Human B Cell Responses to Dominant and Subdominant Antigens Induced by a Meningococcal Outer Membrane Vesicle Vaccine in a Phase I Trial

Christine Rollier; Christina Dold; Leanne Marsay; Aline Linder; Christopher A. Green; Manish Sadarangani; Gunnstein Norheim; Jeremy P. Derrick; Ian M. Feavers; Martin C. J. Maiden; Andrew J. Pollard

doi:10.1128/msphere.00674-21

Human B Cell Responses to Dominant and Subdominant Antigens Induced by a Meningococcal Outer Membrane Vesicle Vaccine in a Phase I Trial

Christine Rollier^*, Christina Dold, Leanne Marsay, Aline Linder, Christopher A. Green, Manish Sadarangani, Gunnstein Norheim, Jeremy P. Derrick, Ian M. Feavers, Martin C. J. Maiden, Andrew J. Pollard

^*Corresponding author for this work

Microbiology and Infection

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Abstract

Neisseria meningitidis outer membrane vesicle (OMV) vaccines are safe and provide strain-specific protection against invasive meningococcal disease (IMD) primarily by inducing serum bactericidal antibodies against the outer membrane proteins (OMP). To design broader coverage vaccines, knowledge of the immunogenicity of all the antigens contained in OMVs is needed. In a Phase I clinical trial, an investigational meningococcal OMV vaccine, MenPF1, made from a meningococcus genetically modified to constitutively express the iron-regulated FetA induced bactericidal responses to both the PorA and the FetA antigen present in the OMP. Using peripheral blood mononuclear cells collected from this trial, we analyzed the kinetics of and relationships between IgG, IgA, and IgM B cell responses against recombinant PorA and FetA, including (i) antibody-secreting cells, (ii) memory B cells, and (iii) functional antibody responses (opsonophagocytic and bactericidal activities). Following MenPF1vaccination, PorA-specific IgG secreting cell responses were detected in up to 77% of participants and FetA-specific responses in up to 36%. Memory B cell responses to the vaccine were low or absent and mainly detected in participants who had evidence of preexisting immunity (P = 0.0069). Similarly, FetA-specific antibody titers and bactericidal activity increased in participants with preexisting immunity and is consistent with the idea that immune responses are elicited to minor antigens during asymptomatic Neisseria carriage, which can be boosted by OMV vaccines.

IMPORTANCE Neisseria meningitidis outer membrane vesicles (OMV) are a component of the capsular group B meningococcal vaccine 4CMenB (Bexsero) and have been shown to induce 30% efficacy against gonococcal infection. They are composed of multiple antigens and are considered an interesting delivery platform for vaccines against several bacterial diseases. However, the protective antibody response after two or three doses of OMV-based meningococcal vaccines appears short-lived. We explored the B cell response induced to a dominant and a subdominant antigen in a meningococcal OMV vaccine in a clinical trial and showed that immune responses are elicited to minor antigens. However, memory B cell responses to the OMV were low or absent and mainly detected in participants who had evidence of preexisting immunity against the antigens. Failure to induce a strong B cell response may be linked with the low persistence of protective responses.

Original language	English
Article number	e00674-21
Number of pages	12
Journal	mSphere
Volume	7
Issue number	1
Early online date	26 Jan 2022
DOIs	https://doi.org/10.1128/msphere.00674-21
Publication status	Published - Feb 2022

Bibliographical note

Acknowledgments:
The authors are grateful to Amber J. Thompson and Rebecca Sie for excellent technical assistance and acknowledge the contributions of Emily McFiggans for memory B cell ELISPOT, Megan Milarski for the opsonophagocytic activity, and Helen Smith for ELISA, the research fellows, nurses, and support staff who were involved in this study at the Oxford Vaccine Group. We thank all the participants. This work was supported by a translational award from the Welcome Trust, Innovation Schemes (Development of a PorA/FetA meningococcal vaccine to A. J. Pollard, Ref 082102/Z/07/A and 091634/Z/10/Z), and by the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom, Vaccine theme. AJP and CR are Jenner Investigators.

CR and CD led the laboratory work, research questions and wrote the manuscript. CAG was the lead physician. CD, LM, and AL performed the laboratory work. GN, MS, JD, IF, MM, and AJP instigated this research and designed the clinical trial. All authors had input into the manuscript and approved the manuscript for publication.

AJP is Chair of UK Dept. Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunization (JCVI) and is a member of the WHO’s SAGE. AJP is an NIHR Senior Investigator. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, NIHR, or WHO. MS is supported via salary awards from the BC Children’s Hospital Foundation, the Canadian Child Health Clinician Scientist Program, and the Michael Smith Foundation for Health Research. MS has been an investigator on projects funded by Pfizer, Merck, Seqirus, Sanofi-Pasteur, VBI Vaccines, and GlaxoSmithKline. JD’s laboratory has received funding from GlaxoSmithKline for vaccine-related research. All funds have been paid to his institute, and he has not received any personal payments. Through the Consulting Services of Oxford University Innovation, MM undertakes occasional consultancy work for Pfizer, GSK, and Novartis. IF was an employee at NIBSC, a center of the Medicines and Healthcare products Regulatory Agency. The clinical trial was approved by the MHRA before the merger of NIBSC with the agency. GN is currently an employee of Vaccibody. AJP, CSR, LM, and CD are inventors on a patent in the field of meningococcal vaccines. AJP waives all his rights on any patent. CAG and AL declare no conflict. The views expressed in this publication are those of the authors.

Keywords

Neisseria
bacteria
genetic modification
infection
meningitidis
meningitis
meningococcal
outer membrane
outer membrane proteins
outer membrane vesicles
vaccine
vesicles

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Rollier, C., Dold, C., Marsay, L., Linder, A., Green, C. A., Sadarangani, M., Norheim, G., Derrick, J. P., Feavers, I. M., Maiden, M. C. J., & Pollard, A. J. (2022). Human B Cell Responses to Dominant and Subdominant Antigens Induced by a Meningococcal Outer Membrane Vesicle Vaccine in a Phase I Trial. mSphere, 7(1), Article e00674-21. https://doi.org/10.1128/msphere.00674-21

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title = "Human B Cell Responses to Dominant and Subdominant Antigens Induced by a Meningococcal Outer Membrane Vesicle Vaccine in a Phase I Trial",

abstract = "Neisseria meningitidis outer membrane vesicle (OMV) vaccines are safe and provide strain-specific protection against invasive meningococcal disease (IMD) primarily by inducing serum bactericidal antibodies against the outer membrane proteins (OMP). To design broader coverage vaccines, knowledge of the immunogenicity of all the antigens contained in OMVs is needed. In a Phase I clinical trial, an investigational meningococcal OMV vaccine, MenPF1, made from a meningococcus genetically modified to constitutively express the iron-regulated FetA induced bactericidal responses to both the PorA and the FetA antigen present in the OMP. Using peripheral blood mononuclear cells collected from this trial, we analyzed the kinetics of and relationships between IgG, IgA, and IgM B cell responses against recombinant PorA and FetA, including (i) antibody-secreting cells, (ii) memory B cells, and (iii) functional antibody responses (opsonophagocytic and bactericidal activities). Following MenPF1vaccination, PorA-specific IgG secreting cell responses were detected in up to 77% of participants and FetA-specific responses in up to 36%. Memory B cell responses to the vaccine were low or absent and mainly detected in participants who had evidence of preexisting immunity (P = 0.0069). Similarly, FetA-specific antibody titers and bactericidal activity increased in participants with preexisting immunity and is consistent with the idea that immune responses are elicited to minor antigens during asymptomatic Neisseria carriage, which can be boosted by OMV vaccines.IMPORTANCE Neisseria meningitidis outer membrane vesicles (OMV) are a component of the capsular group B meningococcal vaccine 4CMenB (Bexsero) and have been shown to induce 30% efficacy against gonococcal infection. They are composed of multiple antigens and are considered an interesting delivery platform for vaccines against several bacterial diseases. However, the protective antibody response after two or three doses of OMV-based meningococcal vaccines appears short-lived. We explored the B cell response induced to a dominant and a subdominant antigen in a meningococcal OMV vaccine in a clinical trial and showed that immune responses are elicited to minor antigens. However, memory B cell responses to the OMV were low or absent and mainly detected in participants who had evidence of preexisting immunity against the antigens. Failure to induce a strong B cell response may be linked with the low persistence of protective responses.",

keywords = "Neisseria, bacteria, genetic modification, infection, meningitidis, meningitis, meningococcal, outer membrane, outer membrane proteins, outer membrane vesicles, vaccine, vesicles",

author = "Christine Rollier and Christina Dold and Leanne Marsay and Aline Linder and Green, {Christopher A.} and Manish Sadarangani and Gunnstein Norheim and Derrick, {Jeremy P.} and Feavers, {Ian M.} and Maiden, {Martin C. J.} and Pollard, {Andrew J.}",

note = "Acknowledgments: The authors are grateful to Amber J. Thompson and Rebecca Sie for excellent technical assistance and acknowledge the contributions of Emily McFiggans for memory B cell ELISPOT, Megan Milarski for the opsonophagocytic activity, and Helen Smith for ELISA, the research fellows, nurses, and support staff who were involved in this study at the Oxford Vaccine Group. We thank all the participants. This work was supported by a translational award from the Welcome Trust, Innovation Schemes (Development of a PorA/FetA meningococcal vaccine to A. J. Pollard, Ref 082102/Z/07/A and 091634/Z/10/Z), and by the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom, Vaccine theme. AJP and CR are Jenner Investigators. CR and CD led the laboratory work, research questions and wrote the manuscript. CAG was the lead physician. CD, LM, and AL performed the laboratory work. GN, MS, JD, IF, MM, and AJP instigated this research and designed the clinical trial. All authors had input into the manuscript and approved the manuscript for publication. AJP is Chair of UK Dept. Health and Social Care{\textquoteright}s (DHSC) Joint Committee on Vaccination & Immunization (JCVI) and is a member of the WHO{\textquoteright}s SAGE. AJP is an NIHR Senior Investigator. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, NIHR, or WHO. MS is supported via salary awards from the BC Children{\textquoteright}s Hospital Foundation, the Canadian Child Health Clinician Scientist Program, and the Michael Smith Foundation for Health Research. MS has been an investigator on projects funded by Pfizer, Merck, Seqirus, Sanofi-Pasteur, VBI Vaccines, and GlaxoSmithKline. JD{\textquoteright}s laboratory has received funding from GlaxoSmithKline for vaccine-related research. All funds have been paid to his institute, and he has not received any personal payments. Through the Consulting Services of Oxford University Innovation, MM undertakes occasional consultancy work for Pfizer, GSK, and Novartis. IF was an employee at NIBSC, a center of the Medicines and Healthcare products Regulatory Agency. The clinical trial was approved by the MHRA before the merger of NIBSC with the agency. GN is currently an employee of Vaccibody. AJP, CSR, LM, and CD are inventors on a patent in the field of meningococcal vaccines. AJP waives all his rights on any patent. CAG and AL declare no conflict. The views expressed in this publication are those of the authors.",

year = "2022",

month = feb,

doi = "10.1128/msphere.00674-21",

language = "English",

volume = "7",

journal = "mSphere",

issn = "2379-5042",

publisher = "American Society for Microbiology",

number = "1",

}

TY - JOUR

T1 - Human B Cell Responses to Dominant and Subdominant Antigens Induced by a Meningococcal Outer Membrane Vesicle Vaccine in a Phase I Trial

AU - Rollier, Christine

AU - Dold, Christina

AU - Marsay, Leanne

AU - Linder, Aline

AU - Green, Christopher A.

AU - Sadarangani, Manish

AU - Norheim, Gunnstein

AU - Derrick, Jeremy P.

AU - Feavers, Ian M.

AU - Maiden, Martin C. J.

AU - Pollard, Andrew J.

N1 - Acknowledgments: The authors are grateful to Amber J. Thompson and Rebecca Sie for excellent technical assistance and acknowledge the contributions of Emily McFiggans for memory B cell ELISPOT, Megan Milarski for the opsonophagocytic activity, and Helen Smith for ELISA, the research fellows, nurses, and support staff who were involved in this study at the Oxford Vaccine Group. We thank all the participants. This work was supported by a translational award from the Welcome Trust, Innovation Schemes (Development of a PorA/FetA meningococcal vaccine to A. J. Pollard, Ref 082102/Z/07/A and 091634/Z/10/Z), and by the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom, Vaccine theme. AJP and CR are Jenner Investigators. CR and CD led the laboratory work, research questions and wrote the manuscript. CAG was the lead physician. CD, LM, and AL performed the laboratory work. GN, MS, JD, IF, MM, and AJP instigated this research and designed the clinical trial. All authors had input into the manuscript and approved the manuscript for publication. AJP is Chair of UK Dept. Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunization (JCVI) and is a member of the WHO’s SAGE. AJP is an NIHR Senior Investigator. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, NIHR, or WHO. MS is supported via salary awards from the BC Children’s Hospital Foundation, the Canadian Child Health Clinician Scientist Program, and the Michael Smith Foundation for Health Research. MS has been an investigator on projects funded by Pfizer, Merck, Seqirus, Sanofi-Pasteur, VBI Vaccines, and GlaxoSmithKline. JD’s laboratory has received funding from GlaxoSmithKline for vaccine-related research. All funds have been paid to his institute, and he has not received any personal payments. Through the Consulting Services of Oxford University Innovation, MM undertakes occasional consultancy work for Pfizer, GSK, and Novartis. IF was an employee at NIBSC, a center of the Medicines and Healthcare products Regulatory Agency. The clinical trial was approved by the MHRA before the merger of NIBSC with the agency. GN is currently an employee of Vaccibody. AJP, CSR, LM, and CD are inventors on a patent in the field of meningococcal vaccines. AJP waives all his rights on any patent. CAG and AL declare no conflict. The views expressed in this publication are those of the authors.

PY - 2022/2

Y1 - 2022/2

N2 - Neisseria meningitidis outer membrane vesicle (OMV) vaccines are safe and provide strain-specific protection against invasive meningococcal disease (IMD) primarily by inducing serum bactericidal antibodies against the outer membrane proteins (OMP). To design broader coverage vaccines, knowledge of the immunogenicity of all the antigens contained in OMVs is needed. In a Phase I clinical trial, an investigational meningococcal OMV vaccine, MenPF1, made from a meningococcus genetically modified to constitutively express the iron-regulated FetA induced bactericidal responses to both the PorA and the FetA antigen present in the OMP. Using peripheral blood mononuclear cells collected from this trial, we analyzed the kinetics of and relationships between IgG, IgA, and IgM B cell responses against recombinant PorA and FetA, including (i) antibody-secreting cells, (ii) memory B cells, and (iii) functional antibody responses (opsonophagocytic and bactericidal activities). Following MenPF1vaccination, PorA-specific IgG secreting cell responses were detected in up to 77% of participants and FetA-specific responses in up to 36%. Memory B cell responses to the vaccine were low or absent and mainly detected in participants who had evidence of preexisting immunity (P = 0.0069). Similarly, FetA-specific antibody titers and bactericidal activity increased in participants with preexisting immunity and is consistent with the idea that immune responses are elicited to minor antigens during asymptomatic Neisseria carriage, which can be boosted by OMV vaccines.IMPORTANCE Neisseria meningitidis outer membrane vesicles (OMV) are a component of the capsular group B meningococcal vaccine 4CMenB (Bexsero) and have been shown to induce 30% efficacy against gonococcal infection. They are composed of multiple antigens and are considered an interesting delivery platform for vaccines against several bacterial diseases. However, the protective antibody response after two or three doses of OMV-based meningococcal vaccines appears short-lived. We explored the B cell response induced to a dominant and a subdominant antigen in a meningococcal OMV vaccine in a clinical trial and showed that immune responses are elicited to minor antigens. However, memory B cell responses to the OMV were low or absent and mainly detected in participants who had evidence of preexisting immunity against the antigens. Failure to induce a strong B cell response may be linked with the low persistence of protective responses.

AB - Neisseria meningitidis outer membrane vesicle (OMV) vaccines are safe and provide strain-specific protection against invasive meningococcal disease (IMD) primarily by inducing serum bactericidal antibodies against the outer membrane proteins (OMP). To design broader coverage vaccines, knowledge of the immunogenicity of all the antigens contained in OMVs is needed. In a Phase I clinical trial, an investigational meningococcal OMV vaccine, MenPF1, made from a meningococcus genetically modified to constitutively express the iron-regulated FetA induced bactericidal responses to both the PorA and the FetA antigen present in the OMP. Using peripheral blood mononuclear cells collected from this trial, we analyzed the kinetics of and relationships between IgG, IgA, and IgM B cell responses against recombinant PorA and FetA, including (i) antibody-secreting cells, (ii) memory B cells, and (iii) functional antibody responses (opsonophagocytic and bactericidal activities). Following MenPF1vaccination, PorA-specific IgG secreting cell responses were detected in up to 77% of participants and FetA-specific responses in up to 36%. Memory B cell responses to the vaccine were low or absent and mainly detected in participants who had evidence of preexisting immunity (P = 0.0069). Similarly, FetA-specific antibody titers and bactericidal activity increased in participants with preexisting immunity and is consistent with the idea that immune responses are elicited to minor antigens during asymptomatic Neisseria carriage, which can be boosted by OMV vaccines.IMPORTANCE Neisseria meningitidis outer membrane vesicles (OMV) are a component of the capsular group B meningococcal vaccine 4CMenB (Bexsero) and have been shown to induce 30% efficacy against gonococcal infection. They are composed of multiple antigens and are considered an interesting delivery platform for vaccines against several bacterial diseases. However, the protective antibody response after two or three doses of OMV-based meningococcal vaccines appears short-lived. We explored the B cell response induced to a dominant and a subdominant antigen in a meningococcal OMV vaccine in a clinical trial and showed that immune responses are elicited to minor antigens. However, memory B cell responses to the OMV were low or absent and mainly detected in participants who had evidence of preexisting immunity against the antigens. Failure to induce a strong B cell response may be linked with the low persistence of protective responses.

KW - Neisseria

KW - bacteria

KW - genetic modification

KW - infection

KW - meningitidis

KW - meningitis

KW - meningococcal

KW - outer membrane

KW - outer membrane proteins

KW - outer membrane vesicles

KW - vaccine

KW - vesicles

U2 - 10.1128/msphere.00674-21

DO - 10.1128/msphere.00674-21

M3 - Article

SN - 2379-5042

VL - 7

JO - mSphere

JF - mSphere

IS - 1

M1 - e00674-21

ER -

Human B Cell Responses to Dominant and Subdominant Antigens Induced by a Meningococcal Outer Membrane Vesicle Vaccine in a Phase I Trial

Abstract

Bibliographical note

Keywords

UN SDGs

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