Sunday, January 17, 2016

How to make vaccine immunity to persist longer?

Most vaccines, if not all, work through antibody mediated neutralization of infection. Within few days of vaccination initial waves of low-affinity antibodies are produced by antigen-specific plasmablasts via extra-germinal center (GC) reactions. However, those plasmablast are short-lived and disappear within next 7-14 days

Long-term vaccine-induced immunity is maintained by long-lived plasma cells (LLPCs) and memory B cells (MBCs), both cell types generated within germinal-center (GC) reactions. The difference between these cell types is that only LLPCs can secrete high affinity antibodies and this happens spontaneously, in a steady-state. Level of neutralizing antibodies secreted by LLPCs determine degree of immunity in vaccinated individuals

But what is the function of MBCs and how are they related to LLPCs? Its not clear. MBCs can express high affinity IgM or IgG but they do not secrete antibodies. However, they can rapidly respond to secondary infection by differentiating into antibody forming cells (maybe even into LLPCs), if LLPC-mediated Ab protection is breached. Since antibody specificity produced by LLPCs are "fixed" during primary infection, they lack flexibility and are in fact useless if secondary infection is slightly different (mutated) from primary infection. 

Precise mechanisms how MBCs or LLPCs are formed during primary infection is lacking. Are they related (derived from the same B cell clones?) or independently generated (based on affinity or time of entering GC?).  

In this paper, the authors have used quite old technique, BrdU pulse chase, to label proliferating naive B cells and follow their fate up to 2 months. BrdU is incorporated into DNA of actively proliferating cells and can be later detected by anti-BrdU antibody. BrdU+ cells are those cells which at some point previously underwent a brief burst of proliferation and then entered a quiet state as expected for MBCs or LLPCs. By "pulsing" mice with BrdU at different times post antigen injection and then "chasing" BrdU+ cells, one could determine what percentage of MBCs or LLPCs are formed at what time.

So, doing this type of analysis, the authors showed that antigen-specific MBCs and LLPCs have different kinetics of formation. Namely, most MBCs are formed before day 14, and most LLPCs are formed after day 14.

This dichotomy between MBCs and LLPCs formation was supported by finding that disruption of GC reaction by anti-CD40L on days 12-14, reduced number of antigen-specific LLPCs but has no or little effect on antigen-specific MBCs formation.

Interestingly, V gene sequencing for mutational analysis revealed that some MBCs are generated at the same time as LLPCs and are similarly enriched with mutations.  

In summary, using simple method of cell labeling, the authors showed that in mice majority of GC-derived MBCs are formed earlier than GC-derived LLPCs.

How this results could applied to vaccination? Clearly, this study suggests that vaccines that allow maintenance of "prolonged" GC reaction would produce more of LLPCs and high levels of serum antibodies.

However, one drawback of this study is that the authors did not analyze actual antigen-specific antibody level in the serum and correlate it with the main findings. For example, would early MBCs compensate for the loss of LLPCs in anti-CD40L injected mice? Without such data, we cannot be sure how "time-span" of vaccine-induced GC reaction would affect level of neutralization antibodies in the serum 

David Usharauli

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