Nucleoside modified mRNA combined with Acuitas Therapeutics’ lipid nanoparticles (LNPs) has been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later in humans with the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due to the LNPs’ ionizable lipid component. The inflammatory property is key to support the development of potent humoral immune responses. However, the mechanism by which this platform drives T follicular helper (Tfh) cells and humoral immune responses remains unknown. Here we show that lack of Langerhans cells or cDC1s neither significantly affected the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cells and humoral immune responses, nor susceptibility towards the lethal challenge of influenza and SARS-CoV-2. However, the combined deletion of these two DC subsets led to a significant decrease in the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cell and humoral immune responses. Despite these observed defects, these mice remained protected from lethal influenza and SARS-CoV-2 challenges. We further found that IL-6, unlike neutrophils, was required to generate normal Tfh cells and antibody responses, but not for protection from influenza challenge. In summary, here we bring evidence that the mRNA-LNP platform can support the induction of protective immune responses in the absence of certain innate immune cells and cytokines. Author summary The mRNA-LNP vaccine platform has gained much attention with the ongoing SARS-CoV-2 pandemic. Millions of people are exposed to these vaccines daily, but their immune mechanism driving the antibody responses and side effects remains unexplored. Therefore, we tested this vaccine platform in the context of influenza and SARS-CoV-2 infections in mouse models that lack specific innate immune cells or cytokines known to play a role in inducing antibody responses. We show that the combined deletion of antigen-presenting innate immune cells and one of the inflammatory cytokines significantly inhibited adaptive immune cell responses triggered by this platform. However, despite the observed defects, the immune responses driven by the mRNA-LNP vaccine were still able to protect the animals from lethal influenza or SARS-CoV-2 challenges. This high degree of redundancy might be associated with the highly inflammatory nature of this platform.
【초록키워드】 Neutrophils, SARS-CoV-2, Vaccine, immune response, vaccination, Cytokines, adaptive, antibody, IL-6, Influenza, SARS-COV-2 infection, SARS-CoV-2 pandemic, susceptibility, Human, cytokine, mice, mRNA, humoral immune response, vaccine platform, mouse model, humoral immune responses, platform, mechanism, Inflammatory cytokine, immune mechanism, Tfh, Lipid nanoparticle, Evidence, Inflammatory, Support, Side effect, protective immune response, nucleoside, significant decrease, driving, responses, Cell, robust, PROTECT, shown, tested, affected, lack, significantly, remained, required, inhibited, generate, absence, triggered, subset, driven by, the antibody response, follicular, immune cell response, innate immune cell, Langerhans cell, PR8 HA, Tfh cell, the SARS-CoV-2, 【제목키워드】 Protective, anti-SARS-CoV-2 immune response, Langerhans cell,