Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost

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,...

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Autores principales:	Amar K. Garg, Soumya Mittal, Pranesh Padmanabhan, Rajat Desikan, Narendra M. Dixit
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	SARS-CoV-2 vaccine efficacy affinity maturation prime-boost immunization germinal center (GC) Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/56051e2f77a54102a8ed5191ba0c60a4
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spelling	oai:doaj.org-article:56051e2f77a54102a8ed5191ba0c60a42021-12-01T16:33:16ZIncreased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost1664-322410.3389/fimmu.2021.776933https://doaj.org/article/56051e2f77a54102a8ed5191ba0c60a42021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.776933/fullhttps://doaj.org/toc/1664-3224The 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.Amar K. GargSoumya MittalPranesh PadmanabhanRajat DesikanNarendra M. DixitNarendra M. DixitFrontiers Media S.A.articleSARS-CoV-2vaccine efficacyaffinity maturationprime-boost immunizationgerminal center (GC)Immunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	SARS-CoV-2 vaccine efficacy affinity maturation prime-boost immunization germinal center (GC) Immunologic diseases. Allergy RC581-607
spellingShingle	SARS-CoV-2 vaccine efficacy affinity maturation prime-boost immunization germinal center (GC) Immunologic diseases. Allergy RC581-607 Amar K. Garg Soumya Mittal Pranesh Padmanabhan Rajat Desikan Narendra M. Dixit Narendra M. Dixit Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost
description	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.
format	article
author	Amar K. Garg Soumya Mittal Pranesh Padmanabhan Rajat Desikan Narendra M. Dixit Narendra M. Dixit
author_facet	Amar K. Garg Soumya Mittal Pranesh Padmanabhan Rajat Desikan Narendra M. Dixit Narendra M. Dixit
author_sort	Amar K. Garg
title	Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost
title_short	Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost
title_full	Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost
title_fullStr	Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost
title_full_unstemmed	Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost
title_sort	increased b cell selection stringency in germinal centers can explain improved covid-19 vaccine efficacies with low dose prime or delayed boost
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/56051e2f77a54102a8ed5191ba0c60a4
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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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