Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS

Roberto de Pascalis, Alicia Y. Chou, Catharine M. Bosio, Chiung Yu Huang, Dean A. Follmann, Karen L. Elkins

Research output: Contribution to journalArticle

Abstract

In contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological measures of antibodies are generally not predictive. Here, we used vaccines varying in efficacy to explore development of clinically useful correlates of protection for intracellular bacteria, using Francisella tularensis as an experimental model. F. tularensis is an intracellular bacterium classified as Category A bioterrorism agent which causes tularemia. The primary vaccine candidate in the U.S., called Live Vaccine Strain (LVS), has been the subject of ongoing clinical studies; however, safety and efficacy are not well established, and LVS is not licensed by the U.S. FDA. Using a mouse model, we compared the in vivo efficacy of a panel of qualitatively different Francisella vaccine candidates, the in vitro functional activity of immune lymphocytes derived from vaccinated mice, and relative gene expression in immune lymphocytes. Integrated analyses showed that the hierarchy of protection in vivo engendered by qualitatively different vaccines was reflected by the degree of lymphocytes' in vitro activity in controlling the intramacrophage growth of Francisella. Thus, this assay may be a functional correlate. Further, the strength of protection was significantly related to the degree of up-regulation of expression of a panel of genes in cells recovered from the assay. These included IFN-γ, IL-6, IL-12Rβ2, T-bet, SOCS-1, and IL-18bp. Taken together, the results indicate that an in vitro assay that detects control of bacterial growth, and/or a selected panel of mediators, may ultimately be developed to predict the outcome of vaccine efficacy and to complement clinical trials. The overall approach may be applicable to intracellular pathogens in general.

Original languageEnglish (US)
Article numbere1002494
JournalPLoS Pathogens
Volume8
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Fingerprint

Synthetic Vaccines
Vaccines
Francisella
Francisella tularensis
Tularemia
Lymphocytes
Bacteria
Biological Warfare Agents
Growth
Interleukin-1
Interleukin-6
Theoretical Models
Up-Regulation
Clinical Trials
Safety
Gene Expression
Antibodies
Infection

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS. / de Pascalis, Roberto; Chou, Alicia Y.; Bosio, Catharine M.; Huang, Chiung Yu; Follmann, Dean A.; Elkins, Karen L.

In: PLoS Pathogens, Vol. 8, No. 1, e1002494, 01.2012.

Research output: Contribution to journalArticle

de Pascalis, Roberto ; Chou, Alicia Y. ; Bosio, Catharine M. ; Huang, Chiung Yu ; Follmann, Dean A. ; Elkins, Karen L. / Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS. In: PLoS Pathogens. 2012 ; Vol. 8, No. 1.
@article{b0020283c839479e802564bc2aa21109,
title = "Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS",
abstract = "In contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological measures of antibodies are generally not predictive. Here, we used vaccines varying in efficacy to explore development of clinically useful correlates of protection for intracellular bacteria, using Francisella tularensis as an experimental model. F. tularensis is an intracellular bacterium classified as Category A bioterrorism agent which causes tularemia. The primary vaccine candidate in the U.S., called Live Vaccine Strain (LVS), has been the subject of ongoing clinical studies; however, safety and efficacy are not well established, and LVS is not licensed by the U.S. FDA. Using a mouse model, we compared the in vivo efficacy of a panel of qualitatively different Francisella vaccine candidates, the in vitro functional activity of immune lymphocytes derived from vaccinated mice, and relative gene expression in immune lymphocytes. Integrated analyses showed that the hierarchy of protection in vivo engendered by qualitatively different vaccines was reflected by the degree of lymphocytes' in vitro activity in controlling the intramacrophage growth of Francisella. Thus, this assay may be a functional correlate. Further, the strength of protection was significantly related to the degree of up-regulation of expression of a panel of genes in cells recovered from the assay. These included IFN-γ, IL-6, IL-12Rβ2, T-bet, SOCS-1, and IL-18bp. Taken together, the results indicate that an in vitro assay that detects control of bacterial growth, and/or a selected panel of mediators, may ultimately be developed to predict the outcome of vaccine efficacy and to complement clinical trials. The overall approach may be applicable to intracellular pathogens in general.",
author = "{de Pascalis}, Roberto and Chou, {Alicia Y.} and Bosio, {Catharine M.} and Huang, {Chiung Yu} and Follmann, {Dean A.} and Elkins, {Karen L.}",
year = "2012",
month = "1",
doi = "10.1371/journal.ppat.1002494",
language = "English (US)",
volume = "8",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "1",

}

TY - JOUR

T1 - Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS

AU - de Pascalis, Roberto

AU - Chou, Alicia Y.

AU - Bosio, Catharine M.

AU - Huang, Chiung Yu

AU - Follmann, Dean A.

AU - Elkins, Karen L.

PY - 2012/1

Y1 - 2012/1

N2 - In contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological measures of antibodies are generally not predictive. Here, we used vaccines varying in efficacy to explore development of clinically useful correlates of protection for intracellular bacteria, using Francisella tularensis as an experimental model. F. tularensis is an intracellular bacterium classified as Category A bioterrorism agent which causes tularemia. The primary vaccine candidate in the U.S., called Live Vaccine Strain (LVS), has been the subject of ongoing clinical studies; however, safety and efficacy are not well established, and LVS is not licensed by the U.S. FDA. Using a mouse model, we compared the in vivo efficacy of a panel of qualitatively different Francisella vaccine candidates, the in vitro functional activity of immune lymphocytes derived from vaccinated mice, and relative gene expression in immune lymphocytes. Integrated analyses showed that the hierarchy of protection in vivo engendered by qualitatively different vaccines was reflected by the degree of lymphocytes' in vitro activity in controlling the intramacrophage growth of Francisella. Thus, this assay may be a functional correlate. Further, the strength of protection was significantly related to the degree of up-regulation of expression of a panel of genes in cells recovered from the assay. These included IFN-γ, IL-6, IL-12Rβ2, T-bet, SOCS-1, and IL-18bp. Taken together, the results indicate that an in vitro assay that detects control of bacterial growth, and/or a selected panel of mediators, may ultimately be developed to predict the outcome of vaccine efficacy and to complement clinical trials. The overall approach may be applicable to intracellular pathogens in general.

AB - In contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological measures of antibodies are generally not predictive. Here, we used vaccines varying in efficacy to explore development of clinically useful correlates of protection for intracellular bacteria, using Francisella tularensis as an experimental model. F. tularensis is an intracellular bacterium classified as Category A bioterrorism agent which causes tularemia. The primary vaccine candidate in the U.S., called Live Vaccine Strain (LVS), has been the subject of ongoing clinical studies; however, safety and efficacy are not well established, and LVS is not licensed by the U.S. FDA. Using a mouse model, we compared the in vivo efficacy of a panel of qualitatively different Francisella vaccine candidates, the in vitro functional activity of immune lymphocytes derived from vaccinated mice, and relative gene expression in immune lymphocytes. Integrated analyses showed that the hierarchy of protection in vivo engendered by qualitatively different vaccines was reflected by the degree of lymphocytes' in vitro activity in controlling the intramacrophage growth of Francisella. Thus, this assay may be a functional correlate. Further, the strength of protection was significantly related to the degree of up-regulation of expression of a panel of genes in cells recovered from the assay. These included IFN-γ, IL-6, IL-12Rβ2, T-bet, SOCS-1, and IL-18bp. Taken together, the results indicate that an in vitro assay that detects control of bacterial growth, and/or a selected panel of mediators, may ultimately be developed to predict the outcome of vaccine efficacy and to complement clinical trials. The overall approach may be applicable to intracellular pathogens in general.

UR - http://www.scopus.com/inward/record.url?scp=84863115960&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863115960&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1002494

DO - 10.1371/journal.ppat.1002494

M3 - Article

C2 - 22275868

AN - SCOPUS:84863115960

VL - 8

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 1

M1 - e1002494

ER -