"Lipid nanoparticles are key immunostimulatory components of messenger RNA vaccines eliciting potent germinal center responses via induction of IL-6"

Emily Bettini, Katlyn Lederer, Brian Gaudette, David Allman, Norbert Pardi and Michela Locci

Vaccines are a life-saving tool that can provide protection from pathogens by eliciting high affinity antibody responses through germinal center (GC) reactions. Within GCs, T follicular helper (Tfh) cells deliver the necessary co-stimulatory molecules and cytokines to GC B cells, resulting in the selection of affinity-matured memory B cells and long-lived plasma cells. With the emergence of the severe acute respiratory coronavirus (SARS-CoV-2) pandemic, the messenger RNA (mRNA) vaccine platform has emerged as an incredibly effective vaccine platform due to its ease of adaptability to target emerging viral variants as well as its ability to drive potent humoral responses in humans. Data from our group has shown that these potent humoral immune responses correlate with a robust induction of Tfh cells, however, the mechanism of Tfh induction by mRNA vaccines remains largely unknown. Most mRNA vaccines do not include a traditional adjuvant but rather consist of mRNA encoding the antigen-of-interest and the lipid nanoparticles (LNPs) which encapsulate it. Herein, we demonstrate that LNPs are endowed with intrinsic adjuvant activity, and promote robust Tfh, GC B cell, long-lived plasma cell, and memory B cell responses when combined with different protein antigens. The presence of mRNA is not required for LNP adjuvant activity. Further, we have investigated the mechanism of LNP-mediated adjuvanticity and found that it is heavily reliant on the induction of IL-6 in the vaccine-draining lymph nodes but not on MyD88 or mitochondrial anti-viral signaling protein sensing mechanisms. We believe that this study identifies a versatile new Tfh-cell inducing adjuvant capable of enhancing vaccine efficacy in both protein subunit as well as mRNA vaccine platforms.