The Molecular Mechanisms of Combination Adjuvants (MMCA) (R01, Clinical Trial Not Allowed) notice of funding opportunity (NOFO) will support research studies to explore the mechanisms of combination adjuvants, with the long-term goal of improving vaccine design by predicting the immune profile they will elicit.
Background and Research Objectives
Using combination adjuvants, i.e., two or more adjuvants, within vaccine formulations offers the potential to fine-tune the resulting immune response toward a desired phenotype for a targeted disease or population, as well as to broaden an immune response and overcome immunodominance of individual pathogen epitopes. However, it is exceedingly difficult to predict how adjuvants will work in concert with one another. Some combinations have been shown to result in synergistic effects, some demonstrate antagonism between adjuvant effects, and others may be simply additive of the individual adjuvant effects. Mechanistic studies of combination adjuvants are needed to understand how adjuvants work together and to improve our capability to rationally design vaccines for a desired immune response.
Studies funded by this NOFO must explore the mechanisms of action (MOA) of combination adjuvants that have already been shown individually to be effective in enhancing or modulating immune responses when compared with an antigen alone. At least one adjuvant combination must be proposed but additional combinations are allowed. Applicants should include a strong rationale for combining adjuvants based on what is known about their individual immunostimulatory properties and effects in previously studied vaccines. Adjuvant combinations that include non-Toll-like receptor agonists are of particular interest.
Other requirements include: 1) examination of immune mechanisms in animal models and 2) if standard inbred and germ-free mouse models are used, validation in more complex model systems to demonstrate translatability toward human use. Refer to the published NOFO for examples.
Specific Areas of Research Interest
MOA studies may include, but are not limited to:
- Quantitative and qualitative assessments of antibody production, avidity, and function.
- CD4 and CD8 T cell activation and function.
- Induction and maintenance of innate and adaptive immune memory.
- Tissue-specific immunity.
- Studies of signaling pathways and cascades.
- Characterization of innate immunity including, but not limited to, studies of dendritic cells, macrophages, NK cells, innate lymphoid cells, neutrophils, and complement.
- Pathogen challenge studies showing protective efficacy or mitigation of disease.
- Systems immunology analyses.
- Safety studies, such as measurement of serum levels of proinflammatory cytokines or determination of weight loss, fever, or tissue damage to demonstrate improved immunogenicity without increased reactogenicity.
- Determination of correlates of immunity.
- Use of computational/mathematical modeling to examine MOA and synergistic effects (must include experimental validation).
NIAID will consider applications including the following types of studies nonresponsive and not review them:
- Studies on AIDS, HIV, or SIV.
- Projects that do not examine immune mechanisms in animal models.
- Projects that only examine immune mechanisms in standard inbred and germ-free mouse lines without validation and/or further mechanistic examination using more complex model systems (e.g., Collaborative Cross mice, microbial experienced (“dirty”) mice, humanized mice, other relevant animal models, in vitro human models).
- Projects that use only one adjuvant without combining it with at least one additional adjuvant.
- Clinical trials (all phases). However, the use of samples obtained from human subjects in clinical trials funded through other mechanisms is allowed, as is the use of samples obtained from human subjects treated with licensed vaccines or drugs for the FDA-approved indication.
- Projects focused primarily on screening assays to identify adjuvants or adjuvant combinations, rather than on mechanism of action.
- Projects that focus primarily on technology, reagent, or animal model development. However, these may be included as necessary parts of the project if well justified by the research aims and preliminary data.
- The use of compounds that have not previously been shown to have adjuvant activity when used individually or when used in combination.
- Studies that are focused on the development of vaccines or on determining vaccine efficacy, rather than focusing on the mechanisms of action of combination adjuvants.
Intra-Program Collaboration
To promote collaboration among program participants, each applicant will set aside a minimum of $50,000 in direct costs during each year of research, beginning in Year 2, for collaborative projects amongst the MMCA investigators.
Investigators should not include or propose specific collaborative projects within their application.
Award Budget and Project Period
Application budgets need to reflect the actual needs of the proposed project and are expected to be less than $500,000 in direct costs per year. The scope of the proposed project should determine the project period, although the maximum is 5 years.
NIAID expects to fund four to six awards in fiscal year 2026.
Application and Submission Information
Applications are due by June 10, 2025, at 5:00 p.m. local time of the applicant organization.
Contact Dr. Ari Joffe at ari.joffe@nih.gov or 240-669-5084 for scientific or research questions. Direct questions about peer review to Dr. Michael Opata at michael.opata@nih.gov or 240-627-3319.