Programming Durable Immune Responses To Vaccination

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Ali Hassan Ellebedy
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $593,729
Funding agency: National Institute of Allergy and Infectious Diseases

ABSTRACT
mRNA-based vaccines use lipid nanoparticles to transport mRNA-encoding antigens to the host cells. We have
recently shown that SARS-CoV-2 mRNA vaccination in humans induces a robust plasmablast response in blood
and a persistent GC reaction in the draining lymph nodes. This corresponded with enhanced anti-spike antibody
avidity in blood and enhanced affinity and neutralization capacity of bone marrow plasma cell (BMPC)-derived
monoclonal antibodies (mAbs). mRNA-based influenza vaccines could be a promising alternative to conventional
influenza vaccine platforms because of their high immunogenicity. The following questions, however, are yet to
be addressed: (1) does an mRNA-based influenza vaccination induce a robust and persistent GC reaction in
humans? (2) if yes, what drives such persistence, and how different is that from the GC response induced by
conventional influenza vaccines? (3) can an mRNA-based influenza vaccination induce a robust GC response
in the elderly (>65 years old)? (4) does robust GC response to influenza vaccination in humans correlate with a
more durable antibody response? (5) does an mRNA-based influenza vaccination induce a more sustained
increase in the frequency of long-lived BMPCs compared to conventional vaccines? (6) can a vaccine-induced
robust GC response overcome influenza antigenic imprinting in humans? (7) what are the molecular
determinants that dictate the persistence of BMPCs? Addressing these questions will allow us to discern the
cellular and molecular determinants associated with durable antibody responses to vaccination in humans. We
will directly examine antigen-specific GC and long-lived BMPC responses induced after mRNA-based and
conventional influenza vaccination in humans in the proposed studies. These responses will be examined in 18-
50 year-old and 65-80 year-old human adults. We will assess the persistence of the vaccine antigen in draining
lymph nodes as a potential mechanism for driving GC longevity in humans. We will examine how robust GC B
cell responses to influenza vaccination in humans could overcome antigenic imprinting and if that correlates with
a more durable antibody response. Finally, we will genetically analyze the mechanisms of action of the
transcriptional determinants that are preferentially expressed in plasma cells destined for longevity. Our findings
will potentially reveal the cellular and molecular determinants dictating the longevity and the breadth of elicited
antibody responses to influenza – and potentially other – vaccination in humans.

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