Opportunity Information: Apply for RFA AI 21 041
The National Institutes of Health (NIH) funding opportunity "Innate Immune Memory Impacting HIV Acquisition and/or Control (R21 Clinical Trial Not Allowed)" (RFA-AI-21-041) supports exploratory, early-stage research aimed at understanding and harnessing innate immune mechanisms to help prevent HIV infection and/or limit the establishment and progression of HIV disease. The central scientific focus is on innate immune cell effector functions and the concept of innate immune memory (often described as "trained immunity"), with an emphasis on how durable functional reprogramming of innate immune responses might influence susceptibility to HIV or improve control of the virus after exposure or infection. The announcement encourages a broad range of studies, including basic molecular and cellular mechanism work, translational research that connects mechanistic findings to practical interventions or biomarkers, and clinical research involving human samples or observational work, as long as the proposed studies do not include a clinical trial.
As an R21 mechanism, the opportunity is geared toward innovative, high-risk/high-reward projects that may be at an earlier proof-of-concept stage rather than fully mature programs. Projects can investigate how innate immune cells (such as monocytes/macrophages, dendritic cells, natural killer cells, and other innate-like populations) develop enhanced or altered responsiveness after certain stimuli, and how those changes affect HIV acquisition at mucosal sites, early viral replication, reservoir establishment, or immune control. Applicants are encouraged to explore the pathways and signals that induce innate memory, the epigenetic and metabolic reprogramming that can sustain it, and the downstream effector functions that might be leveraged for prevention strategies or to reduce disease establishment. The scope is intentionally exploratory, supporting studies that generate new mechanistic insights, identify potential targets, or develop foundational data that could enable later-stage intervention studies under other mechanisms.
A key constraint is reflected in the title: clinical trials are not allowed. That means applicants should not propose interventional studies in humans that prospectively assign participants to an intervention to evaluate health outcomes. However, the FOA explicitly welcomes clinical research examining innate memory, which commonly includes research using human specimens, cohort-based analyses, or other non-interventional approaches that can illuminate innate immune memory signatures and their relationship to HIV risk or control. In practice, competitive applications would clearly separate permissible clinical research (for example, analyses of immune phenotypes, functional assays, or omics profiles from existing or newly collected observational cohorts) from any disallowed clinical trial activities.
Eligibility is broad and includes many types of domestic U.S. organizations such as state, county, and local governments; public and private institutions of higher education; independent school districts; special district governments; federally recognized Native American tribal governments; public housing authorities and Indian housing authorities; nonprofit organizations with or without 501(c)(3) status (as long as they are not institutions of higher education in those categories); for-profit organizations other than small businesses; and small businesses. The announcement also highlights eligibility for a wide range of mission-aligned and capacity-building institution types, including Historically Black Colleges and Universities (HBCUs), Hispanic-serving Institutions, Tribally Controlled Colleges and Universities (TCCUs), Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), as well as faith-based or community-based organizations and eligible federal agencies. Importantly, non-U.S. participation is allowed: non-domestic (non-U.S.) entities and foreign institutions may apply, non-domestic components of U.S. organizations are eligible, and foreign components are permitted as defined in the NIH Grants Policy Statement. This structure supports international and cross-regional collaborations, which is often critical for HIV research given the global distribution of HIV burden and the need to study diverse populations and exposure contexts.
Administratively, this is a discretionary grant opportunity offered by NIH, categorized under Education and Health, and associated with CFDA numbers 93.279 and 93.855. The original closing date listed is December 6, 2021, and the opportunity was created on July 7, 2021. While the provided source data does not specify an award ceiling or expected number of awards, the overarching intent is clear: to catalyze novel research directions on innate immune memory and effector functions that could eventually feed into new prevention concepts, immune-based strategies, or measurable immune correlates relevant to HIV acquisition and early control, with the near-term deliverables often being mechanistic insight, new experimental systems, or translational hypotheses suitable for later-stage funding.Apply for RFA AI 21 041
- The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Innate Immune Memory Impacting HIV Acquisition and/or Control (R21 Clinical Trial Not Allowed)" and is now available to receive applicants.
- Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.279, 93.855.
- This funding opportunity was created on 2021-07-07.
- Applicants must submit their applications by 2021-12-06. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
- Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.
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FAQs: Innate Immune Memory Impacting HIV Acquisition and/or Control (R21 Clinical Trial Not Allowed) (RFA-AI-21-041)
What is this NIH funding opportunity about?
This NIH opportunity supports exploratory, early-stage research focused on innate immune mechanisms that could help prevent HIV infection and/or limit the establishment and progression of HIV disease. The scientific centerpiece is innate immune cell effector functions and "innate immune memory" (often called "trained immunity"), including how durable functional reprogramming of innate immune responses might affect HIV susceptibility or control.
What research areas are encouraged?
The announcement encourages a broad range of studies, including:
- Basic molecular and cellular mechanism studies related to innate immune memory and effector function
- Translational research connecting mechanisms to practical interventions or biomarkers
- Clinical research that uses human samples or observational approaches, provided it does not include a clinical trial
What does "innate immune memory" (trained immunity) mean in the context of this opportunity?
Within the scope described, innate immune memory refers to durable functional changes in innate immune responses after certain stimuli. These changes can involve sustained reprogramming that alters how innate immune cells respond later, potentially influencing HIV acquisition at mucosal sites, early viral replication, reservoir establishment, or immune control after exposure or infection.
Which immune cells or populations can be studied?
The opportunity explicitly mentions innate immune cells such as monocytes/macrophages, dendritic cells, natural killer (NK) cells, and other innate-like populations. Projects can examine how these cells develop enhanced or altered responsiveness and how that relates to HIV acquisition and/or control.
What kinds of scientific questions fit especially well?
Examples of thematic areas encouraged in the description include:
- Pathways and signals that induce innate immune memory
- Epigenetic reprogramming that sustains durable innate immune changes
- Metabolic reprogramming underlying trained immunity
- Downstream effector functions that could be leveraged for prevention or limiting disease establishment
- Mechanisms affecting mucosal susceptibility, early replication, reservoir establishment, and immune control
Is this intended for mature, fully developed projects?
No. As an R21 mechanism, this opportunity is geared toward innovative, high-risk/high-reward projects, often at an earlier proof-of-concept stage rather than a fully mature research program. The scope is intentionally exploratory.
What are the expected near-term outcomes of an R21 project under this FOA?
Based on the stated intent, near-term deliverables commonly include new mechanistic insights, identification of potential targets, foundational datasets, new experimental systems, and translational hypotheses. The goal is to generate evidence that could enable later-stage intervention studies under other mechanisms.
Are clinical trials allowed under this funding opportunity?
No. The title and the description clearly state that clinical trials are not allowed. Applicants should not propose interventional studies in humans that prospectively assign participants to an intervention to evaluate health outcomes.
What types of human research are allowed if clinical trials are not allowed?
The FOA welcomes clinical research examining innate memory through non-interventional approaches. The description gives examples such as research using human specimens, cohort-based analyses, and other observational work that can identify innate immune memory signatures and relate them to HIV risk or control.
How should applicants handle the "no clinical trial" constraint in their application?
Competitive applications, as implied by the description, should clearly separate permissible clinical research (for example, immune phenotyping, functional assays, or omics profiling using existing or newly collected observational cohorts) from activities that would qualify as a disallowed clinical trial (prospective assignment to an intervention to evaluate outcomes).
Does the opportunity support studies related to HIV acquisition at mucosal sites and early infection events?
Yes. The scope explicitly includes research on how trained immunity and innate effector functions might affect HIV acquisition at mucosal sites, early viral replication, reservoir establishment, and early immune control.
Does the opportunity support translational work tied to biomarkers or immune correlates?
Yes. The description encourages translational research connecting mechanistic findings to practical interventions or biomarkers, and it also mentions measurable immune correlates relevant to HIV acquisition and early control as part of the longer-term intent.
Who is eligible to apply (U.S. organizations)?
Eligibility is broad and includes many domestic U.S. organization types, including state, county, and local governments; public and private institutions of higher education; independent school districts; special district governments; federally recognized Native American tribal governments; public housing authorities and Indian housing authorities; nonprofit organizations (with or without 501(c)(3) status, in the categories described); for-profit organizations other than small businesses; and small businesses.
Are minority-serving and capacity-building institutions specifically noted as eligible?
Yes. The announcement highlights eligibility for Historically Black Colleges and Universities (HBCUs), Hispanic-serving Institutions, Tribally Controlled Colleges and Universities (TCCUs), Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions (AANAPISIs). It also notes faith-based or community-based organizations and eligible federal agencies.
Can non-U.S. (foreign) organizations apply?
Yes. Non-domestic (non-U.S.) entities and foreign institutions may apply. The description also states that non-domestic components of U.S. organizations are eligible and that foreign components are permitted as defined in the NIH Grants Policy Statement.
What makes international or cross-regional collaboration relevant for this opportunity?
The description notes that this structure supports international and cross-regional collaborations, which can be critical for HIV research given the global distribution of HIV burden and the need to study diverse populations and exposure contexts.
What is the funding mechanism?
This is an NIH R21 funding opportunity, described as supporting exploratory, early-stage, high-risk/high-reward research.
What is the opportunity number and title?
The opportunity is titled "Innate Immune Memory Impacting HIV Acquisition and/or Control (R21 Clinical Trial Not Allowed)" with FOA number RFA-AI-21-041.
What is the program category and CFDA association mentioned?
Administratively, it is described as a discretionary NIH grant opportunity categorized under Education and Health, and associated with CFDA numbers 93.279 and 93.855.
When was this opportunity created and what was the listed closing date?
The opportunity was created on July 7, 2021, and the original closing date listed is December 6, 2021.
Does the provided information state the award ceiling or number of expected awards?
No. The provided information explicitly notes that it does not specify an award ceiling or the expected number of awards.
What is the overall goal of funding projects under this announcement?
The overall intent is to catalyze novel research directions on innate immune memory and effector functions that could ultimately inform new prevention concepts, immune-based strategies, or measurable immune correlates relevant to HIV acquisition and early control, while producing near-term mechanistic and foundational outputs appropriate for an exploratory R21.
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