Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses
Nicholas You Zhi CheangPeck Szee TanKiren PurushotormaWee Chee YapBenson ChuaKai Sen TanKirsteen M. TullettAileen Ying-Yan YeohCaris Qi Hui TanXinlei QianDouglas Jie Wen TayIrina CaminschiYee‐Joo TanPaul A. MacAryChee Wah TanMireille H. LahoudSylvie Alonso
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ABSTRACT Current COVID-19 vaccines face certain limitations, which include waning immunity, immune escape by SARS-CoV-2 variants, limited CD8 + cellular response, and poor induction of mucosal immunity. Here, we engineered a Clec9A-RBD antibody construct that delivers the Receptor Binding Domain (RBD) from SARS-CoV-2 spike protein to conventional type 1 dendritic cells (cDC1). We showed that single dose immunization with Clec9A-RBD induced high RBD-specific antibody titers with a strong T-helper 1 (T H 1) isotype profile and exceptional durability, whereby antibody titers were sustained for at least 21 months post-vaccination. Uniquely, affinity maturation of the antibody response was observed over time, as evidenced by enhanced neutralization potency and breadth across the sarbecovirus family. Consistently and remarkably, RBD-specific T-follicular helper cells and germinal center B cells were still detected at 12 months post-immunization. Increased antibody-dependent cell-mediated cytotoxicity (ADCC) activity of the immune sera was also measured over time with comparable efficacy against ancestral SARS-CoV-2 and variants, including Omicron. Furthermore, Clec9A-RBD immunization induced a durable poly-functional T H 1-biased cellular response that was strongly cross-reactive against SARS-CoV-2 variants, including Omicron, and with robust CD8 + T cell signature. Lastly, Clec9A-RBD single dose systemic immunization primed effectively RBD-specific cellular and humoral mucosal immunity in lung. Taken together, Clec9A-RBD immunization has the potential to trigger robust and sustained, systemic and mucosal immune responses against rapidly evolving SARS-CoV2 variants.Keywords:
Memory B cell
Antibody titer
Isotype
V(D)J recombination
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Recently, we reported that CD40(-/-) mice, exhibiting exclusively T cell-independent IgA class switch recombination (CSR), demonstrated near normal levels of IgA plasma cells in the gut lamina propria (LP), despite the complete lack of germinal centers (GCs). In this study, we have extended our analysis focusing on how to reconcile these findings using flow cytometry and molecular markers for IgA CSR. In agreement with our previous results with small intestinal LP, the colon LP was found to host IgA CSR only when lymphoid follicles were present. Thus, no IgA CSR was observed in the nonorganized colon LP. By contrast, the Peyer's patch (PP) was the dominant IgA CSR site in both CD40(-/-) and wild type (WT) mice, and they both hosted similar levels of mRNA expression for B cell activating factor of the TNF family, a proliferation inducing ligand, and inducible NO synthase, potential switch-factors for IgA. Unexpectedly, we found that PP B cells undergoing IgA CSR were GL7-intermediate. These cells had not undergone somatic hypermutations (SHMs), whereas GL7-high cells in WT PP, which exhibited GCs, were heavily mutated. Moreover, IgA plasma cells in the LP of CD40(-/-) mice demonstrated few mutations in their Ig V regions, whereas WT LP B cells from different sites showed extensive SHMs, which were also clonally related. Therefore, IgA CSR can occur in PP at a stage preceding manifest GC (GL7-intermediate), whereas SHM require GC formations (GL7-high). These findings reconcile that IgA CSR can occur in PP in the absence of GC with the fact that CD40(-/-) mice host near normal levels of IgA plasma cells in the LP.
RAG2
Lamina propria
Immunoglobulin A
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Integrated single-cell transcriptomic and BCR analyses reveal how antibody class switching influences human B cell fate and function.
Dynamics
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Humoral immunity
Antibody response
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Gene rearrangement
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Memory B cell
B-1 cell
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Emergence from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been facilitated by the rollout of effective vaccines. Successful vaccines generate high-affinity plasma blasts and long-lived protective memory B cells. Here, we show a requirement for T follicular helper (Tfh) cells and the germinal center reaction for optimal serum antibody and memory B cell formation after ChAdOx1 nCoV-19 vaccination. We found that Tfh cells play an important role in expanding antigen-specific B cells while identifying Tfh-cell-dependent and -independent memory B cell subsets. Upon secondary vaccination, germinal center B cells generated during primary immunizations can be recalled as germinal center B cells again. Likewise, primary immunization GC-Tfh cells can be recalled as either Tfh or Th1 cells, highlighting the pluripotent nature of Tfh cell memory. This study demonstrates that ChAdOx1 nCoV-19-induced germinal centers are a critical source of humoral immunity.
Memory B cell
Humoral immunity
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Memory B cell
Naive B cell
Follicular dendritic cells
Affinity maturation
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Establishment of humoral immune memory depends on two layers of defense: pre-existing antibodies secreted by long-lived plasma cells; and the antibodies produced by antigen-reactivated memory B cells. Memory B cells can now be considered as a second layer of defense upon re-infection by variant pathogens that have not been cleared by the long-lived plasma cell-mediated defense. Affinity-matured memory B cells are derived from the germinal center (GC) reaction, but the selection mechanism of GC B cells into the memory compartment is still incompletely understood. Recent studies have revealed the critical determinants of cellular and molecular factors for memory B cell differentiation from the GC reaction. In addition, the contribution of antibody-mediated feedback regulation to B cell selection, as exemplified by the B cell response upon COVID-19 mRNA vaccination, has now garnered considerable attention, which may provide valuable implications for future vaccine design.
Memory B cell
Immunological memory
B-1 cell
Naive B cell
Affinity maturation
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Memory B cell
Naive B cell
B-1 cell
Follicular dendritic cells
Affinity maturation
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