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Title: Strategic priming with multiple antigens can yield memory cell phenotypes optimized for infection with Mycobacterium tuberculosis: A computational study

Abstract

Lack of an effective vaccine results in 9 million new cases of tuberculosis (TB) every year and 1.8 million deaths worldwide. While many infants are vaccinated at birth with BCG (an attenuated M. bovis), this does not prevent infection or development of TB after childhood. Immune responses necessary for prevention of infection or disease are still unknown, making development of effective vaccines against TB challenging. Several new vaccines are ready for human clinical trials, but these trials are difficult and expensive; especially challenging is determining the appropriate cellular response necessary for protection. The magnitude of an immune response is likely key to generating a successful vaccine. Characteristics such as numbers of central memory (CM) and effector memory (EM) T cells responsive to a diverse set of epitopes are also correlated with protection. Promising vaccines against TB contain mycobacterial subunit antigens (Ag) present during both active and latent infection. We hypothesize that protection against different key immunodominant antigens could require a vaccine that produces different levels of EM and CM for each Ag-specific memory population. We created a computational model to explore EM and CM values, and their ratio, within what we term Memory Design Space. Our model captures events involvedmore » in T cell priming within lymph nodes and tracks their circulation through blood to peripheral tissues. We used the model to test whether multiple Ag-specific memory cell populations could be generated with distinct locations within Memory Design Space at a specific time point post vaccination. Boosting can further shift memory populations to memory cell ratios unreachable by initial priming events. By strategically varying antigen load, properties of cellular interactions within the LN, and delivery parameters (e.g., number of boosts) of multi-subunit vaccines, we can generate multiple Ag-specific memory populations that cover a wide range of Memory Design Space. As a result, given a set of desired characteristics for Ag-specific memory populations, we can use our model as a tool to predict vaccine formulations that will generate those populations.« less

Authors:
 [1];  [1];  [1];  [1]
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  1. Univ. of Michigan, Ann Arbor, MI (United States)
Publication Date:
Research Org.:
Univ. of Michigan, Ann Arbor, MI (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1239245
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Frontiers in Microbiology
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 1664-302X
Publisher:
Frontiers Research Foundation
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; subunit vaccine; T cell priming; cell-mediated immunity; agent-based model

Citation Formats

Ziraldo, Cordelia, Gong, Chang, Kirschner, Denise E., and Linderman, Jennifer J. Strategic priming with multiple antigens can yield memory cell phenotypes optimized for infection with Mycobacterium tuberculosis: A computational study. United States: N. p., 2016. Web. doi:10.3389/fmicb.2015.01477.
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Ziraldo, Cordelia, Gong, Chang, Kirschner, Denise E., & Linderman, Jennifer J. Strategic priming with multiple antigens can yield memory cell phenotypes optimized for infection with Mycobacterium tuberculosis: A computational study. United States. https://doi.org/10.3389/fmicb.2015.01477
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Ziraldo, Cordelia, Gong, Chang, Kirschner, Denise E., and Linderman, Jennifer J. Wed . "Strategic priming with multiple antigens can yield memory cell phenotypes optimized for infection with Mycobacterium tuberculosis: A computational study". United States. https://doi.org/10.3389/fmicb.2015.01477. https://www.osti.gov/servlets/purl/1239245.
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@article{osti_1239245,
title = {Strategic priming with multiple antigens can yield memory cell phenotypes optimized for infection with Mycobacterium tuberculosis: A computational study},
author = {Ziraldo, Cordelia and Gong, Chang and Kirschner, Denise E. and Linderman, Jennifer J.},
abstractNote = {Lack of an effective vaccine results in 9 million new cases of tuberculosis (TB) every year and 1.8 million deaths worldwide. While many infants are vaccinated at birth with BCG (an attenuated M. bovis), this does not prevent infection or development of TB after childhood. Immune responses necessary for prevention of infection or disease are still unknown, making development of effective vaccines against TB challenging. Several new vaccines are ready for human clinical trials, but these trials are difficult and expensive; especially challenging is determining the appropriate cellular response necessary for protection. The magnitude of an immune response is likely key to generating a successful vaccine. Characteristics such as numbers of central memory (CM) and effector memory (EM) T cells responsive to a diverse set of epitopes are also correlated with protection. Promising vaccines against TB contain mycobacterial subunit antigens (Ag) present during both active and latent infection. We hypothesize that protection against different key immunodominant antigens could require a vaccine that produces different levels of EM and CM for each Ag-specific memory population. We created a computational model to explore EM and CM values, and their ratio, within what we term Memory Design Space. Our model captures events involved in T cell priming within lymph nodes and tracks their circulation through blood to peripheral tissues. We used the model to test whether multiple Ag-specific memory cell populations could be generated with distinct locations within Memory Design Space at a specific time point post vaccination. Boosting can further shift memory populations to memory cell ratios unreachable by initial priming events. By strategically varying antigen load, properties of cellular interactions within the LN, and delivery parameters (e.g., number of boosts) of multi-subunit vaccines, we can generate multiple Ag-specific memory populations that cover a wide range of Memory Design Space. As a result, given a set of desired characteristics for Ag-specific memory populations, we can use our model as a tool to predict vaccine formulations that will generate those populations.},
doi = {10.3389/fmicb.2015.01477},
journal = {Frontiers in Microbiology},
number = ,
volume = 6,
place = {United States},
year = {Wed Jan 06 00:00:00 EST 2016},
month = {Wed Jan 06 00:00:00 EST 2016}
}
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Naive CD4+ T Cell Frequency Varies for Different Epitopes and Predicts Repertoire Diversity and Response Magnitude
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Human Effector and Memory CD8+ T Cell Responses to Smallpox and Yellow Fever Vaccines
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Endogenous Naive CD8+ T Cell Precursor Frequency Regulates Primary and Memory Responses to Infection
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A Single Peptide-Major Histocompatibility Complex Ligand Triggers Digital Cytokine Secretion in CD4+ T Cells
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Do most lymphocytes in humans really reside in the gut?
journal, December 2007

Association of mycobacterial antigen-specific CD4+ memory T cell subsets with outcome of pulmonary tuberculosis
journal, February 2010

IFNγ/TNFα specific-cells and effector memory phenotype associate with active tuberculosis
journal, June 2013

Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model
journal, December 2004

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journal, October 2013

A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment
journal, February 2015

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Vaccination against tuberculosis: How can we better BCG?
journal, May 2013

Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy
journal, January 2004

Delaying BCG vaccination from birth to 10 weeks of age may result in an enhanced memory CD4 T cell response
journal, September 2009

First-in-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults
journal, August 2015

Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial
journal, March 2013

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A cellular calculus for signal integration by T cells
journal, September 2000

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  • DOI: 10.1038/79782

Complete but curtailed T-cell response to very low-affinity antigen
journal, January 2009

  • Zehn, Dietmar; Lee, Sarah Y.; Bevan, Michael J.
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  • DOI: 10.1038/nature07657

T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation
journal, January 2008

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  • Nature Immunology, Vol. 9, Issue 3
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A multistage tuberculosis vaccine that confers efficient protection before and after exposure
journal, January 2011

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  • Nature Medicine, Vol. 17, Issue 2
  • DOI: 10.1038/nm.2285

Immune responses to Listeria monocytogenes
journal, October 2004

  • Pamer, Eric G.
  • Nature Reviews Immunology, Vol. 4, Issue 10
  • DOI: 10.1038/nri1461

Transcriptional control of effector and memory CD8+ T cell differentiation
journal, October 2012

  • Kaech, Susan M.; Cui, Weiguo
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    Integrating Non-human Primate, Human, and Mathematical Studies to Determine the Influence of BCG Timing on H56 Vaccine Outcomes
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    Integrating Non-human Primate, Human, and Mathematical Studies to Determine the Influence of BCG Timing on H56 Vaccine Outcomes
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