that deals with temporal variability. Aim 2: Extend our framework to handle spatial variability. Aim 3: Expand our framework to handle complex data structures, including failure-time and missing data, while dealing with false-positive results. Our project aligns with NIAID’s mission by advancing key methodologies for infectious disease clinical trials, particularly in adaptive designs for pandemic response, emerging pathogens, and the development of antiviral treatments. While our primary focus is on infectious disease trials, our methods have broader applicability to other disease areas, such as schizophrenia. We show this by also leveraging secondary data from schizophrenia studies, including the DECIFER trial, the RAISE study, and the EPINET study. RELEVANCE (See instructions): This research aims to improve how adaptive clinical trials are designed and analyzed. By developing methods that address key challenges in adaptive trials, our work will help ensure more accurate and reliable results, ultimately leading to better treatments and public health responses to emerging infectious diseases.

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National Institute of Allergy and Infectious Disease