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A recombinant commensal bacteria elicits heterologous antigen-specific immune responses during pharyngeal carriage

A recombinant commensal bacteria elicits heterologous antigen-specific immune responses during pharyngeal carriage
A recombinant commensal bacteria elicits heterologous antigen-specific immune responses during pharyngeal carriage

The human nasopharynx contains a stable microbial ecosystem of commensal and potentially pathogenic bacteria, which can elicit protective primary and secondary immune responses. Experimental intranasal infection of human adults with the commensal Neisseria lactamica produced safe, sustained pharyngeal colonization. This has potential utility as a vehicle for sustained release of antigen to the human mucosa, but commensals in general are thought to be immunologically tolerated. Here, we show that engineered N. lactamica, chromosomally transformed to express a heterologous vaccine antigen, safely induces systemic, antigen-specific immune responses during carriage in humans. When the N. lactamica expressing the meningococcal antigen Neisseria Adhesin A (NadA) was inoculated intranasally into human volunteers, all colonized participants carried the bacteria asymptomatically for at least 28 days, with most (86%) still carrying the bacteria at 90 days. Compared to an otherwise isogenic but phenotypically wild-type strain, colonization with NadA-expressing N. lactamica generated NadA-specific immunoglobulin G (IgG)- and IgA-secreting plasma cells within 14 days of colonization and NadA-specific IgG memory B cells within 28 days of colonization. NadA-specific IgG memory B cells were detected in peripheral blood of colonized participants for at least 90 days. Over the same period, there was seroconversion against NadA and generation of serum bactericidal antibody activity against a NadA-expressing meningococcus. The controlled infection was safe, and there was no transmission to adult bedroom sharers during the 90-day period. Genetically modified N. lactamica could therefore be used to generate beneficial immune responses to heterologous antigens during sustained pharyngeal carriage.

1946-6234
Laver, Jay
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Gbesemete, Diane
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Dale, Adam
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Pounce, Zoe Caroline
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Webb, Carl N
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Roche, Eleanor F
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Guy, Jonathan
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Berreen, Graham A
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Belogiannis, Konstantinos
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Hill, Alison
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Ibrahim, Muktar
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Ahmed, Muhammad
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Cleary, David
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Pandey, Anish
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Humphries, Holly E.
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Allen, Lauren
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De Graaf, Hans
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Maiden, Martin C. J.
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Faust, Saul
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Gorringe, Andrew
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Read, Robert
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Laver, Jay
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Gbesemete, Diane
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Dale, Adam
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Pounce, Zoe Caroline
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Webb, Carl N
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Roche, Eleanor F
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Guy, Jonathan
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Berreen, Graham A
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Belogiannis, Konstantinos
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Hill, Alison
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Ibrahim, Muktar
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Ahmed, Muhammad
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Cleary, David
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Pandey, Anish
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Humphries, Holly E.
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Allen, Lauren
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De Graaf, Hans
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Maiden, Martin C. J.
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Faust, Saul
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Gorringe, Andrew
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Read, Robert
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Laver, Jay, Gbesemete, Diane, Dale, Adam, Pounce, Zoe Caroline, Webb, Carl N, Roche, Eleanor F, Guy, Jonathan, Berreen, Graham A, Belogiannis, Konstantinos, Hill, Alison, Ibrahim, Muktar, Ahmed, Muhammad, Cleary, David, Pandey, Anish, Humphries, Holly E., Allen, Lauren, De Graaf, Hans, Maiden, Martin C. J., Faust, Saul, Gorringe, Andrew and Read, Robert (2021) A recombinant commensal bacteria elicits heterologous antigen-specific immune responses during pharyngeal carriage. Science Translational Medicine, 13 (601), [eabe8573]. (doi:10.1126/scitranslmed.abe8573).

Record type: Article

Abstract

The human nasopharynx contains a stable microbial ecosystem of commensal and potentially pathogenic bacteria, which can elicit protective primary and secondary immune responses. Experimental intranasal infection of human adults with the commensal Neisseria lactamica produced safe, sustained pharyngeal colonization. This has potential utility as a vehicle for sustained release of antigen to the human mucosa, but commensals in general are thought to be immunologically tolerated. Here, we show that engineered N. lactamica, chromosomally transformed to express a heterologous vaccine antigen, safely induces systemic, antigen-specific immune responses during carriage in humans. When the N. lactamica expressing the meningococcal antigen Neisseria Adhesin A (NadA) was inoculated intranasally into human volunteers, all colonized participants carried the bacteria asymptomatically for at least 28 days, with most (86%) still carrying the bacteria at 90 days. Compared to an otherwise isogenic but phenotypically wild-type strain, colonization with NadA-expressing N. lactamica generated NadA-specific immunoglobulin G (IgG)- and IgA-secreting plasma cells within 14 days of colonization and NadA-specific IgG memory B cells within 28 days of colonization. NadA-specific IgG memory B cells were detected in peripheral blood of colonized participants for at least 90 days. Over the same period, there was seroconversion against NadA and generation of serum bactericidal antibody activity against a NadA-expressing meningococcus. The controlled infection was safe, and there was no transmission to adult bedroom sharers during the 90-day period. Genetically modified N. lactamica could therefore be used to generate beneficial immune responses to heterologous antigens during sustained pharyngeal carriage.

Text
abe8573 - Accepted Manuscript - Accepted Manuscript
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Accepted/In Press date: 25 May 2021
Published date: 7 July 2021
Additional Information: Publisher Copyright: © 2021 American Association for the Advancement of Science. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

Identifiers

Local EPrints ID: 450488
URI: http://eprints.soton.ac.uk/id/eprint/450488
ISSN: 1946-6234
PURE UUID: 3f72581c-e8bb-4413-a805-31d8f35fded3
ORCID for Jay Laver: ORCID iD orcid.org/0000-0003-3314-5989
ORCID for Adam Dale: ORCID iD orcid.org/0000-0001-8163-7481
ORCID for Alison Hill: ORCID iD orcid.org/0000-0001-5397-873X
ORCID for Muhammad Ahmed: ORCID iD orcid.org/0000-0003-3234-2788
ORCID for David Cleary: ORCID iD orcid.org/0000-0003-4533-0700
ORCID for Saul Faust: ORCID iD orcid.org/0000-0003-3410-7642
ORCID for Robert Read: ORCID iD orcid.org/0000-0002-4297-6728

Catalogue record

Date deposited: 30 Jul 2021 16:30
Last modified: 26 Nov 2021 03:22

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Contributors

Author: Jay Laver ORCID iD
Author: Diane Gbesemete
Author: Adam Dale ORCID iD
Author: Zoe Caroline Pounce
Author: Carl N Webb
Author: Eleanor F Roche
Author: Jonathan Guy
Author: Graham A Berreen
Author: Konstantinos Belogiannis
Author: Alison Hill ORCID iD
Author: Muktar Ibrahim
Author: Muhammad Ahmed ORCID iD
Author: David Cleary ORCID iD
Author: Anish Pandey
Author: Holly E. Humphries
Author: Lauren Allen
Author: Hans De Graaf
Author: Martin C. J. Maiden
Author: Saul Faust ORCID iD
Author: Andrew Gorringe
Author: Robert Read ORCID iD

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