“…Long-lasting GCs have classically been observed in the context of chronic infections and gut microbiota exposure 25 , 26 , conditions known to have continuous live sources of renewed antigen. Recent reports of longer-lasting GCs in influenza infection 27 , SARS-CoV-2 infection 28 and human RNA vaccines 29 – 31 have raised renewed interest in the possibility of long-lasting GCs potentially under conditions of low or absent renewed antigen exposure. Here we demonstrate clearly that GCs can last for at least 191 days in the absence of new antigen, using an experimental system taking advantage of protein immunization, a 12-day slow-delivery immunization strategy, a robust adjuvant and the use of Env probes to identify antigen-specific B GC cells.…”
Germinal centres are the engines of antibody evolution. Here, using human immunodeficiency virus (HIV) Env protein immunogen priming in rhesus monkeys followed by a long period without further immunization, we demonstrate germinal centre B (B
GC
) cells that last for at least 6 months. A 186-fold increase in B
GC
cells was present by week 10 compared with conventional immunization. Single-cell transcriptional profiling showed that both light- and dark-zone germinal centre states were sustained. Antibody somatic hypermutation of B
GC
cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding B
GC
cells were still 49-fold above baseline at 29 weeks, which suggests that they could remain active for even longer periods of time. High titres of HIV-neutralizing antibodies were generated after a single booster immunization. Fully glycosylated HIV trimer protein is a complex antigen, posing considerable immunodominance challenges for B cells
1
,
2
. Memory B cells generated under these long priming conditions had higher levels of antibody somatic hypermutation, and both memory B cells and antibodies were more likely to recognize non-immunodominant epitopes. Numerous B
GC
cell lineage phylogenies spanning more than the 6-month germinal centre period were identified, demonstrating continuous germinal centre activity and selection for at least 191 days with no further antigen exposure. A long-prime, slow-delivery (12 days) immunization approach holds promise for difficult vaccine targets and suggests that patience can have great value for tuning of germinal centres to maximize antibody responses.
“…Long-lasting GCs have classically been observed in the context of chronic infections and gut microbiota exposure 25 , 26 , conditions known to have continuous live sources of renewed antigen. Recent reports of longer-lasting GCs in influenza infection 27 , SARS-CoV-2 infection 28 and human RNA vaccines 29 – 31 have raised renewed interest in the possibility of long-lasting GCs potentially under conditions of low or absent renewed antigen exposure. Here we demonstrate clearly that GCs can last for at least 191 days in the absence of new antigen, using an experimental system taking advantage of protein immunization, a 12-day slow-delivery immunization strategy, a robust adjuvant and the use of Env probes to identify antigen-specific B GC cells.…”
Germinal centres are the engines of antibody evolution. Here, using human immunodeficiency virus (HIV) Env protein immunogen priming in rhesus monkeys followed by a long period without further immunization, we demonstrate germinal centre B (B
GC
) cells that last for at least 6 months. A 186-fold increase in B
GC
cells was present by week 10 compared with conventional immunization. Single-cell transcriptional profiling showed that both light- and dark-zone germinal centre states were sustained. Antibody somatic hypermutation of B
GC
cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding B
GC
cells were still 49-fold above baseline at 29 weeks, which suggests that they could remain active for even longer periods of time. High titres of HIV-neutralizing antibodies were generated after a single booster immunization. Fully glycosylated HIV trimer protein is a complex antigen, posing considerable immunodominance challenges for B cells
1
,
2
. Memory B cells generated under these long priming conditions had higher levels of antibody somatic hypermutation, and both memory B cells and antibodies were more likely to recognize non-immunodominant epitopes. Numerous B
GC
cell lineage phylogenies spanning more than the 6-month germinal centre period were identified, demonstrating continuous germinal centre activity and selection for at least 191 days with no further antigen exposure. A long-prime, slow-delivery (12 days) immunization approach holds promise for difficult vaccine targets and suggests that patience can have great value for tuning of germinal centres to maximize antibody responses.
“…More than 90% of YFP + lung cells showed a phenotype associated with MBCs (CD38 + GL-7 − ) ( Figure 1 C). By contrast, only 30% of YFP + mediastinal lymph node cells showed an MBC phenotype, and a great majority of them were committed to GCs (CD38 − GL-7 + ) that persisted long after viral clearance ( Figure 1 C; Yewdell et al., 2021 ). Figure 1 MBCs in influenza infection (A) Experimental approach.…”
“…For some broadly neutralizing HIV antibodies, this process can take years (Liao et al, 2013). Even for acute infections where the pathogen is presumably cleared, such as influenza virus, germinal centers can persist for long periods of time (Bannard et al, 2013;Rothaeusler and Baumgarth, 2010;Yewdell et al, 2021). For vaccines to engage this lengthy process, the kinetics of antigen delivery and persistence are critical.…”
Section: Kinetics Of Antigen Delivery Influence Germinal Center and P...mentioning
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