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NIH grant 1R01AI198771-01: Mechanistic Studies of Combination Adjuvants in the Establishment of B Cell Memory
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Luc Teyton. Award: $772010.
Start: 2026-07-23T00:00:00.
In full response to RFA-AI-25-006, we propose to study the mechanisms of cooperativity between three
adjuvants formulated in a single vaccine: NKT cell agonist, TLR7 agonist, and a Qb Virus-like particle (VLP). We
have previously successfully used this combination to produce high affinity protective anti-bacterial glycan
vaccines. In the process of understanding mechanisms of adjuvanticity, the role of the VLP itself was revealed
in long-term studies as critical for memory B cell responses. This phenomenon seems to be linked to the property
of empty VLPs to trigger an immediate inflammatory response dominated by IL-1a. Our goal is to understand
this response and the mechanisms leading to memory B cells. In addition, using novel chemistry, we will evaluate
the importance of a slow delivery as opposed to a bolus delivery of the adjuvants and antigen. In addition, we
contend that mechanistic studies will also allow the limitation of the potential side effects of adjuvants. To this
end, we will manipulate cellular and subcellular delivery of the vaccine cargo. To deliver on these questions,
three specific aims have been designed: Aim 1: Evaluate the coordination of effects between VLP, TLR7,
and NKT cell responses towards B cell helper activities. We have produced nanomolar affinity anti-glycan
antibodies by combining NKT cell and TLR7 agonists. However, in their absence long-term B cell memory
establishes and relies on the induction of an immediate inflammatory response by the VLP itself. This situation,
very similar to what was observed for LNPs in Covid vaccination, appears to be IL-1a-dependent. Genetic tools,
as well as biochemistry, and pharmacological agents will be used to deconvolute the role of VLP adjuvanticity in
B cell responses. Anti-glycan antibodies will be used as our model system. We hypothesize that “secondary
adjuvants” like IL-1 as central to memory establishment. Aim 2: Slow delivery of adjuvants and antigens to
promote B cell memory. Small, repeated administrations of antigen can produce efficient memory. We
hypothesize that in this scenario the dosage and nature of the adjuvant is equally important. This concept will be
tested by using new chemical tools of antigen and adjuvant delivery. Aim 3: Evaluate the importance of the
co-delivery of the adjuvants to subsets of antigen presenting cells. We hypothesize that the physical
aspects of adjuvanticity with respect to antigen uptake and delivery to processing compartments are critical. By
co-delivering antigen and adjuvants to particular cells using synthetic chemistry to control their pairing and
separation, mechanisms of adjuvant activity will be examined. The biological consequences of this molecular
based design of adjuvant combinations will be evaluated with respect to dosage, toxicity, and efficacy. Our
proposal is focused exclusively on the mechanisms of adjuvanticity and the ability for complex adjuvants to
promote long-term protective B cell immunity. Our translational interest is in conjugate vaccines and their
relevance to a large number of infectious and cancer vaccines.document fetched 2026-08-02 08:24