University of Minnesota
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Milestone
2.3.a

Mechanisms of broad and durable immunity

In progress

Determine the mechanisms underlying the production of durable, broadly protective B-cell immunity driven by long-lived plasma cells in the bone marrow.

Progress Highlights

Matz 2024 assessed B-cell responses in peripheral blood and draining lymph nodes in vaccinees receiving licensed inactivated (Fluarix) or investigational mRNA-based quadrivalent influenza (Moderna mRNA-1010) vaccine, characterizing the dynamics of germinal center (GC) reactions that enable the generation of broad and durable antibody responses.

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McIntire 2024 examined the maturation of B cells within germinal centers (GC) that affect breadth and durability of B-cell responses to influenza vaccination. Using fine-needle aspiration of draining lymph nodes to longitudinally track antigen-specific GC B-cell responses to seasonal influenza vaccination, the study found that antigen-specific GC B cells persisted for at least 13 weeks after vaccination in two of seven healthy adult volunteers 13 weeks after vaccination and, in some cases, clones that developed in the persistent GC exhibited increased affinity to vaccine antigens and could bind and neutralize diverse influenza viruses.

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Motsoeneng 2024 measured H1 stalk-specific antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD) and cellular cytotoxicity (ADCC) in plasma samples from pregnant women enrolled in a randomized trial in Soweto, South Africa, to evaluate mechanisms through which vaccine-elicited HA stalk-specific antibodies confer protection against influenza illnesses. Results showed that H1 stalk-specific ADCP and ADCD, but not ADCC potential, were boosted by seasonal TIV and that H1 stalk-specific ADCD correlated with protection against influenza illness.

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Nellore 2023 showed that intramuscular influenza vaccination elicits HA-specific memory B cells that differed in expression of surface marker FcRL5 and transcriptional factor T-bet. The T-bet-expressing effector memory subset response correlated with long-lived Ab responses to influenza vaccination.

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Piepenbrink 2023 demonstrated that IIV vaccination stimulates H3N2-specific mAbs in humans that are broad and potent in their neutralization of virus in vitro, provide protection from H3N2 infection in a mouse model, and persist in long-lived Ab-producing plasma cells in the bone marrow.

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Yang 2023 characterized the breadth and diversity of the polyclonal serum Ab response elicited after H2 vaccination, showing that previous H2 exposure results in higher responses to the variable HA head domain while initial responses in H2-naïve participants are dominated by Abs targeting conserved epitopes. 

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Burton 2022 examined how aging impacts the memory B-cell response, using single-cell RNA sequencing and flow cytometry of influenza-vaccine-specific B-cells to delineate changes in B-cell memory generation, antibody mutation, and their subsequent selection in older persons. Results indicated age-related skewing in the memory B-cell compartment 6 weeks after vaccination.

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Edgar 2023 examined the mechanisms by which passive transfer of broadly reactive stalk-specific IgG Abs, induced in humans in a phase 1 clinical trial using a chimeric HA (cHA) vaccine candidate, protect against lethal influenza virus challenge in humanized mice. Results showed that cHA vaccination-induced IgG Abs fully protected FcγR humanized mice but not FcγR-deficient mice, suggesting a major role for FcγR pathways in the protective function of vaccine-elicited IgG antibodies.

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Moin 2022 examined the role of the immunosubdominant yet conserved HA stem as a target for bnAbs and showed that the co-immunization of two HA stem immunogens derived from group 1 and 2 IAVs (based on a ferritin nanoparticle platform) elicits cross-group protective immunity and nAb responses in mice, ferrets, and NHPs.

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