Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost
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Abstract
The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.
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SciScore for 10.1101/2021.09.08.21263248: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources The latter expression followed from a mechanistic consideration of bond dissociation triggered by the competition between the BCR and the antibody for the antigen (39). antigensuggested: NoneSoftware and Algorithms Sentences Resources If plasma cells died at the per capita rate δp, then the affinity-weighted cumulative plasma cell output would beIf the antibody production rate of plasma cells was β per generation (64), the instantaneous affinity-weighted antibody output would be βP(g), which given the clearance rate, δA, of circulating antibodies yielded the affinity-weighted cumulative antibody output … SciScore for 10.1101/2021.09.08.21263248: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources The latter expression followed from a mechanistic consideration of bond dissociation triggered by the competition between the BCR and the antibody for the antigen (39). antigensuggested: NoneSoftware and Algorithms Sentences Resources If plasma cells died at the per capita rate δp, then the affinity-weighted cumulative plasma cell output would beIf the antibody production rate of plasma cells was β per generation (64), the instantaneous affinity-weighted antibody output would be βP(g), which given the clearance rate, δA, of circulating antibodies yielded the affinity-weighted cumulative antibody output asWe performed the simulations and analysed the results using programs written in MATLAB. MATLABsuggested: (MATLAB, RRID:SCR_001622)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
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