Grants

JUSTICE, DEPARTMENT OF.FEDERAL BUREAU OF INVESTIGATION.FBI-JEH

Locklizard DRM

2026-12-07

general

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Logic-gated CARs to target phenotypic rather than viral features of latent HIV reservoirs

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT Antiretroviral therapy (ART) is remarkably successful at preventing AIDS but is unable to cure HIV infection due to a durable pool of latently infected cells carrying integrated HIV provirus. The persistence of this latent reservoir contributes to a growing population of people living with HIV whose lifespans are shortened by non-AIDS co- morbidities of chronic infection and in whom HIV infection can reactivate upon ART interruption. Selective targeting of the latent HIV reservoir is difficult due to the absence of either detectable viral antigens or cell- surface markers that would reveal viral reservoirs to the immune system. Alternative strategies to reactive latent HIV in these cells and promote susceptibility to immune attack are not sufficiently robust to facilitate elimination of an adequate quantity of the reservoir to achieve cure. Latent provirus in ART-treated HIV-1-infected patients highly enriched in a heterogeneous pool of CD4 T cells exhibiting variably elevated expression of sets of cell surface proteins, including programmed cell death-1 (PD-1) and very late antigen-4 (VLA-4). We believe that logic-gated chimeric antigen receptors (CAR) can be developed to facilitate highly selective killing of cells with these combination of markers (AND gate targeting of cells co-expressing PD-1 and VLA-4, for example) while sparing important uninfected immune effector cells with the similar features (NOT gate to prevent killing of CD8+ T cells). This strategy would permit virus-agnostic eradication of sets of cells with defined phenotypic features that encompass most latently infected cells. Such a strategy could be employed in the context of effective ART to shrink the viral reservoir to a level that can be restrained by antiviral immune responses to facilitate drug-free remission. In this proposal, we will build these CAR molecules and test their ability to durably endow human NK cells with highly selective functional activity against discrete subsets of T cells. In addition, we will characterize the expression of the targeted combination of receptors on latently infected tissue T cells. These studies will provide compelling evidence of the feasibility of these logic-controlled CAR regimens and validate a set of target markers in a pre-clinical latency model. These data will facilitate more advanced preclinical testing in non-human primates, humanized mice, and bona fide reservoir cells from people living with HIV.

Up to $473K

2028-05-31

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Loneliness and inflammatory markers as biopsychosocial pathways to AD/ADRD: Analysis of a rapidly aging segment of the US population

NIA - National Institute on Aging

ABSTRACT Career Goal: My career goal is to become a leading independent investigator contributing rigorous social science research to understand cognitive health differences among the growing population of older immigrants in the US. With the immigrant population 65 and older expected to double to 20 million by 2050, investigating the ways modifiable risk factors for Alzheimer’s disease (AD) and Alzheimer’s disease and related dementias (ADRD) operate for immigrant populations is an imperative area of research. Training towards content area and methodological expertise will enable me to contribute to scholarship aimed at reducing the public burden of AD/ADRD in a growing US population. Career Development: I will undertake four training aims to enhance my knowledge and skills in (1) the biological and social pathways shaping AD/ADRD, (2) geriatric mental health and social relationships, (3) epidemiological causal inference, and (4) professional development for becoming an independent investigator. Research Project: Mexican immigrants, the largest group of immigrants in the US, are rapidly aging, but current research often aggregates US Latinos, overlooking origin- and nativity-specific social, structural, and migration-related factors that influence AD/ADRD risk. Attention to specific immigrant populations is necessary to address heterogeneity in cognitive risk factors. To address this gap, the proposed research focuses on loneliness, a risk factor for AD/ADRD that may be heightened in the older Mexican immigrant population. Using data from a nationally representative panel survey, complemented by data from a Rutgers-based cohort that collects advanced biomarkers, the proposed project uses causal inference to analyze the inter-relationship between loneliness, social relationships, inflammation, and cognition for Mexican immigrants in the US compared to non-migrants, advancing understandings of modifiable risk factors for AD/ADRD. Specific Aims: (1/K99) Determine loneliness trajectories, social relationship risk factors for loneliness, and the contribution of loneliness to cognitive functioning in the Mexican immigrant population compared to non-migrants. (2/R00) Quantify inflammation as a mediator in the loneliness-cognition pathway in the Mexican immigrant population compared to non-migrants. (3/R00) Characterize the loneliness- inflammation and loneliness-AD/ADRD relationships in the Mexican immigrant population compared to non- migrants using advanced biomarker data. Mentorship: A complementary set of accomplished experts in AD/ADRD, geriatric mental health, social networks, immigrant health, biomarker analysis, and causal inference will provide training and professional mentorship to ensure my successful transition to independent investigator. Future Directions: With the proposed training and research experience, I will have a unique combination of substantive expertise and methodological skills to become an independent scientist and submit successful R01 proposals to examine AD/ADRD social determinants among high-risk subpopulations.

Up to $121K

2028-02-29

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Loneliness in Aging with Schizophrenia: Effects of Real-time Positive and Negative Social Motivation

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT: Chronic loneliness is a pervasive issue in persons with schizophrenia and can lead to downstream consequences of worsening symptoms (e.g., paranoia, cognitive and functional impairments), social withdrawal, and diminished quality of life. Central to these challenges are deficits in social motivation, encompassing both positive motivation (i.e., desire for connection) and negative motivation (i.e., avoidance due to anxiety). High rates of anxiety and depressive symptoms further exacerbate these motivation deficits, hindering social engagement and intensifying chronic loneliness. Despite the critical role of social motivation in shaping social interactions and mental health outcomes, existing research has primarily relied on static, retrospective assessments, which fail to capture the real-time fluctuations and bidirectional relationships between social motivation, mood, social interactions, and loneliness. The proposed F31 project will use ecological momentary assessment (EMA) to examine these dynamic processes as they unfold in daily life. By leveraging data from an NIMH-funded R01 study on loneliness and aging in schizophrenia, this study will evaluate moment-to-moment fluctuations in positive and negative social motivation, and their associations with mood, loneliness, and social interactions. Advanced statistical techniques, including linear mixed effects models and mediation analyses, will identify mechanisms linking social motivation to loneliness and mood over time. These insights aim to advance understanding of how momentary changes in social motivation shape real-world experiences in schizophrenia, with the goal of identifying modifiable targets for intervention. Through the training opportunities afforded by the F31 fellowship, the candidate will gain expertise in EMA methodologies, advanced statistical modeling, and translational research approaches. These skills will support the candidate’s long-term goals of becoming an independent investigator specializing in the social and psychological mechanisms of serious mental illness (SMI) and the development of technology-based interventions. The proposal aligns with the NIMH Strategic Plans by advancing the understanding of dynamic, modifiable processes underlying social motivation deficits in schizophrenia, and informing innovative, targeted intervention strategies.

Up to $43K

2028-02-21

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Long Beach Community Foundation Community Grants

Long Beach Community Foundation

Long Beach Community Foundation ($60M in assets) supports nonprofits in CA through grants focused on education, youth development, health, community development. Awards range from $1,000 to $50,000.

$1K – $50K

Educationyouth developmentHealth+1

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Long Range Broad Agency Announcement (BAA) for NSWC Crane

NSWC CRANE - N00164

Long Range Broad Agency Announcement (BAA) for NSWC Crane

general

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Long Range Broad Agency Announcement (BAA) for NSWC Crane

NSWC CRANE - N00164

This announcement seeks revolutionary research ideas, and technology demonstrators that offer potential for advancement and improvement of NSWC Crane’s primary mission areas. NSWC Crane is a field activity of the Naval Sea Systems Command. NSWC Crane supports a wide range of government agencies in the interest of national security. NSWC Crane may publish BAAs and other solicitations in response to specific needs. This BAA is issued to seek innovative solutions and ideas for topics not covered via other means. It is strongly encouraged that potential proposers review existing NSWC Crane solicitations to avoid duplication of effort and to contact the identified points of contact for each BAA topic to discuss specific details of the needs. The mission of NSWC Crane is to provide research, development, test and evaluation, acquisition engineering, in-service engineering and technical support in its assigned technical capabilities for the United States Navy, Department of Defense components and agencies, and other federal agencies and components engaged in national security. NSWC Crane also works to apply component and system-level product and industrial engineering to surface sensors, strategic systems, special warfare devices and electronic warfare systems, as well as to execute other responsibilities as assigned by the Commander, Naval Surface Warfare Center. The focus of NSWC Crane is “Harnessing the Power of Technology for the Warfighter.” Crane specializes in total lifecycle support in three broad focus areas: Expeditionary Warfare, Strategic Missions, and Electronic Warfare, which support ten assigned technical capabilities (TCs) listed below. 1. Electronic Warfare (EW)2. Infrared and Pyrotechnic Countermeasures3. Strategic Systems Hardware4. Expeditionary Warfare and Systems5. Advanced Electronics6. Sensors and Surveillance Systems7. Hypersonic Weapon Systems8. Power and Energy Systems9. Electro-optic and Infrared Technologies10.Force level EW Mission Analysis, Advanced Concepts and Technologies Within each of the TCs, there are multiple thrust areas, which present considerable opportunities for innovative research and solutions to support national security imperatives. There is intentional overlapping space within the listed TC such that a potential technology or research idea may support multiple TCs. Any proposal should list the principal TC as well as any adjunct TCs that should be considered. Proposals that support multiple TCs are strongly desired but not necessary.

science_technology_and_other_research_and_development

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Long Range Broad Agency Announcement (BAA) for NSWC Crane

NSWC CRANE - N00164

This announcement seeks revolutionary research ideas, and technology demonstrators that offer potential for advancement and improvement of NSWC Crane s primary mission areas.NSWC Crane is a field activity of the Naval Sea Systems Command. NSWC Crane supports a wide range of government agencies in the interest of national security. NSWC Crane may publish BAAs and other solicitations in response to specific needs. This BAA is issued to seek innovative solutions and ideas for topics not covered via other means. It is strongly encouraged that potential proposers review existing NSWC Crane solicitations to avoid duplication of effort and to contact the identified points of contact for each BAA topic to discuss specific details of the needs.The mission of NSWC Crane is to provide research, development, test and evaluation, acquisition engineering, in-service engineering and technical support in its assigned technical capabilities for the United States Navy, Department of Defense components and agencies, and other federal agencies and components engaged in national security. NSWC Crane also works to apply component and system-level product and industrial engineering to surface sensors, strategic systems, special warfare devices and electronic warfare systems, as well as to execute other responsibilities as assigned by the Commander, Naval Surface Warfare Center.The focus of NSWC Crane is Harnessing the Power of Technology for the Warfighter. Crane specializes in total lifecycle support in three broad focus areas: Expeditionary Warfare, Strategic Missions, and Electronic Warfare, which support ten assigned technical capabilities (TCs) listed below.1. Electronic Warfare (EW)2. Infrared and Pyrotechnic Countermeasures3. Strategic Systems Hardware4. Expeditionary Warfare and Systems5. Advanced Electronics6. Sensors and Surveillance Systems7. Hypersonic Weapon Systems8. Power and Energy Systems9. Electro-optic and Infrared Technologies10.Force level EW Mission Analysis, Advanced Concepts and TechnologiesWithin each of the TCs, there are multiple thrust areas, which present considerable opportunities for innovative research and solutions to support national security imperatives. There is intentional overlapping space within the listed TC such that a potential technology or research idea may support multiple TCs. Any proposal should list the principal TC as well as any adjunct TCs that should be considered. Proposals that support multiple TCs are strongly desired but not necessary.

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Long Range Broad Agency Announcement for DHS Science & Technology

Office of Procurement Operations - Grants Division

This is a combined synopsis/solicitation. The BAA is available via the FedBizOpps website(http://www.fedbizopps.gov/) and posted on the HSARPA (http://www.hsarpabaa.com) website. Please review the document in its entirety, and submit specific inquiries to the BAA email address (BAA08-01@dhs.gov). DHS S&T is interested in receiving proposals for Long Range Science and Technology Projects and innovative prototypes which offer potential for advancement and improvement of homeland security missions and operations. The overall mission and goal of S&T is to identify revolutionary, evolving, and maturing technologies that can be demonstrated to provide significant improvement to homeland security missions and operations through proof of concept and prototyping with potential for transition to current and future DHS acquisition processes. S&T will focus on those key areas where risk inhibits mission and operation investments and where significant capability payoffs can be expected for successful efforts. Awards may take the form of contracts, grants, cooperative agreements, or other transaction (OTs) agreements.

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Long Read sequencing in Kidney Disease

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary Chronic kidney disease (CKD) poses a major global health burden, yet therapeutic options remain limited and largely repurposed from other diseases. A key barrier to therapeutic progress is the incomplete understanding of CKD’s molecular and genetic mechanisms. Genetic factors explain 30–50% of CKD risk, but genome-wide association studies primarily identify non-coding variants, complicating functional interpretation. Most gene expression studies in CKD have focused on total gene expression, overlooking alternative splicing. Short-read RNA sequencing of 404 human kidney samples showed alternative splicing explains an additional 5% of CKD heritability. However, short-read sequencing fragments RNA, limiting full isoform characterization. Long-read sequencing of 8 kidney samples identified 67% novel isoforms and revealed significant isoform differences between CKD and control samples. Given the limitations of short read sequencing, I will employ long read sequencing to comprehensively characterize the role splicing in kidney disease. I will first employ this in bulk kidney tissue to identify novel isoforms, compare the isoform expression between CKD and controls and to compare the identified isoforms with mass spectrometry data to clarify the relationship between the spliced isoforms and protein levels. I will then perform single cell long read sequencing to generate the first isoform-resolved atlas of kidney cell populations, enabling identification of cellular states associated with disease. Differential isoform usage at single-cell resolution will clarify which kidney cell types and isoforms drive disease pathology. This project will comprehensively characterize the splicing events in the kidney and the role in kidney disease.

Up to $158K

2031-01-31

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Long term impact of maternal opioid use and management strategies on neurodevelopment in rodent offspring

NIDA - National Institute on Drug Abuse

Project Summary The overall goal of this project is to evaluate the long-term impact of in utero oxycodone exposure, opioid maintenance therapy and opioid-withdrawal mitigation strategies on neuro-behavioral development, brain structure and volume and reward processing. Clinical studies have shown concerning long-term, neurodevelopmental outcomes associated with in utero opioid exposure, which include lower social competence scores, memory deficits, and increased risk for behavioral problems and hyperactivity disorders. Clinical data is limited due to a number of challenges, including quality of maternal-infant bonding and care, maternal poly- substance use, epigenetic influences, and socio-economic factors. Given these limitations there is a unique opportunity for mammalian experimental models to investigate the long term effects of in utero opioid exposure, maintenance replacement therapy, as well as opioid withdrawal mitigation treatments on neurobehavioral outcomes. In the first aim we will evaluate the impact of opioid maintenance therapies (methadone and buprenorphine) on offspring, following in utero exposure to oxycodone in dams extending from conception to parturition or through pup weaning. We will also characterize the long-term behavioral impact of clinically- approved opioid withdrawal mitigation treatments, methadone and morphine, as well as buprenorphine in pups, following in utero exposure to oxycodone. In the second aim we will look to correlate changes in brain structure and volume using magnetic resonance imaging in pups following the opioid maintenance therapy in the dams as well as opioid withdrawal mitigation strategies in the pups. In the final aim we will examine whether prenatal opioid exposure and opioid maintenance or withdrawal mitigation strategies disrupt reward processing at the circuit level by examining GABAergic projections from the ventral tegmental area to the nucleus accumbens shell that we have previously shown to modulate reward behavior. Together, this approach will allow us to determine the long-term neuro-behavioral and anatomical changes that occur following in utero oxycodone-exposed pups following: 1) Opioid maintenance therapies in dams and 2) opioid withdrawal mitigation treatments in pups. We hypothesize, that this will impair learning, alter social and reward behavior, induce anxiety- and depressive- related behaviors, and reduce sensitivity to tactile and pain sensation (aim 1); decrease volume in a number of brain regions involved in reward processing and cognitive function such as the basal ganglia, thalamus, hippocampus and amygdala, change amygdalar functional connectivity as well as cause microstructural damage in the corpus callosum (aim 2); increase rewarding valance of GABAergic projection from the ventral tegmental area to the nucleus accumbens shell (aim 3). We hypothesize that exposure to buprenorphine may improve these outcomes due it’s activity at the kappa opioid receptor system. Understanding the long-term impact of oxycodone exposure in tandem with opioid maintenance therapy and opioid withdrawal mitigation strategies will allow us to explore treatment strategies and/or targets that may limit these long-term negative consequences.

Up to $733K

2031-02-28

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Long Term Monitoring of Selected Coral Reef Sites in Dry Tortugas

National Park Service

The primary project goal is to evaluate long term status and trends of common and rare coral reef types and benthic communities in Dry Tortugas National Park. The objectives are to collect benthic data which provides a quantitative assessment of stony coral species richness density, abundance, and spatial cover, benthic cover values for major taxonomic groups (e.g., stony corals, macroalgae, octocorals, sponges, and zoanthids) and an evaluation of stony coral and octocoral condition including the prevalence of disease and bleaching and causes of mortality. Targeted surveys also focus on the abundance of Diadema antillarum within the park. In addition, in situ water temperature data is collected at many sites to determine its influence on benthic community structure. Lastly, surveys to assess the effects of diving activities on coral communities within the Research Natural Area dive sites are performed.

$90K – $450K

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Long Term Research in Environmental Biology

U.S. National Science Foundation

Through the LTREB program, the Division of Environmental Biology (DEB) and the Division of Integrative Organismal Systems (IOS) encourage the submission of proposals that generate extended time series of biological and environmental data to address ecological and evolutionary processes and resolve important issues in organismal and environmental biology. Researchers must have collected at least six years of previous data to qualify for funding, and these data must motivate the proposed research. The proposal also must present a cohesive conceptual rationale or framework for ten years of research. Questions or hypotheses outlined in this conceptual framework must guide an initial 5-year proposal as well as a subsequent, abbreviated renewal. Together, these will constitute a decadal research plan appropriate to begin to address critical and novel long-term questions in organismal and environmental biology. As part of the requirements for funding, projects must show how collected data will be shared broadly with the scientific community and the interested public.All proposals submitted to the LTREB program are co-reviewed by participating Clusters in the two participating Divisions, and specifically Ecosystem Science, Population and Community Ecology, and Evolutionary Processes in DEB, and Behavioral Systems and Physiological and Structural Systems in IOS. Proposals must address topics supported by these programs. Researchers who are uncertain about the suitability of their project for the LTREB Program are encouraged to contact the cognizant program director.

Up to $450K

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Long Term Research in Environmental Biology

U.S. National Science Foundation

Long Term Research in Environmental Biology

researchEnvironmental

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Long Term Resource Monitoring Program FY 2014

Geological Survey

The Long Term Resource Monitoring Program (LTRMP) Cooperative Agreement ProgramLTRMP is a monitoring effort with the U.S. Geological Survey (USGS) and five Upper Mississippi River System states (Illinois, Iowa, Minnesota, Missouri, and Wisconsin).

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Long Term Resource Monitoring Program FY 2015

Geological Survey

The Long Term Resource Monitoring Program (LTRMP) Cooperative Agreement Program LTRMP is a monitoring effort with the U.S. Geological Survey (USGS) and five Upper Mississippi River System states (Illinois, Iowa, Minnesota, Missouri, and Wisconsin).

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Long Term Resource Monitoring Program FY 2016

Geological Survey

The Long Term Resource Monitoring Program (LTRMP) Cooperative Agreement Program LTRMP is a monitoring effort with the U.S. Geological Survey (USGS) and five Upper Mississippi River System states (Illinois, Iowa, Minnesota, Missouri, and Wisconsin).

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Long Term Resource Monitoring Program FY 2017

Geological Survey

$1 – $1M

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Long Term Resource Monitoring Program FY 2018

Geological Survey

The Long Term Resource Monitoring Program (LTRMP) Cooperative Agreement Program LTRMP is a monitoring effort with the U.S. Geological Survey (USGS) and five Upper Mississippi River System states (Illinois, Iowa, Minnesota, Missouri, and Wisconsin).

$1 – $1M

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Long Term Resource Monitoring Program FY 2020

Geological Survey

The Long Term Resource Monitoring (LTRM) Element Cooperative Agreement Program. LTRM is the monitoring and research element of the UMRR Program, managed by the U.S. Geological Survey(USGS) and implemented by the five Upper Mississippi River System states (Illinois, Iowa, Minnesota, Missouri, and Wisconsin). Overall guidance, funding, and Program responsibility is provided by the U.S. Army Corps of Engineers(USACE). A directive outlining the mode of operation and the respective roles of each agency is embodied in a 1988 Memorandum of Agreement.

$1 – $1M

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Long Trail Maintenance and Trail Projects on State Lands

Community DevelopmentEquity & Access

Forests, Parks & Recreation

Long Trail Maintenance and Trail Projects on State Lands

Up to $80K

2026-12-31

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Long-acting nanoparticle antidotes for the treatment of synthetic opioid overdose

NIDA - National Institute on Drug Abuse

Project Abstract This project focuses on the development of long-acting opioid antagonist, mixed agonist-antagonist, and agonist nanoparticle formulations for the treatment of overdose, reduction of opioid withdrawal, and prevention of renarcotization from fentanyl and fentanyl analogs (F/FAs), including carfentanil. These compounds are extremely potent mu opioid receptor (MOR) agonists that are easy to manufacture in clandestine laboratories and used as adulterants in counterfeit prescription medications and illicit street mixtures. Because of their widespread availability, F/FAs are responsible for over 70% of overdose deaths in the US. While antagonists like naloxone and nalmefene are FDA approved to treat opioid overdose, they can precipitate severe opioid withdrawal and may be insufficient to prevent toxicity and renarcotization in accidental F/FA overdoses. Renarcotization occurs when the antagonist effects wear off and the respiratory depressive effects of the opioid return due to differences in elimination half-lives. Management of overdoses involving F/FA is complex, often requiring intensive acute medical care and extended observation of patients. To reverse fentanyl-induced respiratory depression and prevent fentanyl effects out to 48 hours, our group has developed a novel long-acting naloxone nanoparticle (cNLX-NP). This project will focus on further development of this naloxone nanoparticle as well as development of other antagonist formulations (nalmefene and naltrexone), mixed agonist-antagonist (MAA) formulations (buprenorphine, nalbuphine, and butorphanol), and an agonist formulation (desmetramadol). The specific aims of the project are Aim 1: Develop antagonist nanoparticles, determine the lowest effective doses of each nanoparticle, and test whether antagonist nanoparticles induce anhedonia or precipitate opioid withdrawal via somatic signs; Aim 2: Develop MAA and agonist nanoparticles, determine the lowest effective doses, test whether MAA and agonist nanoparticles elicit rewarding, antinociceptive, or anhedonic effects, and test whether these nanoparticles precipitate opioid withdrawal; Aim 3: The 3 most effective formulations will be further characterized by determining the highest F/FA doses that each formulation is effective against, testing efficacy out to 120 hours, testing efficacy against a combination of fentanyl and alprazolam, test the efficacy in animals chronically exposed to fentanyl, characterize the pharmacokinetics of the lead formulation, and determine whether these formulations (which include a mixture with free naloxone) precipitate opioid withdrawal in rats using intracranial self-stimulation.

Up to $723K

2031-03-31

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Long-noncoding RNAafu-182- A novel regulator of fungal triazole tolerance

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Invasive infections related to the saprophytic mold Aspergillus fumigatus are on the rise, and drug resistance often exacerbates the problem. The mechanisms of fungal adaptation to the azole drugs are not clear. Recently, it has been shown that A. fumigatus can form persistent colonies in response to azole drugs. Long non-coding (lnc)RNAs have been associated with stress adaptation that may eventually lead to resistance. This research team has identified a lncRNA, afu-182, that acts as a negative regulator of azole tolerance. This project will now use innovative approaches to identify the role(s) of afu-182 and delineate the azole response network in A. fumigatus. Aim 1 will characterize the roles of the RTM family of proteins, a class of protein that is involved in ameliorating xenobiotic stress, and define their regulation by afu-182. Aim 2 will study the structure-function relationship of afu-182 to understand the mechanistic basis of afu-182 action. Aim 3 will study a closely related homothallic fungus, Aspergillus nidulans, with a short, defined sexual cycle in an unbiased forward-genetics approach to identify novel factors in azole response. Using a new fundamental paradigm of study, this project will determine the novel mechanisms of azole response in Aspergilli, which will eventually reveal new strategies to combat the rise of azole drug resistance.

Up to $418K

2031-03-31

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Long-term Cardiometabolic Disease in COVID-19

NIH

Background: People with COVID-19 have increased risk of death and cardiometabolic disease including cardiovascular disease, diabetes mellitus, dyslipidemia and kidney disease. However, the evidence base is limited in 3 key aspects: (1) Existing studies have characterized the risks of adverse outcomes associated with earlier variants of SARS-CoV-2 and have limited follow-up. (2) It is not clear whether an annual vaccination for COVID-19 beyond the third dose reduces risk of adverse events. (3) Comparative analyses of COVID-19 vs. influenza are helpful to benchmarking risks but are only available for earlier variants and for limited follow up. Significance/Impact: Our proposal aims to answer key questions that are critical to guiding public health policy – including 1) characterizing short- and long-term risks of old, new and yet to emerge variants and subvariants of SARS-CoV-2 (proxied by the era in which they predominate); 2) on an ongoing annual basis, evaluate the effectiveness of COVID-19 vaccines in reducing risks of adverse health outcomes; and 3) on an ongoing basis, provide a comparative assessment of COVID-19 vs seasonal influenza. The proposal is specifically designed to address several key research questions outlined in the US Government National Research Action Plan on Long Covid. The results will have direct and substantial real-world impact in informing policy and clinical care. Innovation: The proposal leverages the unique power of the VA’s large-scale electronic health records and recent methodologic innovations in causal inference and clinical epidemiology to expand the evidence base about the health effects of COVID-19 and the role of vaccines. Specific Aims: To use healthcare data from the VA to: (1) characterize the acute and long-term risks of death and cardiometabolic disease in people with COVID-19 from 2020-2029, cohorted into variant-predominant eras, versus a matched historical control; (2) evaluate the effectiveness of receipt of the COVID-19 vaccine in each year (from 2022-2029) in reducing risk adverse health outcomes in the 12 months after receipt of the vaccine; and (3) comparatively evaluate the acute and long-term risks of death and cardiometabolic disease in people hospitalized for COVID-19, cohorted into variant-predominant eras, versus those hospitalized for seasonal influenza in each influenza season (from 2020 to 2029). Methodologies: VA electronic health record data will be used to construct independent cohorts for each aim and outcome being examined. COVID-19 test results and vaccination data will be collected form the COVID-19 Shared Data Resource, VA laboratory data and Medicare data. Incident outcome definitions validated for use with EHR data will be used. Inverse probability weighing will be used to balance for individual-level patient characteristics (predefined and algorithmically selected covariates), contextual characteristics, and characteristics related to the pandemic. Censoring weights will additionally be used to address situations that may result in informative loss to follow- up. Survival and mixed effect regression models will then be used to estimate differences in risk of outcomes between the COVID-19 exposure group of interest and reference groups, and estimates will be reported as hazard ratios and adjusted incidence rates, or differences in slopes. Implementation/Next Steps: Results from this proposal will inform public health policies (e.g. vaccine policies) and clinical care. Future studies will investigate optimizing care of people with cardiometabolic disease.

2029-09-30