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    Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. Pardi Norbert,Hogan Michael J,Naradikian Martin S,Parkhouse Kaela,Cain Derek W,Jones Letitia,Moody M Anthony,Verkerke Hans P,Myles Arpita,Willis Elinor,LaBranche Celia C,Montefiori David C,Lobby Jenna L,Saunders Kevin O,Liao Hua-Xin,Korber Bette T,Sutherland Laura L,Scearce Richard M,Hraber Peter T,Tombácz István,Muramatsu Hiromi,Ni Houping,Balikov Daniel A,Li Charles,Mui Barbara L,Tam Ying K,Krammer Florian,Karikó Katalin,Polacino Patricia,Eisenlohr Laurence C,Madden Thomas D,Hope Michael J,Lewis Mark G,Lee Kelly K,Hu Shiu-Lok,Hensley Scott E,Cancro Michael P,Haynes Barton F,Weissman Drew The Journal of experimental medicine T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4 T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses. 10.1084/jem.20171450
    Single-Cell Profiling of the Antigen-Specific Response to BNT162b2 SARS-CoV-2 RNA Vaccine. Kramer Kevin J,Wilfong Erin M,Voss Kelsey,Barone Sierra M,Shiakolas Andrea R,Raju Nagarajan,Roe Caroline E,Suryadevara Naveenchandra,Walker Lauren,Wall Steven C,Paulo Ariana,Schaefer Samuel,Dahunsi Debolanle,Westlake Camille S,Crowe James E,Carnahan Robert H,Rathmell Jeffrey C,Bonami Rachel H,Georgiev Ivelin S,Irish Jonathan M bioRxiv : the preprint server for biology RNA-based vaccines against SARS-CoV-2 are critical to limiting COVID-19 severity and spread. Cellular mechanisms driving antigen-specific responses to these vaccines, however, remain uncertain. We used single-cell technologies to identify and characterized antigen-specific cells and antibody responses to the RNA vaccine BNT162b2 in longitudinal samples from a cohort of healthy donors. Mass cytometry and machine learning pinpointed a novel expanding, population of antigen-specific non-canonical memory CD4 and CD8 T cells. B cell sequencing suggested progression from IgM, with apparent cross-reactivity to endemic coronaviruses, to SARS-CoV-2-specific IgA and IgG memory B cells and plasmablasts. Responding lymphocyte populations correlated with eventual SARS-CoV-2 IgG and a donor lacking these cell populations failed to sustain SARS-CoV-2-specific antibodies and experienced breakthrough infection. These integrated proteomic and genomic platforms reveal an antigen-specific cellular basis of RNA vaccine-based immunity. ONE SENTENCE SUMMARY:Single-cell profiling reveals the cellular basis of the antigen-specific response to the BNT162b2 SARS-CoV-2 RNA vaccine. 10.1101/2021.07.28.453981