Induction of Robust B Cell Responses after Influenza mRNA Vaccination Is Accompanied by Circulating Hemagglutinin-Specific ICOS+ PD-1+ CXCR3+ T Follicular Helper Cells.

Gustaf Lindgren,Giuseppe Ciaramella,Karin Loré,Hugh Salter,Fredrika Hellgren,Ang Lin,Sebastian Ols,Shinu John,Olga Yuzhakov,Kapil Bahl,Elizabeth A Thompson,Frank Liang,Kimberly J Hassett,Luis A Brito

doi:10.3389/fimmu.2017.01539

Gustaf Lindgren, Giuseppe Ciaramella + Show 12 more

Open Access

https://doi.org/10.3389/fimmu.2017.01539

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Abstract

Modified mRNA vaccines have developed into an effective and well-tolerated vaccine platform that offers scalable and precise antigen production. Nevertheless, the immunological events leading to strong antibody responses elicited by mRNA vaccines are largely unknown. In this study, we demonstrate that protective levels of antibodies to hemagglutinin were induced after two immunizations of modified non-replicating mRNA encoding influenza H10 encapsulated in lipid nanoparticles (LNP) in non-human primates. While both intradermal (ID) and intramuscular (IM) administration induced protective titers, ID delivery generated this response more rapidly. Circulating H10-specific memory B cells expanded after each immunization, along with a transient appearance of plasmablasts. The memory B cell pool waned over time but remained detectable throughout the 25-week study. Following prime immunization, H10-specific plasma cells were found in the bone marrow and persisted over time. Germinal centers were formed in vaccine-draining lymph nodes along with an increase in circulating H10-specific ICOS+ PD-1+ CXCR3+ T follicular helper cells, a population shown to correlate with high avidity antibody responses after seasonal influenza vaccination in humans. Collectively, this study demonstrates that mRNA/LNP vaccines potently induce an immunological repertoire associated with the generation of high magnitude and quality antibodies.

Highlights

Emerging infections such as Ebola, Zika, Chikungunya, and pandemic influenza virus need vaccines that can be rapidly produced with antigen precision
We demonstrate that protective levels of antibodies to hemagglutinin were induced after two immunizations of modified non-replicating mRNA encoding influenza H10N8 strain (H10) encapsulated in lipid nanoparticles (LNP) in non-human primates
Advances in mRNA synthesis technology have led to increased mRNA stability, optimized translation capacity, and less indiscriminate activation of innate immunity by mRNA vaccines [2, 3, 6]. mRNA vaccines do not require device-mediated delivery methods as with DNA vaccines, and there is no concern of pre-existing immunity typically associated with viral vector vaccine platforms [3]. mRNA vaccines delivered in lipid nanoparticles (LNP) are well tolerated and highly immunogenic in mice, ferrets, non-human primates, and humans [5, 7]

Summary

Introduction

Emerging infections such as Ebola, Zika, Chikungunya, and pandemic influenza virus need vaccines that can be rapidly produced with antigen precision. Modified mRNA vaccines have received considerable attention as they are attractive in this aspect and were recently shown to induce sterilizing immunity to Zika virus infection and protection against lethal challenge with influenza virus [1,2,3,4,5]. Durable vaccine-induced antibody responses with a high degree of affinity maturation confer protection against most pathogens [8]. Within the dark zone of GCs, B cells that encounter cognate antigens undergo multiple rounds of proliferation and somatic hypermutation This is followed by antibody affinity maturation in the GC-light zone in a T follicular helper (Tfh) cell-dependent manner [11]. CXCR3+ cTfh cells in humans as well as CXCR3+ Tfh cells in LNs of rhesus macaques have been reported to correlate with the generation of high-avidity antibodies following vaccination [17, 18, 20]

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