Key Dates

Related Announcements

PA-20-272 - Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)

Issued by

Office of The Director, National Institutes of Health (OD)

National Eye Institute (NEI)

National Heart, Lung, and Blood Institute (NHLBI)

National Human Genome Research Institute (NHGRI)

National Institute on Aging (NIA)

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

National Institute of Allergy and Infectious Diseases (NIAID)

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

National Institute of Biomedical Imaging and Bioengineering (NIBIB)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute on Deafness and Other Communication Disorders (NIDCD)

National Institute of Dental and Craniofacial Research (NIDCR)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

National Institute on Drug Abuse (NIDA)

National Institute of Environmental Health Sciences (NIEHS)

National Institute of General Medical Sciences (NIGMS)

National Institute of Mental Health (NIMH)

National Institute of Neurological Disorders and Stroke (NINDS)

National Institute of Nursing Research (NINR)

National Institute on Minority Health and Health Disparities (NIMHD)

National Library of Medicine (NLM)

National Center for Complementary and Integrative Health (NCCIH)

National Center for Advancing Translational Sciences (NCATS)

Division of Program Coordination, Planning and Strategic Initiatives, Office of Research Infrastructure Programs (ORIP)

National Cancer Institute (NCI)

All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers. The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Division of Program Coordination, Planning and Strategic Initiatives, Office of Disease Prevention (ODP)

Office of Research on Women's Health (ORWH)

Purpose

Purpose

This Notice of Special Interest (NOSI) is being issued to encourage investigators with expertise and insights germane to post-acute sequelae of SARS-CoV-2 infection (PASC) pathobiology to apply for supplemental funding that would enable them to leverage current awards to rapidly advance understanding of the pathobiological underpinnings of PASC, including the pathogenic mechanisms responsible for persistent symptoms after acute infection and/or pathology in multiple organ/systems that has, or will, lead to clinically significant health problems.

Background

To further the goals of the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Initiative, the agency is publishing this Notice to request applications for administrative supplements to current active NIH grants in order to address the urgent need to identify the pathobiological mechanisms that underpin the long-term effects of SARS CoV-2 infection. These effects can include multiple symptoms and multi-tissue/organ injury that persist long past the time that patients have recovered from the initial stages of COVID-19 (often referred to as long COVID) as well as new symptoms that arise after the time of initial infection and may evolve over time (e.g., MIS-C). These effects give rise to multiple, and as yet not well-defined, clinical phenotypes. Symptoms can persist for months and can range from mild to incapacitating. Symptoms can include fatigue, post exertional malaise, shortness of breath, difficulties with concentration and attention ( brain fog ), sleep disorders, fevers, gastrointestinal symptoms, anxiety, depression, headache, a variety of pain syndromes, postural orthostatic tachycardia, and others identified and as yet unidentified. The clinical phenotypes may also represent prodromes to future health threats (i.e., development of autoimmune diseases). While still being defined, these clinical and sub-clinical effects are collectively referred to as post-acute sequelae of SARS-CoV-2 infection (PASC).

Research Objectives

To make rapid progress in understanding the biological mechanisms underlying the pathogenesis of PASC (including viral-host interactions that result in PASC), the NIH encourages the submission of applications for Administrative Supplements to active NIH grants to support this research. It is envisioned that the applicants for this highly competitive program will propose cross-disciplinary and collaborative research teams to address their proposed hypotheses and will have one or more of the following:

• Expertise in developing models of similar diseases/syndromes; have particular focus on animal models of SARS-CoV-2 infection that accurately simulate the disease process in humans (e.g., nonhuman primates and other relevant models) and elucidate the pathogenesis of the cluster of multi-tissue/organ dysfunction characteristic of PASC;
• Expertise in the pathobiology of similar post-infection disorders that share clinical manifestations with PASC;
• Mechanistic hypotheses regarding the pathobiology of PASC based on experience or expertise in chronic viral infection, germane biological pathways, systems, organs, or diseases;
• Expertise and experience in cross-disciplinary modeling of tissue/organ/system dysfunction caused by other forms of tissue/organ/system injury relevant to multisystem dysfunction in PASC;
• Expertise and experience in using biospecimens from COVID-19 and/or PASC patients to pursue assays and in vitro studies to gain mechanistic insights.

Supported research is expected to inform the diagnosis, prevention, mitigation, and/or treatment of PASC through elucidating the pathogenesis of post-acute sequelae and the identification of associated mechanistic pathways. This could include studies that develop or leverage nonhuman primate (NHP) and/or other animal models to study the long-term consequences of SARS-CoV-2 infection, its protean symptomatology, and the possible multiple clinical clusters/sub-phenotypes it potentiates.

Possible research interests include but are not limited to the following:

• Studies of SARS-CoV-2 clearance in different tissues after acute infection, with focus on potential persistence of virus and its effects on organ function and chronic immune activation;
• In-depth characterization of immune response that could shed light on development of autoantibodies;
• Modeling of the interaction between pre-existing organ dysfunction/pathology (e.g., obesity, diabetes, hypertension) and the superimposition of viral infection/injury;
• Host and environmental factors and associated biological pathways (including the microbiome or existing cardiac, respiratory, metabolic, neurologic, or hematologic conditions) that predispose to development of, or resistance to, PASC;
• Time course and features of virus-host interactions leading to PASC, including the impact of SARS-CoV-2 infection on innate and adaptive immune responses;
• Host and environmental factors and the associated biological pathways that mediate the intensity and duration of the neurological, metabolic, immunologic, hematologic, and cardiopulmonary and vascular dimensions of PASC, including long-term host tissue responses, and affect recovery (e.g., modeling of viral infection on inflammation in the brain and CNS dysfunction);
• Biological effects/consequences of the virus-host interaction of SARS-CoV2 infection via ACE2 on modulating tissue/organ function over time including both short-term and long-term sequelae (e.g., mechanistic interplay between the ACE2-expressing neuroepithelial cells, the host-tissue pro-inflammatory milieu, the blood-brain-barrier and alterations in sensory neuron function in the pathogenesis of anosmia in PASC);
• Development of animal or in vitro models of PASC suitable for pathobiological studies;
• Animal model studies of PASC pathobiology that evaluate intermediate and/or analogous endpoints of potential clinical correlates of PASC (e.g., learning/memory, anxiety as well as loss of smell, etc.);
• Studies elucidating the pathogenesis of the cluster of multi-tissue/organ dysfunction characteristic of PASC;
• Use of artificial intelligence or machine learning approaches to understand the pathobiology of PASC, its manifestations, and potential prevention strategies;
• Cellular, metabolic, and immune factors as a result of viral infection as a trigger/sustainer of PASC;
• Dynamics of innate and adaptive immune responses in PASC and implications for screening and diagnostic assay development;
• Using single cell -omics and spatial -omics to systematically (unbiasedly) discover key individual cells and molecular pathways likely responsible for PASC. Discovery studies such as this may generate innovative hypotheses for future PASC-related studies;
• Models or methods which serve as predictors for risk or resilience in the development of PASC that incorporate the study of sex differences in susceptibility or pathobiological mechanisms, including but not limited to biologically based variables such as hormones, physical features, anatomy, or biomarkers;
• Studies assessing the pathobiology of PASC across the lifespan (e.g., mechanisms relevant to populations such as infants, children, adolescents, and pregnant and lactating individuals).

Applicants are strongly encouraged to visit https://www.nhlbi.nih.gov/node-general/frequently-asked-questions-notice-special-interest-nosi-pathobiological-mechanisms to review FAQs associated with this NOSI.

Applications proposing to conduct clinical trials are not appropriate for this initiative, will be considered nonresponsive, and will not proceed to review. Supplements to existing clinical trials are allowed. However, supplement funding may only be used to support the pathobiology research activities described above.

Requirements

The NIH expects and supports the timely release and sharing of research data from NIH-supported studies for use by other researchers to expedite the translation of research results into knowledge, products, and procedures to improve human health (https://grants.nih.gov/grants/policy/data_sharing/). The overarching goal of this NOSI is to lead to rapid delineation of PASC pathobiology in order to foster progress in diagnostic, therapeutic, and preventive avenues for this condition. To achieve those goals, applicants must pledge to rapidly share data and biospecimens where it is not prohibited (i.e., Tribal data sovereignty) with the NIH RECOVER (https://recovercovid.org/) data and biospecimen repositories and ultimately with the broader research community.

Award recipients will work closely with RECOVER on data sharing activities to advance the science of PASC research across the country.

Application and Submission Information

Applications for this initiative must be submitted using the following opportunity or its subsequent reissued equivalent.

• PA-20-272 Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)

For the purpose of this NOSI, eligible activity codes for applications are limited to the following: U01, U19, R01, P01, R33, R61/R33, UG3/UH3.

To be eligible for a one-year Administrative Supplement under this NOSI, the parent award that the administrative supplement is based on must be an active NIH award (i.e., not be in an extension period) at the time the supplement is awarded.

To be eligible for a two-year Administrative Supplement under this NOSI, the parent award that the administrative supplement is based on must:

• be an active NIH award (i.e., not be in an extension period) at the time the supplement is awarded; and
• have sufficient time left to complete the studies proposed, after the supplement has been awarded within the existing project period.

All instructions in the SF424 (R&R) Application Guide and PA-20-272, must be followed, with the following additional instructions:

• Research Strategy section is limited to 6 pages and should include a summary or abstract of the funded parent award or project and the planned timeline for the proposed research.
  • Describe how the proposed project will have potential to inform the diagnosis, prevention, mitigation, and/or treatment of PASC through elucidating the pathogenesis of post-acute sequelae and the identification of associated mechanistic pathways. Provide intended plans for achieving cross-disciplinary and collaborative research.
  • If proposing to develop or leverage NHP and/or other animal models, provide a rationale to justify the use and appropriateness of the model to study the long-term consequences of SARS-CoV-2 infection, its protean symptomatology, and the possible multiple clinical clusters/sub-phenotypes it potentiates.
  • Describe plans to address relevant biological variables, such as sex, for studies in vertebrate animals, in vitro models or human biospecimens
  • Describe plans for rapidly sharing data and biospecimens with the NIH RECOVER data and biospecimen repositories and ultimately with the broader research community, including as appropriate, deposition into dbGaP. Include a description of how data will be made to be findable and accessible to the research community.
  • Describe plans for rapidly submitting results for publication.
• Application Due Date January 24, 2022 by 5:00 PM local time of applicant organization.
• Budget
  • Given the need for rapid progress toward an understanding of the pathobiology underpinning PASC, a one-year project period is strongly preferred. Up to 2 years of support may be requested only with compelling justification and sufficient time remains on parent award as described above.
  • The application budget is not expected to exceed a maximum direct cost of $750,000 per year. Supplement applications for COVID-19 research may request budgets that exceed the parent award. The proposed budget must be reasonable and reflect the actual needs of the proposed project.
  • The NIH anticipates funding up to 25 awards.

• Some NHP species have greater availability than others. If proposing to use NHPs from a ORIP-supported resource, please review NIH's Updated Notice of Limited Availability of Research Non-Human Primates (NOT-OD-21-080). Applicants are encouraged to use additional large animal resources supported by the NIH such as the National Swine Resource and Research Center (https://nsrrc.missouri.edu/) or National Ferret Resources and Research Center (https://medicine.uiowa.edu/nfrc/). If proposing the use or development of a large animal model, include information on animal availability and justify the selection of species and animal source.

IMPORTANT:: For funding consideration, all applicants must designate NOT-OD-22-038 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 (R&R) Form. Applications without this information in box 4B will not be considered for this initiative.

Before submitting a supplement request, applicants are strongly encouraged to contact their program officer at the Institute or Center (IC) supporting the parent award with any questions and to discuss whether the proposed supplement is within the scope of the parent award. For general questions regarding the content of this Notice, please send questions to the RECOVER Initiative mailbox.

Review Process and Criteria

Proposals submitted in response to this NOSI will be reviewed by the trans-NIH RECOVER Initiative staff. Each IC that issued the parent award will conduct an initial administrative review of applications that will then be reviewed and prioritized by staff of the trans-NIH RECOVER Initiative. Applications will be evaluated for responsiveness, scientific, technical, and programmatic merit.

Only the administrative review criteria described below will be considered in the review process:

Budget and Period of Support

NIH staff will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Overall Impact

Given that the scope of this administrative supplement announcement is to make rapid progress in understanding the biological mechanisms underpinning the pathogenesis of PASC, including the pathogenic mechanisms responsible for the multi-tissue/organ/system dysfunction leading to the various symptoms of PASC:

• To what extent will the proposed research have the potential to increase understanding of the pathobiological mechanisms that underlie the long-term effects of SARS CoV-2 infection?
• If development of an animal or in vitro model is proposed, how strong is the applicant expertise in developing and/or using animal or in vitro models of similar diseases/syndromes? Of particular interest, how strong is the applicant expertise in developing and/or using animal models of SARS-CoV-2 infection that accurately simulate the disease process in humans (e.g., NHPs and other relevant models) and elucidate the pathogenesis of the cluster of multi-tissue/organ dysfunction characteristic of PASC?
• To what extent do the applicants have expertise in the pathobiology of similar post-infection disorders or that share clinical manifestations with PASC?
• To what extent have the applicants developed mechanistic hypotheses regarding the pathobiology of PASC based on experience or expertise in pertinent biological pathways, systems, organs, or diseases?
• How strong are the expertise and experience in cross-disciplinary modeling of tissue/organ/system dysfunction caused by other forms of tissue/organ/system injury relevant to multisystem dysfunction in PASC?
• To what extent do the applicants propose cross-disciplinary and collaborative research?
  • For this particular announcement, note the following: A Multiple PD/PI leadership format is strongly encouraged. The application should include at least one PD/PI with expertise in SARS-CoV-2 science and at least one PD/PI whose primary expertise is in physiology, pathophysiology, pathobiology, and/or metabolism. The Multiple PD/PI leadership team might not have previously published together or otherwise have an extensive history of collaboration. The development of the project itself, as reflected in the quality of the preliminary data, the rigor of the approach, and the Multiple PD/PI leadership plan, can provide evidence of a strong and dedicated Multiple PD/PI team.
• To what extent is the parent award highly related to the new research proposed and focused on the pathobiology of PASC and/or other relevant post-viral infection condition(s)?
• If the applicants propose to develop or leverage NHP and/or other animal models, how sufficient is the rationale to justify the use of the model and its appropriateness to study the long-term consequences of SARS-CoV-2 infection, its protean symptomatology, and the possible multiple clinical clusters/sub-phenotypes it potentiates?
• What potential does the proposed research have to inform the diagnosis, prevention, mitigation, and/or treatment of PASC through elucidating the pathogenesis of post-acute sequelae and the identification of associated mechanistic pathways?
• Do the applicants indicate that they will rapidly share data and biospecimens with the NIH RECOVER data and biospecimen repositories and ultimately with the broader research community, including, as appropriate, deposition into dbGaP, and do they indicate they will rapidly submit results for publication?
• How strong are the plans for data sharing? Will the results and data be findable and accessible to the research community?
• Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals, in vitro models or human biospecimens?

Inquiries

Please contact the program officer from the Institute or Center supporting the active award regarding specific questions on the proposed project.

Please direct general inquiries regarding this Notice to:

RECOVER Initiative
Email: [email protected]